DRAGANOIU ELENA SIMONA

UNIVERSITY OF CINCINNATI

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I,______________________________________________,hereby submit this as part of the requirements for thedegree of:

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in:

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It is entitled:

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Approved by:________________________________________________________________________________________________________________________

EVALUATION OF KOLLIDON® SR FOR pH-INDEPENDENT EXTENDED RELEASE MATRIX

SYSTEMS

A dissertation submitted to the

Division of Research and Advanced Studies of the University of Cincinnati

in partial fulfillment of the

requirements for the degree of

DOCTOR OF PHILOSOPHY

Industrial Pharmacy Program Division of Pharmaceutical Sciences

College of Pharmacy 2003

by

Elena Simona Draganoiu, B.Sc. Pharm. University of Medicine and Pharmacy ‘Gr. T. Popa’ Iasi, Romania

Committee Chair Adel Sakr, Ph.D.

Abstract

The characteristics of a new Polyvinylacetate/Povidone based excipient,

Kollidon® SR were evaluated for application in extended release matrix tablets.

The effects of the following formulation and process variables on tablet properties

and drug release were tested: Kollidon® SR concentration in the tablet, addition

of external binder for wet granulation, presence of an enteric polymer in the

matrix, method of manufacturing and compression force. The similarities in

release profiles were evaluated by applying the model independent f2 similarity

factor. A pilot bioequivalence study was performed in human volunteers to

confirm in vivo the extended release characteristics of the propranolol tablets

manufactured with Kollidon® SR.

It was found that Kollidon® SR is suitable for pH-independent extended release

matrix tablets. A minimum concentration of 30% polymer was necessary to

achieve a coherent matrix, able to extend the release of the incorporated drugs.

Increasing the Kollidon® SR concentration in the tablet led to a slower drug

release. Drug release followed square root of time dependent kinetics, thus

indicating a diffusion-controlled release mechanism. The drug release was

influenced by the aqueous solubility of the drug. The drug release rate was faster

for wet granulation than direct compression, thus making direct compression the

method of choice for manufacturing Kollidon® SR extended release systems. It

was found that Kollidon® SR was the main release controlling agent in the

presence of an external binder or enteric polymer in the matrix. A significant

reduction in the dissolution rates associated with an increase in tablet hardness

was observed during the stability test under accelerated conditions.

The developed propranolol matrix tablets formulation was compared in a pilot

bioequivalence study to the reference listed product (Inderal® LA capsules). It

was found that the two products were not bioequivalent according to the FDA

bioequivalence criteria. The tablets had higher bioavailability than the capsules

as shown by higher Cmax and AUC 0-24h. For the developed tablet formulation

the higher initial plasma concentrations correlated with the faster initial release

observed in vitro.

It was concluded that Kollidon® SR is a potentially useful excipient for the

production of pH-independent extended release matrix tablets.

Acknowledgments

My gratitude to the committee members for their valuable comments and advice

and for guiding my efforts to complete this research.

My deepest gratitude to my advisor, Dr. Adel Sakr, for his constant professional,

financial and emotional support. Special thanks for giving me the chance to be

one of the researchers he has fostered in the Industrial Pharmacy Program

(Family), for mentoring my professional steps, for all the meetings I have

participated, for the interactions with the professional world I have had through

him. Most of all, for his continuous encouragement, confidence in me and

friendship.

To Dr. Hussein AlKhalidi for guiding me explore the ‘statistics world’ through

courses and valuable advice in preparation of the comprehensive exam and

dissertation.

To Dr. Bernadette D’Souza, my special thanks for her major contribution in the

Bioequivalence study and for her kind and warm support.

To Dr. Ronald Millard for sharing his knowledge and for being an academic

model.

To Dr. Apryll Stalcup for providing guidance through the Chemical Separation

course and interactions during the analytical work.

Special thanks to Dr. Karl Kolter and BASF Germany for the donation of

Kollidon® SR and all the support they provided.

To my colleagues Ehab, Hatim, Himanshu, Juan, Julia, Murad, Oliver, Rajesh,

Shadi who volunteered for the Bioequivalence study. I highly appreciate their

generous support.

To Dr. Lubna Izzatullah and Mr. Nosa Ekhator (Veterans Affair Medical Center)

for their kind help during the Bioequivalence study.

To Dr. Pankaj Desai for allowing me to use some equipment in his lab, and for

valuable discussions. Thanks to Murad Melhem for useful suggestions in the

bioanalytical work and help with the WinNonlin software.

Special thanks to Dr. James Ebel for the great experience of two summer

internships in the Procter & Gamble Health Care Research Center, and for his

assistance with equipment and advice during my Ph.D. research.

To Dr. Ronald Shoup (BAS Analytics) for the loan of analytical equipment without

knowing me; his generosity impressed me.

To the College of Pharmacy for providing me with the University Graduate

Scholarship.

To my professors at the University of Cincinnati and at the University of Medicine

and Pharmacy, Iasi, Romania, for doing such a good job in educating

generations.

To my colleagues in Industrial Pharmacy Program, for being such good company

and for all I have learnt from them: Julia, Laxmi, Susan, Ehab, Hamid, Hatim,

Himanshu, John, Juan, and Mohamed. Special thanks to some of them for their

true friendship.

To my Romanian friends from here and home, for being such good friends as

one could have and for all the memories we share.

To my parents and my family for their love. They are the reason for what I am

now. This work is dedicated to them.

Contents

1. Introduction............................................................................................ 9

1.1. Extended release matrix systems............................................................ 9

1.2. Mechanisms of drug release from matrix systems................................. 11

1.2.1. Dissolution controlled systems .............................................................. 11

1.2.2. Diffusion controlled systems .................................................................. 12

1.2.3. Bioerodible and combination diffusion and dissolution systems ............ 19

1.3. Impact of the formulation and process variables on the drug release

from extended release matrix systems .................................................. 24

1.3.1. Formulation variables ............................................................................ 24

1.3.2. Process variables .................................................................................. 37

1.4. Rationale for studying Kollidon® SR as extended release matrix

excipient ................................................................................................ 40

1.5. Kollidon® SR - background ................................................................... 41

1.6. Propranolol extended release formulations ........................................... 45

2. Objective, hypothesis and specific aims........................................... 52

2.1. Objective................................................................................................ 52

2.2. Hypothesis............................................................................................. 52

2.3. Specific aims ......................................................................................... 52

3. Experimental ........................................................................................ 54

3.1. Materials and supplies ........................................................................... 54

3.2. Equipment ............................................................................................. 57

3.3. Tablet composition................................................................................. 59

3.4. Tablet manufacture................................................................................ 61

3.5. Tablet testing ......................................................................................... 65

3.6. Experimental design and methodology.................................................. 68

3.6.1. Propranolol 10 mg tablets...................................................................... 68

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3.6.1.1. Manufacture of propranolol 10mg tablets by direct compression........... 68

3.6.1.2. Manufacture of propranolol 10mg tablets by wet granulation ................ 69

3.6.1.3. Drug release profiles from propranolol 10mg matrix tablets

manufactured with Eudragit® RSPO ..................................................... 71

3.6.1.4. Testing of propranolol 10mg tablets....................................................... 71

3.6.2. Buspirone 10 mg tablets ........................................................................ 71

3.6.3. Propranolol 80 mg tablets...................................................................... 73

3.6.3.1. Manufacture of propranolol 80mg tablets with 40-60% Kollidon® SR ... 73

3.6.3.2. Testing of propranolol 80mg tablets with 40-60% Kollidon® SR............ 74

3.6.3.3. Manufacture of propranolol 80mg tablets with 70% polymer

(Kollidon® SR alone or in combination with Eudragit® L100-55)........... 74

3.6.3.4. Testing of propranolol 80mg tablets with 70% polymer

(Kollidon® SR alone or in combination with Eudragit® L100-55)........... 75

3.6.3.5. Testing of Inderal® LA capsules (reference listed drug product) ........... 76

3.6.3.6. Selection of propranolol 80mg formulation for pilot bioequivalence

study ...................................................................................................... 76

3.6.3.7. Testing of propranolol 80mg tablets for the pilot bioequivalence

study ...................................................................................................... 76

3.6.4. Pilot bioequivalence study ..................................................................... 77

3.6.4.1. Design and methodology ....................................................................... 77

3.6.4.2. Analysis of propranolol in plasma .......................................................... 81

3.6.4.3. Pharmacokinetic and statistical analysis................................................ 83

4. Results and Discussions .................................................................... 84

4.1. Propranolol 10 mg tablets...................................................................... 84

4.1.1. Effect of Kollidon® SR on drug release from propranolol 10mg

tablets manufactured by direct compression ......................................... 84


tablets manufactured by wet granulation ............................................... 88

4.1.3. Effect of external binder on drug release from propranolol 10mg

tablets manufactured by wet granulation ............................................... 93

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4.1.4. Effect of dissolution medium on drug release from propranolol

10mg matrix tablets ............................................................................... 95

4.1.5. Drug release profiles from matrix tablets with Eudragit® RSPO.......... 103

4.2. Buspirone 10mg tablets ....................................................................... 105

4.2.1. Effect of Kollidon® SR and compression force on physical

properties and drug release of buspirone 10mg tablets....................... 105

4.2.2. Effect of dissolution medium on drug release from buspirone 10mg

tablets .................................................................................................. 113

4.3. Propranolol 80mg tablets..................................................................... 118


properties and drug release from propranolol 80mg tablets ................ 118


80mg tablets ........................................................................................ 125

4.3.3. Effect of Kollidon® SR – Eudragit® L100-55 combination on drug

release from propranolol 80mg tablets ................................................ 127

4.3.4. Comparison of the propranolol 80 mg tablet formulations with the

reference listed capsule product .......................................................... 133

4.3.5. Effect of storage conditions on propranolol 80 mg tablets physical

properties and drug release................................................................. 141

4.4. Evaluation of bioequivalence of propranolol 80 mg matrix tablets to

Inderal® LA capsules........................................................................... 145

4.4.1. Analysis of propranolol in plasma ........................................................ 145

4.4.2. Subjects monitoring during the pilot bioequivalence study .................. 145

4.4.3. Pharmacokinetic and statistical analysis.............................................. 146

5. Conclusions ....................................................................................... 160

6. References ......................................................................................... 162

7. Appendix 1 ......................................................................................... 171

8. Appendix 2 ......................................................................................... 197

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List of Figures

Figure 1. Schematic representation of a matrix release system ......................... 14

Figure 2. The fronts in a swellable HPMC matrix................................................ 22

Figure 3. Process flow chart for tablets manufactured by direct compression.... 62

Figure 4. Process flow chart for tablets manufactured by wet granulation.......... 63

Figure 5. Effect of Kollidon® SR on drug release in water from propranolol 10mg tablets manufactured by direct compression .............................. 86

Figure 6. Effect of Kollidon® SR on diffusion controlled drug release in water from propranolol 10mg tablets manufactured by direct compression ......................................................................................... 87

Figure 7. Effect of Kollidon® SR on drug release in water from propranolol 10mg tablets manufactured by wet granulation .................................... 90

Figure 8. Effect of Kollidon® SR on diffusion controlled drug release in water from propranolol 10mg tablets manufactured by wet granulation............................................................................................ 91

Figure 9. Effect of external binder on drug release in water from propranolol 10mg tablets with 30% and 50% Kollidon® SR .................................... 94

Figure 10. Effect of dissolution medium on drug release from propranolol 10mg tablets with 30% Kollidon® SR manufactured by direct compression ......................................................................................... 96

Figure 11. Effect of dissolution medium on drug release from propranolol 10mg tablets with 30% Kollidon® SR manufactured by wet granulation............................................................................................ 97

Figure 12. Effect of dissolution medium on drug release from propranolol 10mg tablets with 40% Kollidon® SR manufactured by direct compression ......................................................................................... 98

Figure 13. Effect of dissolution medium on drug release from propranolol 10mg tablets with 40% Kollidon® SR manufactured by wet granulation............................................................................................ 99

Figure 14. Effect of dissolution medium on drug release from propranolol 10mg tablets with 50% Kollidon® SR manufactured by direct compression ....................................................................................... 100

Figure 15. Effect of dissolution medium on drug release from propranolol 10mg tablets with 50% Kollidon® SR manufactured by wet granulation.......................................................................................... 101

Figure 16. Effect of Eudragit® RSPO on drug release in water from propranolol 10mg tablets .................................................................... 104

Figure 17. Effect of Kollidon® SR concentration and compression force on the hardness of buspirone 10mg tablets............................................. 106

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Figure 18. Effect of compression force on drug release from buspirone 10mg tablets with 10 - 30% Kollidon® SR .......................................... 108

Figure 19. Effect of compression force on drug release from buspirone 10mg tablets with 40 - 60% Kollidon® SR .......................................... 109

Figure 20. Effect of Kollidon® SR on drug release from buspirone 10mg tablets ................................................................................................. 111

Figure 21. Effect of Kollidon® SR on diffusion controlled drug release from buspirone 10mg tablets ...................................................................... 112

Figure 22. Effect of dissolution medium on drug release from buspirone 10mg tablets with 30% Kollidon® SR ................................................. 114




Figure 26. Effect of Kollidon® SR and compression force on the hardness of propranolol 80mg tablets ................................................................ 121

Figure 27. Effect of Kollidon® SR and compression force on drug release in water from propranolol 80mg tablets .................................................. 122

Figure 28. Effect of Kollidon® SR on diffusion controlled drug release from propranolol 80mg tablets .................................................................... 124

Figure 29. Effect of dissolution medium on drug release from propranolol 80mg tablets ....................................................................................... 126

Figure 30. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in water from propranolol 80mg tablets.......................... 129

Figure 31. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in 0.1N HCl from propranolol 80mg tablets.................... 130

Figure 32. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in pH 6.8 buffer from propranolol 80mg tablets.............. 131

Figure 33. Propranolol release in water over 48 hours from tablets manufactured with 70% Kollidon® SR................................................ 132

Figure 34. Comparison of drug release from propranolol 80 mg tablets with 60 and 70% Kollidon® SR and Inderal® LA ....................................... 134

Figure 35. Compression and ejection forces recorded during manufacturing of propranolol 80 mg tablets with 65% Kollidon® SR ......................... 136

Figure 36. Comparison of the drug release profiles from propranolol 80mg tablets with 65% Kollidon® SR and Inderal® LA ................................ 138

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Figure 37. Reproducibility of propranolol 80 mg tablets formulation with 65% Kollidon® SR ...................................................................................... 140

Figure 38. Effect of storage on drug release from propranolol 80 mg tablets – ICH long term stability conditions .................................................... 143

Figure 39. Effect of storage on drug release from propranolol 80 mg tablets – ICH accelerated stability conditions................................................. 144

Figure 40. Plasma levels of propranolol following administration – subject #1 ........................................................................................... 147








Figure 48. Plasma levels of propranolol following administration (mean ± SEM)................................................................................................... 155

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List of Tables

Table 1. Application of matrix for drug delivery systems..................................... 24

Table 2. Pharmacokinetic properties of propranolol ........................................... 47

Table 3. Propranolol 10mg matrix tablets formulation ........................................ 69

Table 4. Propranolol 10mg matrix tablets formulations with external binders..... 70

Table 5. Propranolol 10mg tablets formulated with Eudragit® RSPO................. 70

Table 6. Formulation of buspirone 10mg tablets................................................. 72

Table 7. Formulation of propranolol 80mg tablets with 40-60% Kollidon® SR ... 74

Table 8. Formulation of propranolol 80mg tablets with 70% polymer ................. 75

Table 9. Stability study design ............................................................................ 77

Table 10. Analytical method for analysis of propranolol in plasma ..................... 82

Table 11. Effect of Kollidon® SR on physical properties of propranolol 10mg tablets manufactured by direct compression ........................................ 84

Table 12. Regression parameters of the diffusion drug release curves for propranolol 10mg tablets manufactured by direct compression............ 85

Table 13. Effect of Kollidon® SR on the physical properties of Propranolol 10mg tablets manufactured by wet granulation .................................... 89

Table 14. Regression parameters of the diffusion drug release curves for propranolol 10mg tablets manufactured by wet granulation ................. 92

Table 15. f2 values - effect of dissolution medium on drug release from propranolol 10mg tablets .................................................................... 102

Table 16. Physical properties of buspirone 10mg tablets ................................. 107

Table 17. f2 values - effect of compression force on drug release from buspirone 10mg tablets ...................................................................... 110

Table 18. Regression parameters of the diffusion drug release curves for buspirone 10mg tablets ...................................................................... 113

Table 19. f2 values – effect of dissolution medium on drug release from buspirone 10mg tablets ...................................................................... 118

Table 20. Effect of compression force and Kollidon® SR concentration on physical properties of propranolol 80mg tablets ................................. 119

Table 21. f2 values – effect of compression force on drug release from propranolol 80mg tablets .................................................................... 123

Table 22. Regression parameters of the diffusion drug release curves in water from propranolol 80mg tablets .................................................. 125

Table 23. Composition of the propranolol 80mg tablets formulation used in the pilot bioequivalence study............................................................. 135

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Table 24. Characteristics of propranolol 80mg tablets used in the pilot bioequivalence study .......................................................................... 137

Table 25. Drug release from the propranolol 80 mg tablets with 65% Kollidon® SR (used for the pilot bioequivalence study) ...................... 139

Table 26. Effect of storage on the hardness of propranolol 80 mg tablets........ 142

Table 27. Pharmacokinetic parameters after administration of propranolol 80mg tablets and Inderal® LA 80mg .................................................. 157

Table 28. Results of the bioequivalence testing using WinNonlin software ...... 158

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1. Introduction

1.1. Extended release matrix systems

Extended release dosage forms are formulated in such manner as to make the

contained drug available over an extended period of time following

administration. Expressions such as controlled-release, prolonged-action, repeat-

action and sustained-release have also been used to describe such dosage

forms. A typical controlled release system is designed to provide constant or

nearly constant drug levels in plasma with reduced fluctuations via slow release

over an extended period of time. In practical terms, an oral controlled release

should allow a reduction in dosing frequency as compared to when the same

drug is presented as a conventional dosage form (Qiu and Zhang, 2000).

A matrix device consists of drug dispersed homogenously throughout a polymer

matrix.

Two major types of materials are used in the preparation of matrix devices

(Venkatraman et al., 2000):

♦ Hydrophobic carriers:

• Digestible base (fatty compounds) – glycerides - glyceryltristearate, fatty

alcohols, fatty acids, waxes - carnauba wax (Chiao and Robinson, 1995);

• Nondigestible base (insoluble plastics) - methylacrylate -

methylmethacrylate, polyvinyl chloride, polyethylene, ethyl cellulose;

- 9 -

♦ Hydrophilic polymers – methyl cellulose, sodium carboxy methyl cellulose,

hydroxypropyl methyl cellulose, sodium alginate, xanthan gum, polyethylene

oxide, carbopols.

Matrix systems offer several advantages:

• easy to manufacture

• versatile, effective, low cost

• can be made to release high molecular weight compounds

• since the drug is dispersed in the matrix system, accidental leakage of the

total drug component is less likely to occur, although occasionally, cracking

of the matrix material can cause unwanted release.

Disadvantages of the matrix systems:

• the remaining matrix must be removed after the drug has been released

• the drug release rates vary with the square root of time. Release rate

continuously diminishes due to an increase in diffusional resistance and/or a

decrease in effective area at the diffusion front (Qiu and Zhang, 2000).

However, a substantial sustained effect can be produced through the use of

very slow release rates, which in many applications are indistinguishable

from zero-order (Jantzen and Robinson, 1996).

- 10 -

1.2. Mechanisms of drug release from matrix systems

The release of drug from controlled devices is via dissolution or diffusion or a

combination of the two mechanisms.

1.2.1. Dissolution controlled systems

A drug with slow dissolution rate will demonstrate sustaining properties, since the

release of the drug will be limited by the rate of dissolution. In principle, it would

seem possible to prepare extended release products by decreasing the

dissolution rate of drugs that are highly water-soluble. This can be done by:

• preparing an appropriate salt or derivative

• coating the drug with a slowly dissolving material – encapsulation dissolution

control

• incorporating the drug into a tablet with a slowly dissolving carrier – matrix

dissolution control (a major disadvantage is that the drug release rate

continuously decreases with time) (Jantzen and Robinson, 1996).

The dissolution process can be considered diffusion-layer-controlled, where the

rate of diffusion from the solid surface to the bulk solution through an unstirred

liquid film is the rate-determining step. The dissolution process at steady-state is

described by the Noyes-Whitney equation:

)()( CCAhDCCAk

dtdC

ssD −⋅⋅=−⋅⋅= (1)

- 11 -

where:

dC/dt dissolution rate

kd the dissolution rate constant (equivalent to the diffusion coefficient divided

by the thickness of the diffusion layer D/h)

D diffusion coefficient

Cs saturation solubility of the solid

C concentration of solute in the bulk solution

Equation (1) predicts that the rate of release can be constant only if the following

parameters are held constant:

• surface area

• diffusion coefficient

• diffusion layer thickness

• concentration difference.

These parameters, however, are not easily maintained constant, especially

surface area, and this is the case for combination diffusion and dissolution

systems (Jantzen and Robinson, 1996).

1.2.2. Diffusion controlled systems

Diffusion systems are characterized by the release rate of a drug being

dependent on its diffusion through an inert membrane barrier (Higuchi, 1963).

Usually, this barrier is an insoluble polymer. In general, two types or subclasses

of diffusional systems are recognized: reservoir devices and matrix devices

(Jantzen and Robinson, 1996). It is very common for the diffusion-controlled

- 12 -

devices to exhibit a non-zero order release rate due to an increase in diffusional

resistance and a decrease in effective diffusion area as the release proceeds.

(Venkatraman et al, 2000).

Diffusion in matrix devices

In this model, drug in the outside layer exposed to the bathing solution is

dissolved first and then diffuses out of the matrix. This process continues with the

interface between the bathing solution and the solid drug moving toward the

interior. It follows obviously that for this system to be diffusion controlled, the rate

of dissolution of drug particles within the matrix must be much faster than the

diffusion rate of dissolved drug leaving the matrix (Jantzen and Robinson, 1995).

Derivation of the mathematical model to describe this system involves the

following assumptions:

a) a pseudo-steady state is maintained during drug release;

b) the diameter of the drug particles is less than the average distance of drug

diffusion through the matrix;

c) the diffusion coefficient of drug in the matrix remains constant (no change

occurs in the characteristics of the polymer matrix (Jantzen and Robinson,

1995);

d) the bathing solution provides sink conditions at all times;

e) no interaction occurs between the drug and the matrix;

- 13 -

f) the total amount of drug present per unit volume in the matrix is substantially

greater than the saturation solubility of the drug per unit volume in the matrix

(excess solute is present) (Chiao and Robinson, 1995);

g) only the diffusion process occurs (Qiu and Zhang, 2000).

dh

Depleted Matrix Zone

Cs Solid Drug

“Ghost” Matrix

Drug

x=0 x=h

Figure 1. Schematic representation of a matrix release system

Figure 1

For a homogenous monolithic matrix system (Jantzen and Robinson, 1996),

corresponding to the schematic in – page 14, the release behavior can

be described by the following equation:

20sCdhC

dhdM

−⋅= (2)

where

dM change in the amount of drug released per unit area

dh change in the thickness of the zone of matrix that has been depleted of

drug

C0 total amount of drug in a unit volume of matrix

Cs saturated concentration of the drug within the matrix.

- 14 -

From diffusion theory:

dthCDdM sm ⋅⋅

= (3)

where Dm is the diffusion coefficient in the matrix.

By combining equations (2) and (3):

2/10 ])2([ tCCDCM sms ⋅−⋅⋅= (4)

When the amount of drug is in excess of the saturation concentration, (C0 >>Cs)

2/10 ]2[ tCDCM ms ⋅⋅⋅= (5)

That indicates that the amount of drug released is a function of square root of

time.

Drug release from a porous monolithic matrix involves the simultaneous

penetration of surrounding liquid, dissolution of drug and leaching out of the drug

through tortuous interstitial channels and pores. The volume and length of the

openings must be accounted for in the drug release from a porous or granular

matrix:

2/10 ])2([ tCpC

TpCDM aas ⋅⋅−⋅⋅⋅= (6)

where:

p porosity of the matrix

t tortuosity

Ca solubility of the drug in the release medium

Ds diffusion coefficient in the release medium.

Similarly for pseudo-steady state (C0 >>Cs):

- 15 -

2/10 ]2[ tTpCCDM as ⋅⋅⋅= (7)

The porosity is the fraction of matrix that exists as pores or channels into which

the surrounding liquid can penetrate. It is the total porosity of the matrix after the

drug has been extracted; it consists of initial porosity due to the presence of air or

void space in the matrix before the leaching process begins as well as the

porosity created by extracting the drug and the water-soluble excipients.

ex

exa

CCpp

ρρ++= 0 (8)

where ρ is the drug density and ρex and Cex are the density and the concentration

of water-soluble excipient respectively. In a case where no water-soluble

excipient is used in the formulation and initial porosity is much smaller than

porosity created by drug extraction, total porosity becomes:

ρ0Cp = (9)

Hence the release equations can be written as:

2/10 ])2([ tCpC

TpCDM aas ⋅⋅−⋅⋅⋅= (10)

2/1

0 ]2[ tTpCCDM as ⋅⋅⋅= (11)

For purpose of data treatment, equation (6) can be reduced to:

2/1tkM ⋅= (12) where k is a constant, so that the amount of drug released versus the square root

of time will be linear, if the release of drug from matrix is diffusion-controlled. If

- 16 -

this is the case, one may control the release of drug from a homogeneous matrix

system by varying the following parameters:

• initial concentration of drug in the matrix

• porosity

• tortuosity

• polymer system forming the matrix

• solubility of the drug (Jantzen and Robinson, 1996, Chiao and Robinson,

1995).

In a hydrophilic matrix, there are two competing mechanisms involved in the

drug release: Fickian diffusional release and relaxation release. Diffusion is not

the only pathway by which a drug is released from the matrix; the erosion of the

matrix following polymer relaxation contributes to the overall release. The relative

contribution of each component to the total release is primarily dependent on the

properties of a given drug.

For example, the release of a sparingly soluble drug from hydrophilic matrices

involves the simultaneous absorption of water and desorption of drug via a

swelling-controlled diffusion mechanism. As water penetrates into a glassy

polymeric matrix, the polymer swells and its glass transition temperature is

lowered. At the same time, the dissolved drug diffuses through this swollen

rubbery region into the external releasing medium.

This type of diffusion and swelling does not generally follow a Fickian diffusion

mechanism (Qiu and Zhang, 2000). Peppas (1985) introduced a semi-empirical

equation to describe drug release behavior from hydrophilic matrix systems:

- 17 -

ntkQ ⋅= (13) where Q is the fraction of drug released in time t, k is the rate constant

incorporating characteristics of the macromolecular network system and the drug

and n is the diffusional exponent. It has been shown that the value of n is

indicative of the drug release mechanism.

For n=0.5, drug release follows a Fickian diffusion mechanism that is driven by a

chemical potential gradient.

For n=1 drug release occurs via the relaxational transport that is associated with

stresses and phase transition in hydrated polymers.

For 0.5<n<1 non-Fickian diffusion is often observed as a result of the

contributions from diffusion and polymer erosion (Qiu and Zhang, 2000).

In order to describe relaxational transport, Peppas and Sahlin (1989) introduced

a second term in equation (13):

nn tktkQ 221 ⋅+⋅= (14)

where k1 and k2 are constants reflecting the relative contributions of Fickian and

relaxation mechanisms.

In the case the surface area is fixed, the value of n should be 0.5 and equation

(14) becomes:

tktkQ ⋅+⋅= 25.0

1 (15) where the first and second term represent drug release due to diffusion and

polymer erosion, respectively (Qiu and Zhang, 2000).

- 18 -

1.2.3. Bioerodible and combination diffusion and dissolution

systems

Strictly speaking, therapeutic systems will never be dependent on dissolution or

diffusion only. In practice, the dominant mechanism for release will overshadow

other processes enough to allow classification as either dissolution rate-limited or

diffusion-controlled release (Jantzen and Robinson, 1996).

As a further complication these systems can combine diffusion and dissolution of

both the drug and the matrix material. Drugs not only can diffuse out of the

dosage form, as with some previously described matrix systems, but also the

matrix itself undergoes a dissolution process. The complexity of the system

arises from the fact that as the polymer dissolves the diffusional path length for

the drug may change. This usually results in a moving boundary diffusion

system. Zero-order release is possible only if surface erosion occurs and surface

area does not change with time.

Swelling-controlled matrices exhibit a combination of both diffusion and

dissolution mechanisms. Here the drug is dispersed in the polymer, but instead

of an insoluble or non-erodible polymer, swelling of the polymer occurs. This

allows for the entrance of water, which causes dissolution of the drug and

diffusion out of the swollen matrix. In these systems the release rate is highly

dependent on the polymer-swelling rate and drug solubility. This system usually

- 19 -

minimizes burst effects, as rapid polymer swelling occurs before drug release

(Jantzen and Robinson, 1996).

With regards to swellable matrix systems, different models have been proposed

to describe the diffusion, swelling and dissolution processes involved in the drug

release mechanism (Siepman and Kranz, 2000, Siepman et al., 1999a, Siepman

et al., 1999b, Siepman et al., 1999c, Peppas and Colombo, 1997, Colombo et al.,

1999, Colombo et al., 1996, Colombo et al., 1995, Colombo et al., 1992, Wan et

al., 1995). However the key element of the drug release mechanism is the

forming of a gel layer around the matrix, capable of preventing matrix

disintegration and further rapid water penetration.

When a matrix that contains a swellable glassy polymer comes in contact with a

solvent or swelling agent, there is an abrupt change from the glassy to the

rubbery state, which is associated with the swelling process. The individual

polymer chains, originally in the unperturbed state absorb water so that their end-

to-end distance and radius of gyration expand to a new solvated state. This is

due to the lowering of the transition temperature of the polymer (Tg), which is

controlled by the characteristic concentration of the swelling agent and depends

on both temperature and thermodynamic interactions of the polymer– water

system. A sharp distinction between the glassy and rubbery regions is observed

and the matrix increases in volume because of swelling. On a molecular basis,

this phenomenon can activate a convective drug transport, thus increasing the

- 20 -

reproducibility of the drug release. The result is an anomalous non-Fickian

transport of the drug, owing to the polymer-chain relaxation behind the swelling

position. This, in turn, creates osmotic stresses and convective transport effects.

The gel strength is important in the matrix performance and is controlled by the

concentration, viscosity and chemical structure of the rubbery polymer. This

restricts the suitability of the hydrophilic polymers for preparation of swellable

matrices. Polymers such as carboxymethyl cellulose, hydroxypropyl cellulose or

tragacanth gum, do not form the gel layer quickly. Consequently, they are not

recommended as excipients to be used alone in swellable matrices (Colombo et

al., 2000, Colombo et al., 1996).

The swelling behavior of heterogeneous swellable matrices is described by front

positions, where ‘front’ indicates the position in the matrix where the physical

conditions sharply change. Three fronts are present (Colombo et al., 2000), as

shown in Figure 2 – page 22:

• the ‘swelling front’ clearly separates the rubbery region (with enough water to

lower the Tg below the experimental temperature) from the glassy region

(where the polymer exhibits a Tg that is above the experimental

temperature).

• the ‘erosion front’, separates the matrix from the solvent. The gel-layer

thickness as a function of time is determined by the relative position of the

swelling and erosion moving fronts.

- 21 -

• the ‘diffusion front’ located between the swelling and erosion fronts, and

constituting the boundary that separates solid from dissolved drug, has been

identified.

During drug release, the diffusion front position in the gel phase is dependent on

drug solubility and loading. The diffusion front movement is also related to drug

dissolution rate in the gel.

Erosion front

Diffusion front

Swelling front

Figure 2. The fronts in a swellable HPMC matrix

Drug release is controlled by the interaction between water, polymer and drug.

The delivery kinetics depends on the drug gradient in the gel layer. Therefore,

drug concentration and thickness of the gel layer governs the drug flux. Drug

concentration in the gel depends on drug loading and solubility. Gel-layer

thickness depends on the relative contributions of solvent penetration, chain

disentanglement and mass (polymer and drug) transfer in the solvent. Initially

solvent penetration is more rapid than chain disentanglement, and a rapid build-

- 22 -

up of gel-layer thickness occurs. However, when the solvent penetrates slowly,

owing to an increase in the diffusional distance, little change in gel thickness is

observed since penetration and disentanglement rates are similar. Thus gel-layer

thickness dynamics in swellable matrix tablets exhibit three distinct patterns. The

thickness increases when solvent penetration is the fastest mechanism, and it

remains constant when the disentanglement and water penetration occur at a

similar rate. Finally, the gel-layer thickness decreases when the entire polymer

has undergone the glassy–rubbery transition. In conclusion, the central element

of the release mechanism is a gel-layer forming around the matrix in response to

water penetration. Phenomena that govern gel-layer formation, and consequently

drug-release rate, are water penetration, polymer swelling, drug dissolution and

diffusion, and matrix erosion. Drug release is controlled by drug diffusion through

the gel layer, which can dissolve and/or erode.

- 23 -

1.3. Impact of the formulation and process variables on the

drug release from extended release matrix systems

1.3.1. Formulation variables

The physicochemical characteristics of the drug, in particular its aqueous

solubility, should be considered in the formulation of a matrix system. According

to Qiu and Zhang (2000), the following recommendations apply to matrix systems

(Table 1 – page 24):

Table 1. Application of matrix for drug delivery systems

Matrix system Drug delivery mechanism

Drugs not recommended

Hydrophilic

Swellable / erodible Diffusion and erosion Very soluble

Erodible Erosion Freely soluble

Hydrophobic

Monolithic Diffusion Practically insoluble

Multiparticulate Diffusion Freely soluble

Erodible/Degradable Erosion/enzymatic degradation

-

Qiu and Zhang, (2000)

- 24 -

Other drug properties affecting system design include drug stability in the system

and at the site of absorption, pH-dependent solubility, particle size and specific

surface area.

Drug particle size

Effect of drug particle size on release is important in the case of moderately

soluble drugs. Velasco et al. (1999) showed that for a given effective surface

area, diclofenac particle size influenced the release rate from hydroxypropyl

methyl cellulose (HPMC) tablets. The smallest particle size of drug dissolved

more easily when dissolution medium penetrated through the matrix resulting in a

greater role for diffusion. The larger particle size dissolved less readily and

therefore was more prone to erosion at the matrix surface. A similar dependence

was shown for a less soluble drug, indomethacin (Ford et al., 1995).

Hogan (1989) showed that in the case of water-soluble aminophylline or

propranolol HPMC-based tablets an increase in drug particle size did not

significantly alter the release rate of the drug. A noticeable effect was seen only

at a low drug: HPMC ratio and at a large drug particle size (above 250µm) any

was seen; in this case, rapid dissolution of the water soluble drug would leave a

matrix with low tortuosity and high porosity.

Drug: polymer ratio

For diclofenac tablets formulated with HPMC, Velasco et al. (1999) showed that

an increase in drug: polymer ratio reduced the release rate. This was because an

increase in polymer concentration caused an increase in the viscosity of the gel

- 25 -

(by making it more resistant to drug diffusion and erosion) as well as the

formation of a gel layer with a longer diffusional path.

Similar findings were reported by Rekhi et al. (1999). Diffusional release of water-

soluble drug metoprolol (primarily controlled by the gel thickness) decreased with

increasing HPMC incorporation.

By varying the polymer level (Methocel® K4M 10-40%), Nellore et al. (1998)

achieved different metoprolol in vitro release profiles.

Sung et al. (1996) demonstrated that changes in HPMC: lactose ratio can be

used to produce a wide range of drug (adinazolam mesylate) release rates.

For Ethocel® 100 and Eudragit® RSPO matrices, Boza et al. (1999) showed that

an increase in the polymer content resulted in a decrease in the drug release

rates due to a decrease in the total porosity of the matrices (initial porosity plus

porosity due to the dissolution of the drug).

Polymer type

Various grades of commercially available HPMC differ in the relative proportion

of the hydroxypropyl and methoxyl substitutions; increasing the amount of

hydrophilic hydroxypropyl groups lead to a faster hydration: Methocel®K >

Methocel®E > Methocel®F. Generally rapid hydrating Methocel®K grade is

preferred, especially for highly soluble drugs where a rapid rate of hydration is

- 26 -

necessary. It is important to note that an inadequate polymer hydration rate may

lead to dose dumping, due to quick penetration of gastric fluids into the tablet

core (Dow Pharmaceutical Excipients, 1996).

In each grade, for a fixed polymer level, the viscosity of the selected polymer

affects the diffusional and mechanical characteristics of the matrix. By comparing

different Methocel®K viscosity grades, Nellore et al. (1998) found that the higher

viscosity gel layers provided a more tortuous and resistant barrier to diffusion,

which resulted in slower release of the drug (metoprolol HCl).

Sung et al. (1996) compared different viscosity grades of HPMC (Methocel®

K100LV, K15, K100). The fastest release of adinazolam mesilate was achieved

for the K100LV formulation. The K4M formulation exhibited a slightly greater drug

release than K15M and K100M. Due to the lack of a significant difference in the

release profiles between K15M and K100M, the authors suggested a limiting

HPMC viscosity of 15000cP, above which if viscosity increased, the release rate

would no longer decrease. Similarly, formulations containing higher HPMC

viscosity grades had slower HPMC release, but no limiting HPMC viscosity was

observed for polymer release.

In a study by Campos-Aldrete and Villafuerte-Robles (1997), for low HPMC

concentration (10%) formulations, the lag time was found to be dependent on the

viscosity grade. The increasing burst effect produced by higher viscosity grades

- 27 -

was attributed to slower swelling with increasing polymer viscosity, allowing

greater time for the dissolution of the drug (metronidazole) before the gel barrier

was established. For HPMC concentration of 20% or more, the porosity was a

less important factor in the drug release and the effect of viscosity grade was

minimized.

In the case of ethyl cellulose, the findings are completely different. The lower

viscosity grades of ethylcellulose are more compressible than the higher viscosity

grades, resulting in harder tablets and slower release (Katikaneni et al., 1995a,

Shileout and Zessin, 1996, Upadrashta et al., 1993).

By comparing Eudragit® RSPO to Ethocel® 100, the release rate of lobenzarit

sodium was slower for the Eudragit® based matrix (Boza et al., 1999). The

explanation was based on the chemical structure of the polymers. Ethocel® 100

has hydrophilic hydroxyl and ethoxyl groups, which make the matrix water

sensitive. Consequently, it was more difficult to control the release of the

hydrophilic drug. Eudragit® RSPO is only slightly permeable to water due to its

low content of quaternary ammonium groups; therefore it was more suitable for

controlling the release of the hydrophilic drug.

Polymer particle size

Velasco et al. (1999) found that the diclofenac sodium release rate from HPMC

tablets decreased as the polymer particle increased. Also, as the HPMC particle

size increased, the lag period decreased – the drug release occurred during the

- 28 -

initial dissolution stage, prior to the formation of the gel layer (coarse fraction of

HPMC hydrated slower).

Campos-Aldrete and Villafuerte-Robles (1997) found that increasing particle size

of HPMC allowed the free dissolution of metronidazole at higher proportion

before the gel was established. Decreasing particle size caused a smaller burst

effect and induced lag times. The explanation was based on a faster swelling of

the smaller particles that allowed a rapid establishment of the gel barrier.

Heng et al. (2001) observed significant effect of HPMC particle size on aspirin

release for polymer concentrations up to 20%.

A mean HPMC (Methocel® K15M Premium) particle size of 113µm was identified

as a critical threshold for the release of aspirin. The drug release rate increased

markedly when polymer particle size was increased above 113µm. The release

rate was much less sensitive to changes in particle size below 113µm. The

aspirin release mechanism followed first order kinetics, when mean HPMC

particle size was below 113µm. The release mechanism deviated from first order

kinetics, when the mean particle size was above 113µm. Polymer fractions with

similar mean particle size but differing size distribution were also found to

influence drug release rates but not the release mechanism.

In the case of ethyl cellulose, using a constant compression force and increasing

the particle size, caused a decrease in tablet hardness and an increase in

- 29 -

dissolution rate, due to a reduction in the interparticular forces. Erosion occurred

for tablets manufactured with ethylcellulose particle size above 120µm

(Kakiketeni et al., 1995a). Characterization of tablets prepared using different

particle sizes revealed that the porosity increased with increase in particle size

(Katiketeni et al., 1995b) and the increase in porosity resulted in a faster drug

release.

Fillers

Nellore et al. (1998) studied the effect of filler (57% of the tablet weight) on a

metoprolol formulation at 20% Methocel® K4M level. They concluded that filler

solubility had a limited effect on release rate. The release profiles showed a

decrease of about 5-7% after 6h, as the filler was changed from lactose to

lactose – microcrystalline cellulose then to dicalcium phosphate dihydrate -

microcrystalline cellulose. Addition of soluble fillers enhanced the dissolution of

soluble drugs by decreasing the tortuosity of the diffusion path of the drug, while

insoluble fillers like dicalcium phosphate dihydrate got entrapped in the matrix.

Also, they assumed that presence of a swelling insoluble filler like

microcrystalline cellulose changed the release profile to a small extent due to a

change in swelling at the tablet surface.

Changing the filler from 100% dicalcium phosphate dihydrate to 100% lactose

resulted in an increase in metoprolol release from Methocel® K100LV tablets at

4, 6 and 12h (Rekhi et al., 1999). This was explained by dissolution of lactose

and the consequent reduction in the tortuosity and or gel strength of the polymer.

- 30 -

Similar dissolution profiles were obtained for filler concentration up to 48%. No

dose dumping due to stress cracks (Dow Pharmaceutical Excipients, 1996)

during gelling were observed in the case of insoluble fillers.

Ion-exchange resins

Ion exchange resins can be used as release modifiers in matrix formulation

containing oppositely charged drugs, based on in situ drug-resin complex

formation.

Sriwongjanya and Bodmeier (1998) studied the release of cationic drug

propranolol from HPMC matrix tablets containing drug without resin (Amberlite®

IRP69), drug-resin complex and drug - resin physical mixture. The fastest release

was observed for resin free tablets (in all the dissolution media). In the case of

drug-resin complex tablets, the drug was not released in water, since there were

no counterions in the medium to replace drug ions from the ion exchange resin

within the gelled matrix. The drug was released in 0.1N HCl and pH 7.4

phosphate buffer, indicating that the drug release was initiated by an ion-

exchange process (the counterions present in the dissolution medium diffused

through the gel layer to replace the drug, which was then released by diffusion).

A similar extended release pattern was obtained by using the physical mixture of

drug and resin, which denoted the in situ complex formation within the gelled

region. The in situ method is more advantageous with regard to simplifying the

manufacturing process compared to the use of the preformed complexes.

- 31 -

The rate of drug binding to the resin increased with decreasing the resin particle

size, thus explaining the slower release and the absence of the burst phase with

smaller sized resin particles.

As the amount of resin increased, the drug release initially decreased, leveling up

at a resin level enough to bind the drug in situ.

Using a weak cation exchange resin (Amberlite® IRP88), in situ complex

formation and release retardation was observed only in pH 7.4 buffer, but not in

0.1N HCl, because of the non-ionization of the carboxyl groups.

Comparing different matrix materials, a rapid formation of a strong gel layer was

important for the in situ complex formation; drug release decreased in the

following order glyceryl palmitostearate > polyethylene oxide 400K > HPMC

K15M.

For different HPMC sorts, the rate of hydration influenced the release; tablets

based on methyl cellulose or HPMC E4M (higher degree of methoxyl group

substitution) disintegrated shortly after exposure to the medium because of the

slow rate of hydration and the disintegrating effect of the resin (resins have large

swelling ability).

Similar results were observed for sodium diclofenac and the anion exchange

resin cholestiramine.

The phenomenon was not observed in case of the non-ionic drug guaifenesin.

Surfactants

Feely and Davis (1988) characterized the ability of charged ionic surfactants to

retard the release of oppositely charged drugs from HPMC tablets

- 32 -

(chlorphemiramine maleate and sodium alkylsulphates, sodium salicylate and

cetylpiridinium bromide). The mechanism involved was an in situ drug-surfactant

ionic interaction, resulting in a complex with low aqueous solubility, that the

release would be more dependent on the matrix erosion than diffusion. The

retarding effect was dependent upon the surfactant concentration in the matrix

and independent on the surfactant hydrocarbon chain length. The pH of the

environment played an important role, by altering the ionization of both the drug

and the surfactant. The ionic strength of the dissolution medium affected the

action of the resin.

Polymeric excipients

Feely and Davis (1988) studied the effect of polymeric additives (non-ionic

polyethylene glycol 6000 or ethyl cellulose, cationic diethylaminoethyl dextran,

anionic sodium carboxymethyl cellulose Na-CMC) on drug release

(chlorpheniramine maleate, sodium salicylate and potassium

fenoxymethylpenicillin) from HPMC matrix (85%). Non-ionic polymers (15% of

tablet weight) did not significantly alter the release rates.

Na-CMC (50% replacement of HPMC) reduced the chlorpheniramine maleate

release in pH 7 buffer (near zero order release), but not in an acidic medium.

This was explained by a complexation of the drug with the cationic polymer;

which was not possible below pH 3, when Na-CMC was in its un-ionized

insoluble form. As a result of the complexation, the gel erosion became the

prominent release mechanism instead of diffusion.

- 33 -

No interaction occurred between sodium salicylate and Na-CMC (both anionic).

In the presence of diethylaminoethyl dextran, sodium salicylate release was

slower at pH 7, but not altered at pH 1 (when the drug was present in its

unionized form).

Overall, the effect of ionic polymers incorporated into HPMC matrices on the

release of oppositely charged drugs was small compared to the ion-exchange

resins.

Goldberg and Sakr (2003) used the drug-polymer ionic complexation approach in

designing oral dosage formulation for controlled release of buspirone. As anionic

exchange polymers sodium carboxymethyl cellulose and methacrylic acid /

ethylacrylate copolymer were recommended based on the complexation affinity

and dispersability in the aqueous environment of the gastrointestinal tract

(average molecular weight of less than 500,000). The weight ratio of buspirone to

anionic exchange polymer varied between 4:1 and 1:6, preferably between 2:1

and 1:4.

In addition to facilitating the controlled release of buspirone, the formulations

increased the bioavailability and reduced the inter-individual variability.

Therefore, the buspirone-ion exchange polymer HPMC tablets permitted

enhanced targeting of therapeutic amounts and effects of the drug.

Takka et al. (2001) studied the effect of the addition of anionic polymers

(Eudragit® S, Eudragit® L 100-55, and Na-CMC) on the release of weakly basic

- 34 -

propranolol hydrochloride from HPMC matrices. The interaction between

propranolol hydrochloride and anionic polymers influenced the drug release. The

HPMC: anionic polymer ratio also affected the drug release. The matrix

containing HPMC: Eudragit® L 100-55 (1:1) produced pH-independent extended-

release tablets.

Bonferoni et al. (1998) used an optimization procedure to determine the HPMC:

λ-carrageenan ratio (34:30) required for a pH-independent release of

chlorpheniramine maleate. λ-Carrageenan was added to overcome the increase

in diffusion path length and decrease in the release rate associated with HPMC

systems. λ-carrageenan was subjected to erosion, which was higher at acidic

pH.

Streubel et al. (2000) failed to achieve a pH independent release of weakly basic

drugs (verapamil HCl) from matrix tablets (ethylcellulose or HPMC) by adding an

enteric polymer HPMCAS (HPMC acetate succinate). The creation of the water-

filled pores at high pH by dissolution of the enteric polymer was expected to

accelerate the drug release and thus compensating the effect of the reduced

solubility of the drug.

However the addition of the HPMCAS to the ethylcellulose matrix reduced the

verapamil release both in 0.1N HCl and pH 6.8 buffer compared to the ethyl

cellulose solely based matrix. The authors explained this by a reduction of the

matrix pore size in case of addition of HPMCAS due to the effect of particle size

- 35 -

difference: 33µm for ethyl cellulose, 6µm for HPMCAS on compaction behavior

(larger pores in the ethyl cellulose matrix). As the release mechanism was

predominantly diffusion, a reduction of the pore size significantly reduced the

release rate.

In contrast to ethyl cellulose, no effect was found when adding HPMCAS to the

HPMC systems either in 0.1N HCl, or in pH 6.08 buffer. It was considered that

this happened because the drug was predominantly released by diffusion

through the swollen polymer network and not through the water filled pores.

Thus, reduction of the initial porosity of the system was of minor significance in

drug release rate. On the other hand, due to its high molecular weight, HPMCAS

dissolution in phosphate buffer was hindered by the presence of the HPMC

network; pre-existing cavities within the HPMC network could not accommodate

diffusing HPMCAS molecules.

Addition of organic acids

In order to overcome the pH dependent release of a weakly basic drug

(verapamil HCl) from matrix tablets, Streubel et al. (2000) added organic acids,

which were expected to create a constant acidic microenvironment inside the

tablets. Substances selected (fumaric, sorbic and adipic acid) had high acidic

strength (low pKa value) and relatively low solubility in 0.1N HCl. These acids

dissolved rather slowly and remained in the tablets during the entire period of

drug release. Independent of the pH of the dissolution medium, the pH inside the

tablet was acidic and thus the solubility of the weakly basic drug was high. In

addition, at high pH, the organic acids acted as pore formers. The release rates

- 36 -

obtained for both ethyl cellulose and HPMC matrices were pH-independent.

Among the three acids, fumaric acid showed the best results, due to the lowest

pKa value.

1.3.2. Process variables

Compression force

It has been reported (Velasco et al., 1999) for HPMC tablets, that although the

compression force had a significant effect on tablet hardness, its effect on drug

release from HPMC tablets was minimal. It could be assumed that the variation

in compression force should be closely related to a change in the porosity of the

tablets. However, as the porosity of the hydrated matrix is independent of the

initial porosity, the compression force seems to have little influence on drug

release. The influence of compression force could only be observed in the lag

time (Velasco et al., 1999). Tablets made at the lowest crushing strength

(compression force 3kN) with Methocel®K4M showed an initial burst effect due

to an initial partial disintegration. Once the polymer was swollen, the dissolution

profiles became similar to those tablets compressed to a higher crushing

strength.

Rekhi et al. (1999) reported similar findings, i.e. changes in compression force or

crushing strength appeared to have minimal effect on drug release from HPMC

matrix tablets once a critical hardness was achieved. Increased dissolution was

- 37 -

only observed when the tablets were too soft and it was attributed to the lack of

powder compaction or consolidation (3kP).

Tablet shape

Rekhi et al. (1999) showed that the size and shape of the tablet for the matrix

system undergoing diffusion and erosion might impact the drug dissolution rate.

Modification of the surface area for metoprolol tartrate tablets formulated with

Methocel® K100LV from the standard concave shape (0.568sq. in.) to caplet

shape (0.747 sq. in.) showed an approximately 20-30% increase in dissolution at

each time point. Furthermore they recommended that for maximum maintenance

of controlled release characteristics, tablet matrices should be as near spherical

as possible to produce minimum release rate.

The release rate of the drug (theophylline) from erodible hydrogel matrix tablets

(HPMC E50) having different geometrical shapes (compressed under the same

compression force) was found (Karasulu et al., 2000) to be the highest on

triangular tablets and successively in order of decreasing amounts on half-

spherical and cylindrical tablets. This was attributed to heterogenous erosion of

the matrices.

Siepman et al. (1999b) showed that varying the aspect ratio (radius/height) of the

HPMC tablets is the very easy and effective tool to modify the release rate of the

matrix system. Release rate for tablets with the same volume was higher for flat

shape (ratio = 20) than regular cylinders (ratio 2) and almost rod-shaped

- 38 -

cylinders (ratio 0.2). The reason for this phenomenon was the difference in the

surface area of the tablets. They proposed a new mathematical model that can

be applied to calculate the optimal aspect ratio and size of a cylindrical tablet to

achieve a desired profile. The model takes into account Fickian diffusion of water

in and drug out of the tablets and swelling; it does not take into account

dissolution and it cannot be applied for water insoluble drugs, which are released

by dissolution process. Model applicability in predicting the dissolution rates was

confirmed for water-soluble drugs (propranolol HCl and chlorpheniramine

maleate) (Siepmann et al., 2000).

Tablet size

For tablets having the same aspect ratio and drug concentration, Siepman et al.

(1999b) found that the tablet size had a very strong influence on the release rate;

within 24 hours, 99.8% was released from the small tablets, 83.1% from the

medium size and 50.9% from the large tablets. The explanation was based on

the higher surface area referred to the volume for the small tablets than for the

large ones. In addition, the diffusion pathways were much longer in large tablets

than in small ones. Thus the relative amount of drug released versus time was

much higher for small tablets. The variation of the size of the tablet was an

effective tool to achieve a desired release.

- 39 -

1.4. Rationale for studying Kollidon® SR as extended release

matrix excipient

Due to technological accessibility, manufacturing capability and cost of the

monolithic drug delivery systems, the pharmaceutical industry has placed a lot of

emphasis on the design and development of these formulations. However, there

are some distinct disadvantages of some of these matrix formers, which

complicate the development and production of matrix tablets. Some of these

include lack of flowability of polymers hampering the direct compression process,

poor compressibility of the polymer forms resulting in tablets of low hardness, the

influence of pH values or ionic strengths on the release profiles, burst effect and

diminishing release rate with time.

These disadvantages limit the application of currently used polymers and require

development and evaluation of new polymers for extended release matrices.

Therefore evaluation of newly available matrix materials for their ability to

promote pH-independent extended release of drugs is much warranted.

Kollidon® SR was introduced to the pharmaceutical market recently, and thus its

evaluation constitutes a novel research topic for the pharmaceutical industry.

- 40 -

1.5. Kollidon® SR - background

Polyvinylacetate/Povidone based polymer (Kollidon® SR) is a relatively new

extended release matrix excipient. It consists of 80% Polyvinylacetate and 19%

Povidone in a physical mixture, stabilized with 0.8% sodium lauryl sulfate and

0.2% colloidal silica.

Polyvinylacetate – homopolymer of vinyl acetate. It is obtained by emulsion

polymerization.

Description: water white, clear solid resin, soluble in benzene and acetone,

insoluble in water or emulsion readily diluted with water (Ash and Ash, 1995).

Polyvinylacetate is a very plastic material that produces a coherent matrix even

under low compression forces.

Regulatory status: diluent in color additive mixtures for food use exempt from

certification, food additive (21CFR73).

Povidone (polyvinylpyrrolidone) – white amorphous hygroscopic powder, soluble

in water (Ash and Ash, 1995). It has good binding properties both under dry or

wet conditions. Due to its hygroscopicity, Povidone promotes water uptake and

facilitates diffusion and drug release (Shivanand and Sprockel, 1998).

Manufacture

US Patent 6,066,334 describes the manufacture procedure for the

polyvinylacetate / povidone redispersible polymer powders and their application

- 41 -

as binder at 0.5-20% (of the tablet weight), when the active ingredients are

released within a time of 0.1 to 1.0 hour.

The redispersible polymer powders are manufactured by emulsion

polymerization of vinyl acetate followed by addition of polyvinylpyrrolidone (as

10-50w/w solution) and spray- or freeze-drying. The polymerization takes place

at temperature of 60-80°C and results in shear-stable fine-particle dispersion.

The k value of the polymers should be in the range from 10-350, preferably 50-

90. To prevent particles caking together, silica (spraying aid) is added to the

dispersion before spraying. Spray drying is done in spray towers (with disks or

nozzles) or in fluid beds.

Physicochemical properties

Description: white or slightly yellowish, free flowing powder;

Particle size distribution: average particle size of about 100µm;

Molecular weight of polyvinyl acetate 450 000;

Bulk density: within the range of 0.30-0.45g/ml; 0.37g/ml (Ruchatz et al., 1999);

Tap density: 0.44g/ml (Ruchatz et al., 1999);

Flowability: good flow properties with a response angle below 30° (BASF, 1999),

21° (Ruchatz et al., 1999).

Solubility: Polyvinylacetate is insoluble in water. Povidone gradually dissolves in

water; in tablets it acts as a pore-former.

pH: 3.5-5.5.

- 42 -

The manufacturer generally claims for Kollidon® SR good compressibility and

drug release independent of the dissolution medium (pH and salt/ion content)

and rotation speed. Compressibility results were published for propranolol 160mg

tablets (drug: polymer 1:1). The compression force did not affect the drug release

profile. The pH-independent release was also tested for caffeine (BASF, 1999).

Pathan and Jalil (2000) evaluated Kollidon® SR as matrix excipient for

Theophylline tablets. Tablets containing 20-70% theophylline showed Higuchian

release kinetics; the release rates increased exponentially with the drug loading.

The increase in compressional force from 20kN to 60kN caused a slight linear

decrease in the release rate. Annealing of the tablets for 24 hours at

temperatures of 45 and 55°C showed a slight decrease in the release rate

compared to the room temperature.

Shao et al. (2001) reported the effect of accelerated stability conditions on

diphenhydramine HCl tablets prepared with Kollidon® SR. A decrease in

dissolution rate along with an increase in tablet hardness was noticed for tablets

with high level of Kollidon® SR (>37%) prepared without diluents or with 15%

diluent (lactose, Emcompress®). At 25% Emcompress®, no changes occurred.

Such changes were not observed for tablets stored at 25°C/ 60%RH or cured at

60°C for at least one hour.

- 43 -

Rock et al. (2000) evaluated different additives: diacetyl-tartaric acid diglyceride

ester, pectin, stearic acid and methyl hydroxyethyl cellulose for optimization of

caffeine release from Kollidon® SR -based matrix tablets. Stearic acid retarded

the initial drug release in acidic medium due to its hydrophobic character, but

failed to accelerate it in neutral medium. Diacetyl-tartaric acid diglyceride ester,

methyl hydroxyethyl cellulose and pectin reduced the initial drug release and

intensified the dissolution after the pH change.

Flick et al. (2000) showed the applicability of Kollidon® SR in hot melt technology

using acetaminophen.

Regulatory status: Kollidon® SR is not a pharmacopoeial or NF listed additive.

In 2001, BASF filled a DMF (drug master file) for this product with the FDA (FDA

Drug Master Files).

- 44 -

1.6. Propranolol extended release formulations

Propranolol HCl is a racemic mixture of dextrorotary and levorotary forms of 1-

(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride

It is a white, odorless crystalline powder, readily soluble in water and ethanol

(1:20), soluble in 0.1 N HCl: 220 mg/ml and in pH 7.4 phosphate buffer: 254

mg/ml (Siepmann and Kranz, 2000); pKa=9.5 (Avdeef et al., 2000).

Propranolol is a highly lipophilic (log Kp=3.65), non-selective beta-adrenergic

antagonist, which interacts with beta1 and beta2 receptors with equal affinity,

lacks intrinsic sympathomimetic activity, possesses membrane stabilizing activity

and does not block alpha-adrenergic receptors (Goodman and Gilman, 2001).

Propranolol is almost completely absorbed from the gastrointestinal tract, by

passive non-stereoselective diffusion (Goodman and Gilman, 2001, Mehvar and

Brocks, 2001). The absorption takes place from both the proximal and distal

intestine, making it a good candidate for extended release dosage forms (Buch

and Barr, 1998). Propranolol is subjected to an extensive and highly variable

hepatic first pass metabolism, with a reported systemic bioavailability between 15

and 23% (Cid et al., 1986, Walle et al., 1986). Propranolol binds (90% of the

dose) to both albumin and α1-acid glycoprotein in plasma stereoselectively,

resulting in higher free fraction of S(-) propranolol in plasma. The age and gender

- 45 -

of the patients do not appear to have a substantial effect on the protein binding of

propranolol enantiomers (Mehvar and Brocks, 2001). Peak effect occurs after 1-2

hours and can vary up to seven fold after oral administration due to individual

variations in hepatic metabolic activity (Shand et al., 1970). Propranolol is

metabolized by three main pathways of ring hydroxylation (40% of the dose),

side chain oxidation (35-40%) and glucuronidation (remaining 20-25% of the

dose), the metabolism being overall stereoselective for the less active R(+)

enantiomer, resulting in a higher plasma concentrations of the S(-) enantiomer

(Buch and Barr, 1998, Mehvar and Brocks, 2001). The metabolism is affected by

genetic polymorphism for both CYP1A and CYP2D6 isozymes in the liver

(Mehvar and Brocks, 2001). The biologic half-life is approximately four hours

(Shand et al., 1970, Mehvar and Brocks, 2001).

No conclusive results were reported for the effect of the input rate on the ratio of

the enantiomers in plasma (Mehvar and Brocks, 2001).

The cardiac beta-blocking activity of propranolol resides in S(-) enantiomer,

which is x100 times more potent than the R(+) enantiomer (Mehvar and Brocks,

2001).

Due to relatively short plasma half-life, propranolol conventional tablets are

administrated at 6 to 8 hours intervals. Such frequent drug administration may

reduce patient compliance and thus therapeutic efficacy (Serlin et al., 1983).

Several extended release systems have been developed in order to enable daily

administration of the drug and a 24-hour maintained beta-adrenoceptor blockade.

- 46 -

There are some reported problems associated with propranolol extended release

(ER) formulations. Besides the variable propranolol bioavailability (due to first

pass degradation, influence of food, ethnic factor, other medication), ER

formulations generally exhibit a lower systemic bioavailability than the

conventional tablets ( – page 47). This is due to a slower/poor absorption

and higher first pass effect or sometimes due to an underestimation of the area

under the plasma concentration-time curve due to limited blood sampling or low

analytical sensitivity (Nace and Wood, 1987). However similar bioavailability for

ER and conventional products has been reported (Bottini et al., 1983, Dunn et

al., 1985).

Table 2

Table 2. Pharmacokinetic properties of propranolol

Unlike conventional formulations of propranolol, absorption of propranolol from

the ER formulations has been shown to be unaffected by food or stimulation of

gastrointestinal motility by coadministration of metoclopramide (Nace and Wood,

1987).

Formulation Extent of absorption (%of dose)

Bioavailability (% of dose)

Interpatient variation in

plasma level

β-Blocking plasma

concentration

Protein binding

(%)

Immediate release

>90% 30 20 fold 50-100ng/ml 93

Extended release

>90% 20 10-20 fold 20-100ng/ml 93

(Frishman and Jorde, 2000)

- 47 -

The apparent elimination half-life of ER propranolol formulations ranges from 8 to

11 hours, or approximately 2 to 3 times that of conventional propranolol. This

marked increase in the apparent half-life is due to continued absorption of the

drug from the gastrointestinal tract (Nace and Wood, 1987).

Currently it is well accepted that once daily ER propranolol is as effective as

conventional immediate release propranolol given in divided doses. Once daily

dosing of ER products produced relatively constant plasma concentrations and

prolonged beta-adrenoblockade and offers the potential for improved patient

compliance in the treatment of hypertension and prevention of angina. Different

studies showed that single daily doses of ER propranolol produce significant

blockade of cardiac beta-adrenoceptors throughout a 24-hour dose interval, as

assessed by inhibition of exercise-induced tachycardia (Perucca et al., 1984,

McAinsh et al., 1978, Serlin et al., 1983, Garg et al., 1987, Lalonde et al., 1987).

The time course and degree of beta-adrenoblockade were similar to those

obtained with conventional propranolol given in divided doses and correlated well

with plasma concentrations. Shanks (1984) suggested that 15-20% inhibition of

exercise-induced tachycardia is necessary for therapeutic cardiac beta-

adrenoceptor blockade. Propranolol ER produced a significant fall in blood

pressure throughout the 24-hour dosing interval, although no correlation could be

established between propranolol concentrations and hypotensive effects. This

lack of correlation could be attributed to the multiple mechanisms involved in the

antihypertensive action, including effects on the renin-angiotensin system and

central nervous system (Nace and Wood, 1987).

- 48 -

Takahashi et al. (1990) showed no significant differences in the hepatic

metabolism of propranolol administered as extended release capsules 60mg

once-a-day or immediate release tablets 20mg x 3/day. The observed differences

in the area under the curve for propranolol, 4-hydroxy-propranolol glucuronide

and naphthoxylactic acid after the administration of the two products were

explained by the lower absorption and consequently lower bioavailability of the

ER capsules compared to the immediate release tablets.

Bioavailability of a 160mg slow release formulation following single dose

administration was about one third that of the conventional preparation (Drummer

et al., 1981). Garg et al. (1987) showed that area under the curve and the peak

concentration was lower for two propranolol long-acting formulations (80mg and

160mg) than for the conventional tablets; in addition the elimination half-life was

longer (9 hours) for the extended release products than for conventional

propranolol (4 hours). In a crossover study performed in healthy subjects,

bioavailability of propranolol 160mg as extended release capsules was 52% for

single dose and 54% for steady state compared to the regular tablet formulation

(Straka et al., 1987). Mean bioavailabilities of extended release Duranol®

capsules (single dose in the morning) and Inderal® conventional formulation (two

doses: morning and evening) were similar despite prolonged absorption time for

the sustained action capsules (Bottini et al., 1983).

In a study with extended release propranolol (Elanol® 120mg, Inderal® LA

160mg) and conventional Inderal® (40mgx3/day) single doses of controlled

- 49 -

release preparations produced a smoother drug serum level profile with lower

and delayed peak times. At steady state, all regimens ensured relatively

sustained serum levels and a stable degree of pharmacological effect. Dose

corrected AUC decreased in the following order:

Elanol® > Inderal® > Inderal® LA.

These results demonstrated that long acting formulations of propranolol can be

developed which are not necessarily associated with reduced bioavailability

secondary to enhanced first pass metabolism (Perucca et al., 1984).

The bioavailability of Inderal® LA (80, 160 and 240mg once daily for 4 days) was

proportional to the dose administrated as sustained action capsules. Steady state

was attained after two doses (Dvornik et al., 1983).

For different extended release formulations, the peak blood level and AUC

decreased as the dissolution time increased and the half-lives were inversely

proportional to the dissolution rate. The lowering of the systemic bioavailability as

the dissolution time increased, was assumed to be caused by an increased

metabolism of propranolol (McAinsh et al., 1981)

An attempt to develop plastic matrix tablets was done in 1974 by Grundy et al.

The matrix consisted on propranolol 125 mg embedded in an insoluble matrix of

Pevikon D-42-P (polyvinyl chloride, 273 mg). The formulation had a satisfactory

in vitro release profile (50% of the dose in 3 hours, at 100rpm). However, when

administered in dogs, the in vivo release profile was unsatisfactory (the drug was

not completely released from the matrix) (Grundy et al., 1974). Single entity

- 50 -

extended release formulations of propranolol were therefore abandoned in favor

of multiparticulate systems.

All the propranolol extended release formulations currently in use in the United

States are capsules (Electronic Orange Book, 2002). Therefore, this research

represents a novel approach in development of extended release propranolol

dosage forms by formulating them as tablets.

The reference listed product, Inderal® LA, consists of hard gelatin capsules

containing film coated spheroids each comprising propranolol hydrochloride in

admixture with microcrystalline cellulose. The drug containing spheroids are in

turn coated with ethylcellulose alone or in combination with hydroxypropyl

methylcellulose and/or plasticizer; the semipermeable membrane allows drug to

diffuse at a controlled rate (US Patent 4, 138, 475).

- 51 -

2. Objective, hypothesis and specific aims

2.1. Objective

The objective of this study is to evaluate Kollidon® SR as extended release

matrix forming excipient.

2.2. Hypothesis

Kollidon® SR promotes in vitro pH-independent extended release of drugs.

2.3. Specific aims

Studying the effect of the following variables on the tablet properties and in vitro

release of drugs from matrix tablets based on Kollidon® SR:

♦

♦

♦

Formulation variables:

• polymer concentration

• external binder addition in the wet granulation process

• enteric polymer addition.

Process variables:

• method of manufacturing (direct compression, wet granulation)

• compression force.

Dissolution medium.

- 52 -

Evaluation for one developed tablet formulation of its bioequivalence to an

extended release reference listed product.

- 53 -

3. Experimental

3.1. Materials and supplies

Acetonitrile HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)

Ammonio methacrylate copolymer type B NF Eudragit® RSPO (Rohm,

Darmstadt, Germany)

Buspirone HCl (Brantford Chemicals Inc., Brantford Ontario, Canada)

Citric acid (Sigma Chemicals, St. Louis MO, USA)

Colloidal silicon dioxide (Aerosil® 200, Degussa, Parsippany NJ, USA)

Dibasic calcium phosphate dihydrate (Emcompress®, Penwest, Patterson NY,

USA)

DL propranolol hydrochloride 99% (Acros Organics, Fair Lawn NJ, USA)

Ethyl acetate HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)

Hydrochloric acid (Fisher Chemicals, Fair Lawn NJ, USA)

Inderal® LA (Ayerst Laboratories Inc., Philadelphia PA, lot # 9010268, expiration

date 07/2003)

Magnesium stearate (Mallinckrodt Chemical Inc., St. Louis MO, USA)

Methacrylic acid copolymer type C NF Eudragit® L100-55 (Rohm, Darmstadt,

Germany)

Microcrystalline cellulose (Emcocel® 90M, Penwest, Patterson NY, USA)

o-Phosphoric acid 85% HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)

- 54 -

Polyvinyl acetate and Povidone based excipient, Kollidon® SR (BASF,

Ludwigshafen, Germany)

Polyvinyl acetate dispersion, Kollicoat® SR 30D (BASF, Ludwigshafen,

Germany)

Polyvinyl pyrrolidone, Kollidon® 30 (BASF, Ludwigshafen, Germany)

Potassium phosphate monobasic (Fisher Scientific, Fair Lawn NJ, USA)

Pronethalol hydrochloride (Tocris, Ellisville MO, USA)

Propranolol hydrochloride (Wychoff Chemicals, South Haven MI, USA)

Sodium chloride (Mallinckrodt Chemical Inc., St. Louis MO, USA)

Sodium chloride Injection USP 0.9% 10ml (American Pharmaceutical Partners

Inc., Los Angeles CA, USA)

Sodium hydroxide (Fisher Chemicals, Fair Lawn NJ, USA)

Sodium phosphate dibasic anhydrous (Fisher Chemicals, Fair Lawn NJ, USA)

Triethylamine (Fisher Scientific, Fair Lawn NJ, USA)

Water HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)

BD Vacutainer Lithium Heparin 5ml (Becton Dickinson, Franklin Lakes NJ, USA)

Clear glass threaded vials 1.5dr. (Fisher Scientific, Pittsburgh PA, USA)

Full flow filters 35µm (VanKel Technology Group, Carry NC, USA)

Glass inserts 250µl for HPLC vials (Agilent Technologies, Palo Alto CA, USA)

High-density polyethylene bottles 60cc, 90cc (Selco Inc., Anaheim CA, USA)

IEC Centra-8R Centrifuge (International Equipment Company, Needham

Heights, MA, USA)

- 55 -

Luer Adapter Venoject (Terumo Corp., Tokyo, Japan)

Metachem Inertsil ODS-3 5µm 250x4.6mm HPLC Column with MetaGuard

4.6mm Inertsil ODS-3 5µm (Metachem Technologies Inc., Torrance CA, USA)

Millipore MF TM 0.45µm membrane filters (Millipore Corp., Bedford MA, USA)

Millipore swinnex disks filter holders 25mm (Millipore Corp., Bedford MA, USA)

Polypropylene conical tubes 15ml (Becton Dickinson, Franklin Lakes NJ, USA)

Polypropylene flat top microcentrifuge tubes 2ml (Fisher Scientific, Pittsburgh PA,

USA)

Redi-Tip general purposes (200-1000µ) (Fisher Scientific, Pittsburgh PA, USA)

Septa Target (National Scientific Company, Duluth GA, USA)

Serological Disposable pipettes 5ml (Fisher Scientific, Pittsburgh PA, USA)

Target Vials 2ml (National Scientific Company, Duluth GA, USA)

Terumo Needles 20gx11/2’’ (Terumo Medical Corp., Elkton MD, USA)

Terumo Syringes 2ml, 5ml, 10ml (Terumo Medical Corp., Elkton MD, USA)

USA standard testing sieves (Gilson Company, Worthington OH, USA)

- 56 -

3.2. Equipment

Accumet 1002 pH meter (Fisher Scientific, Fair Lawn NJ, USA)

Balances PB1502, AB104 (Mettler Toledo International, Greifensee Switzerland)

HPLC Beckman System Gold 126 Solvent Module with 507e Autosampler

(Beckman Coulter, Fullerton CA, USA) and Waters 474 Scanning Fluorescence

Detector (Waters Corporation, Milford MA, USA)

Computrac Moisture Analyzer MAX 50 (Arizona Instrum., Phoenix AZ, USA)

Dissolution Tester VK7000 (VanKel Technology Group, Carry, NC, USA) coupled

to a Spectrophotometer DU 640 (Beckman Coulter, Fullerton CA, USA)

Espec Humidity Cabinet LHL112 (Tabai Espec Corp, Osaka, Japan)

Hardness Tester (Key International Inc., Englishtown NJ, USA)

Integrapette Digital Pipette 1000µl, 20µl (Liquid Handling Systems, Indianapolis

IN, USA)

Isotemp Incubator 655D (Fisher Scientific, Pittsburg PA, USA)

Planetary Mixer (Kitchen Aid, St. Joseph MI, USA)

ReactiTherm III TM with Heating Stirring Module Reacti Vap TM III (Pierce,

Rockford IL, USA)

Rotary tablet press Manesty D3B (Manesty Machines Ltd., Liverpool, UK)

Ultra Low Temperature Freezer Sanyo (Sanyo Electric Biomedical Co. Osaka,

Japan)

Micrometer Starrett (Starrett, Athol MA, USA)

Stirrer/Hot plate PC 620 (Corning Inc., New York NY, USA)

- 57 -

Tumbling Mixer Turbula T2G (Glen Mills Inc., Maywood NJ, USA)

Ultrasonic Cleaner FS30 (Fisher Scientific, Pittsburg PA, USA)

Integrator Varian 4270 (Varian Inc., Palo Alto CA, USA)

Vortex Genie (Scientific Industries Inc., Springfield MA, USA)

Software

Beam Spider (Hottinger Baldwin Messtechnik, Darmstadt, Germany)

DU Data Capture 600-7000 (Beckman Coulter, Fullerton CA, USA)

WinNonlin 4.0.1 (Pharsight Corporation, Mountain View CA, USA)

SAS software systems for Windows Release 8.02 (SAS Institute Inc, Cary NC,

USA)

- 58 -

3.3. Tablet composition

Two water-soluble model drugs were used in the experiments.

Propranolol HCl (section 1.6 – page 45)

Buspirone hydrochloride : (MW 421.97)

8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione

hydrochloride - racemic mixture.

Buspirone HCl is a white crystalline powder, soluble in water, pKa1=4.12,

pKa2=7.32 (Takacs-Novak and Avdeef, 1996).

The hydrophilic Polyvinylpyrrolidone (Kollidon® 30) and the hydrophobic

polyvinylacetate dispersion (Kollicoat® SR 30D) were added in the wet

granulation experiments, as external binders.

Ammonio methacrylate copolymer (Eudragit® RSPO), a direct compressible

matrix-forming polymer with extended release properties was used for

comparative studies (section 3.6.1.3 – page 71)

A mixture of dibasic calcium phosphate dihydrate (Emcompress®) and

microcrystalline cellulose (Emcocel® 90M) in ratio 1:1 was used as tablet filler.

- 59 -

This ratio was selected based on literature data (Sakr et al., 1988, Sakr et al.,

1987) and preliminary experiments.

Other tablets components were colloidal silicon dioxide (Aerosil® 200) as a

glidant and magnesium stearate as a lubricant.

Eudragit® L100-55 was added to some propranolol 80mg formulations to see the

effect of the addition of an enteric polymer on the drug release (section 3.6.3.4 –

page 75).

- 60 -

3.4. Tablet manufacture

Tablets were manufactured by direct compression or wet granulation, according

to the process flow presented in – page 62 and – page 63,

respectively and then stored in airtight high-density polyethylene (HDPE) bottles

till further testing.

Figure 3 Figure 4

Direct Compression - Process flow:

• The corresponding amounts of drug and Kollidon® SR were accurately

weighed.

• The powders were screened using screen #35.

• The screened powder was transfered into the turbula mixer jar and mixed for

5 minutes.

• The corresponding amounts of Emcocel® 90M, Emcompress®, Aerosil® 200

(and Eudragit® L100-55 for some formulations) were accurately weighed,

screened through screen #35, added to the turbula jar and mixed for 10

minutes.

• The corresponding amount of magnesium stearate was accurately weighed

and mixed with the powder in the turbula jar for additional 3 minutes.

• The powder was compressed into tablets using an instrumented tablet press

and tablets were collected during compression for in-process testing (weight

and hardness).

- 61 -

(Manesty D3B Press)

(Turbula Mixer)

Final Mixing 3 Minutes

Compression(*)

Mixing 10 Minutes

Mixing 5 Minutes

Drug Kollidon® SR (sieve #35)

Fillers Glidant (sieve #35)

Lubricant (sieve #35)

(*) in process control of tablets’ weight and hardness

recording of the compression and ejection forces (Beam Spider Software)

Figure 3. Process flow chart for tablets manufactured by direct compression

- 62 -

(Manesty D3B Press)

(Planetary Mixer)

Drug Kollidon® SR (sieve #35)

(Turbula Mixer)

Dry screening (# 18 mesh)

(# 12 mesh)

Drying (1.5%) (Oven 40°C)

Distilled water or Binder dispersion

Wet screening

(Turbula Mixer)

Glidant Lubricant

Fillers (sieve #35)

Final Mixing 3 Minutes

Compression(*)

Mixing 10 Minutes

Mixing 5 Minutes

Granulation

(*) in process control of tablets’ weight and hardness recording of the compression and ejection forces (Beam Spider Software)

Figure 4. Process flow chart for tablets manufactured by wet granulation

- 63 -

Wet Granulation - Process flow:

• The corresponding amounts of drug and Kollidon® SR were accurately

weighed.

• The powders were screened using screen #35.

• The screened powder was transferred into the turbula mixer jar and mixed for

5 minutes.

• The corresponding amounts of Emcocel® 90M, Emcompress® were

accurately weighed, screened through screen #35, added to the turbula jar

and mixed for 10 minutes.

• The powder mixture was transferred to the planetary mixer and granulated

with water or binder dispersion.

• The wet mass was passed through a #12 sieve and the resulting granules

were placed on trays for drying into the oven at 40°C to a moisture content of

1.5%.

• The dried granules were passed through a #18 sieve.

• The dried granules and the corresponding amount of magnesium stearate

and Aerosil® 200 were accurately weighed and then mixed in the turbula jar

for additional 3 minutes.

• The mixture was compressed into tablets using an instrumented tablet press

and tablets were collected during compression for in-process testing (weight

and hardness).

- 64 -

3.5. Tablet testing

Tablet weight variation - twenty tablets from each batch were individually

weighed and the average weight and relative standard variation were reported.

Thickness - was determined for 10 pre-weighed tablets of each batch using a

micrometer and the average thickness and relative standard variation were

reported.

Hardness - was determined for 10 tablets (of known weight and thickness) of

each batch; the average hardness and relative standard variation were reported.

Uniformity of dosage units was assessed according to the USP requirements

<905> for content uniformity. The batch meets the USP requirements if the

amount of the active ingredient in each of the 10 tested tablets lies within the

range of 85% to 115% of the label claim and RSD is less than or equal to 6%.

According to the USP criteria, if one of these conditions is not met, additional 20

tablets need to be tested. Not more than 1 unit of the 30 tested should be outside

the range of 85% and 115% of the label claim and no unit outside the range of

75% to 125% of label claim; also RSD should not exceed 7.8%.

In vitro drug release

In vitro drug release was performed for the manufactured tablets according to the

USP 25 “Dissolution procedure” <711>, over a 24-hour period, using an

automated dissolution system. A minimum of 6 tablets per batch were tested.

Method A - Apparatus 2 (paddle) was used at 50rpm, with 1000ml dissolution

medium at 37°C; the UV absorbance of the dissolution medium was measured at

- 65 -

0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours. The release was calculated

using a standard solution. The drug release was tested in different dissolution

media: distilled water, 0.1N HCl and USP 25 pH=6.8 phosphate buffer. The pH

range (pH = 1.2 – 6.8) was chosen to reflect the physiologic conditions of the

gastrointestinal tract.

Method B - in addition to the general method (method A), some of the

propranolol 80mg tablet batches were tested according to the USP dissolution

method required in the propranolol 80mg extended release capsules USP

monograph (apparatus 1, 100rpm, 900ml, first 1.5 hours pH 1.2 buffer, then pH

6.8 buffer). Additional sampling times (1.5 and 14 hours) were included in

establishing the dissolution profile.

Different dissolution profiles were compared to establish the effect of formulation

or process variables or dissolution medium on the drug release. The dissolution

similarity was assessed using the FDA recommended approach (f2 similarity

factor). This model independent mathematical approach was described by Moore

and Flanner (1996):

}])TtRt()n/(log{[fn

t

. 100115021

502 ⋅−+⋅= ∑=

− (16)

where Rt and Tt are the cumulative percentage dissolved at each of the selected

n time points of the reference and test product respectively

Factor f2 is inversely proportional to the average squared difference between the

two profiles, with emphasis on the larger difference among all the time-points.

- 66 -

The transformation is such that the f2 equation takes values less or equal to 100.

When the two profiles are identical, f2=100. An average difference of 10% at all

measured time points results in an f2 value of 50 (Shah et al., 1998). FDA has

set a public standard of f2 value between 50 -100 to indicate similarity between

two dissolution profiles. To use mean data for extended release products, the

coefficient of variation for mean dissolution profile of a single batch should be

less than 10% (FDA, 1997b). The average difference at any dissolution sampling

point should not be greater than 15% between the tested and reference products

(FDA, 1997a). Because f2 values are sensitive to the number of dissolution time

points, for extended release products only one point past the plateau of the

profiles should be used in the calculation (FDA, 1997a).

The dissolution profiles were fitted using the Higuchi model (for drug release up

to 60%) and the R2 was reported. For the dissolution profiles, which confirmed

this diffusion model, the slopes of the curves were used to compare the release

rates.

- 67 -

3.6. Experimental design and methodology

3.6.1. Propranolol 10 mg tablets

Literature data were available just on Kollidon® SR application as extended

release excipient for high dose drug matrix tablets manufactured by direct

compression method (BASF, 1999, Pathan and Jalil, 2000, Rock et al., 2000).

In this dissertation the suitability of Kollidon® SR was evaluated for low-dose

drug extended release systems, using propranolol HCl (10mg) as a model drug.

A full factorial design was applied to study the effect of polymer concentration

(10-50% w/w of the tablet weight) and the method of manufacture (direct

compression and wet granulation) on tablet properties and drug release. Tablets

were manufactured by direct compression or wet granulation (section 3.6.1.1 –

page 68, section 3.6.1.2 – page 69). For the wet granulation technology, the

effect of the addition of an external hydrophilic or hydrophobic binder was

investigated.

3.6.1.1. Manufacture of propranolol 10mg tablets by direct compression

All ingredients in their specified ratios as mentioned in Table 3 – page 69 were

blended in a turbula mixer and tablets manufactured by direct compression

method (process flow chart - Figure 3, page 62) to a target weight of

133.33mg/tablet and hardness of about 10 KP, using 7 mm round punches.

- 68 -

Table 3. Propranolol 10mg matrix tablets formulation

Table 3

Ingredients Formula 1 Formula 2 Formula 3 Formula 4 Formula 5

Propranolol HCl 7.50 7.50 7.50 7.50 7.50

Kollidon® SR 10.00 20.00 30.00 40.00 50.00

Emcocel® 90M 40.75 35.75 30.75 25.75 20.75

Emcompress® 40.75 35.75 30.75 25.75 20.75

Aerosil® 200 0.50 0.50 0.50 0.50 0.50

Magnesium stearate

0.50 0.50 0.50 0.50 0.50

Total 100.00 100.00 100.00 100.00 100.00 (% of the tablet weight)

3.6.1.2. Manufacture of propranolol 10mg tablets by wet granulation

For wet granulation, the blends were granulated in a planetary mixer by adding

distilled water (Formulations 1-5, – page 69) or binder dispersion

(Formulations 6-9, – page 70) and the tablets were compressed to a

target weight of 133.33mg/tablet and hardness of about 10 KP, using 7 mm

round punches (process flow chart – Figure 4 – page 63).

Table 4

Reproducibility batches were manufactured under the same conditions.

- 69 -

Table 4. Propranolol 10mg matrix tablets formulations with external binders

Ingredients Formula 6 Formula 7 Formula 8 Formula 9

Propranolol HCl 7.50 7.50 7.50 7.50

Kollidon® SR 30.00 30.00 50.00 50.00

Kollidon® 30 5.00 - 5.00 -

Kollicoat® SR30D - 5.00 - 5.00

Emcocel® 90M 28.25 28.25 18.25 18.25

Emcompress® 28.25 28.25 18.25 18.25

Aerosil® 200 0.50 0.50 0.50 0.50

Magnesium stearate 0.50 0.50 0.50 0.50

Total 100 100 100 100 (% of the tablet weight)

Table 5. Propranolol 10mg tablets formulated with Eudragit® RSPO

Ingredients Eudragit® RSPO 30%

Eudragit® RSPO 40%

Eudragit® RSPO 50%

Propranolol HCl 7.50 7.50 7.50

Eudragit® RSPO 30.00 40.00 50.00

Emcocel® 90M 30.75 25.75 20.75

Emcompress® 30.75 25.75 20.75

Aerosil® 200 0.50 0.50 0.50

Magnesium stearate

0.50 0.50 0.50

Total 100.00 100.00 100.00 (% of the tablet weight)

- 70 -

3.6.1.3. Drug release profiles from propranolol 10mg matrix tablets manufactured with Eudragit® RSPO

Kollidon® SR was replaced in direct compression with a polymethacrylate

polymer, Eudragit® RSPO at 30, 40 and 50% concentration levels and the drug

release profiles in distilled water were compared (Table 5– page 70).

3.6.1.4. Testing of propranolol 10mg tablets

Tablets were tested for physical properties and in vitro drug release according to

the USP 25 (apparatus 2) paddle method at 50 rpm in 1000 ml of distilled water

maintained at 37±0.5°C (Method A – section 3.5, page 65).

The effect of dissolution medium on drug release was tested for the formulations

with 30, 40 and 50% Kollidon® SR. The release profiles in three different

dissolution media, distilled water, USP pH 6.8 phosphate buffer and 0.1N

Hydrochloric acid (method A – section 3.5, page 65) were compared using the

FDA recommended approach (f2 similarity factor).

The applicability of the diffusional release mechanism (Higuchi time square

model) was assessed.

3.6.2. Buspirone 10 mg tablets

Buspirone HCl was selected as model drug in this set of experiments, based on

its solubility in water, basic character and low-dose loading (10mg).

Buspirone HCl has a short and variable biological half-life (2-3 hours), and high

- 71 -

first pass metabolism (Sakr and Andheria, 2001, Mahmood and Sahajwalla,

1999).

Two independent variables, polymer level as formulation parameter and

compression force, as process parameter were tested. A full factorial design at

three levels of compression force (1000, 2000, 3000lbs) and six levels of polymer

concentration (10-60%) was used. Also a control batch without the polymer was

manufactured.

Buspirone and fillers were optimally mixed with Kollidon® SR at various

concentrations and directly compressed into capsule-shaped tablets

(0.185 x 0.426 in) of label claim 10 mg Buspirone (tablet weight 160.0mg), under

standardized conditions, according to the process flow chart presented in

– page 62.

Figure

3

Table 6. Formulation of buspirone 10mg tablets

Ingredient (%) KSR 0%

KSR 10%

KSR 20%

KSR 30%

KSR 40%

KSR 50%

KSR 60%

Buspirone HCl 6.25 6.25 6.25 6.25 6.25 6.25 6.25

Kollidon® SR 0.00 10.00 20.00 30.00 40.00 50.00 60.00

Emcocel® 90M 46.375 41.375 36.375 31.375 26.375 21.375 16.375

Emcompress® 46.375 41.375 36.375 31.375 26.375 21.375 16.375

Aerosil® 200 0.50 0.50 0.50 0.50 0.50 0.50 0.50

Magnesium stearate

0.50 0.50 0.50 0.50 0.50 0.50 0.50

Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00(% of the tablet weight)

- 72 -

The physical properties of the tablets and the drug release in water, 0.1N HCl

and pH 6.8 phosphate buffer were tested and evaluated as mentioned in

section 3.5 – page 65.

3.6.3. Propranolol 80 mg tablets

This set of experiments was designed to evaluate the potential of Kollidon® SR

as matrix former for propranolol 80mg tablets (high dose), knowing that the

development of monolithic extended release matrices for high dose highly

soluble drugs presents a challenge.

3.6.3.1. Manufacture of propranolol 80mg tablets with 40-60% Kollidon® SR

The experimental design was a full factorial for two factors at three levels each:

polymer concentration (40, 50 and 60%) ( – page 74) and compression

force (1000, 2000, 3000lbs). Tablets were manufactured by direct compression

according to the process flow chart presented in Figure 3 – page 62, using bisect

capsule shaped punches (0.185 x 0.0.426 in) to a target weight of 225mg/tablet.

Table 7

- 73 -

Table 7. Formulation of propranolol 80mg tablets with 40-60% Kollidon® SR

Ingredient (%) 40% KSR 50% KSR 60% KSR

Propranolol HCl 35.55 35.55 35.55

Kollidon® SR 40.00 50.00 60.00

Emcocel® 90M 11.725 6.725 1.725

Emcompress® 11.725 6.725 1.725

Aerosil® 200 0.50 0.50 0.50 Magnesium stearate

0.50 0.50 0.50


3.6.3.2. Testing of propranolol 80mg tablets with 40-60% Kollidon® SR

Tablets were tested for physical properties and drug release in distilled water,

0.1N HCl and pH 6.8 buffer (method A – section 3.5, page 65). The released

amounts were plotted as function of square root of time, to determine the

mechanism of drug release. A model independent approach using similarity

factor f2 was used to compare the dissolution profiles.

3.6.3.3. Manufacture of propranolol 80mg tablets with 70% polymer (Kollidon® SR alone or in combination with Eudragit® L100-55)

In this set of experiments, propranolol 80mg tablets were formulated by

increasing the polymer level up to 70% of the tablet weight and/or partial

replacement of Kollidon® SR with of an enteric polymer (Eudragit® L100-55)

(Table 8 – page 75). As a result of increasing the polymer level, tablet weight had

to be increased to allow 70% polymer addition.

- 74 -

The objective was to study the effect of addition of an enteric polymer on drug

release and to modify the release to be close / similar to the USP requirements

for extended release propranolol capsules. Tablets were manufactured by direct

compression, using bisect capsule shaped punches (0.220 x 0.500 in) to a target

weight of 275.86mg (~276mg) and hardness 10-15 kP (flow chart Figure 3 –

page 62).

Table 8. Formulation of propranolol 80mg tablets with 70% polymer Ingredient (%) 70% KSR 65% KSR

5% Eudragit® L100-55 60% KSR

10% Eudragit® L100-55 Propranolol HCl 29.00 29.00 29.00

Kollidon® SR 70.00 65.00 60.00

Eudragit® L100-55 - 5.00 10.00

Aerosil® 200 0.50 0.50 0.50

Magnesium stearate

0.50 0.50 0.50


3.6.3.4. Testing of propranolol 80mg tablets with 70% polymer (Kollidon® SR alone or in combination with Eudragit® L100-55)

Tablets were tested for physical properties and drug release in various media

(method A – section 3.5, page 65) and according to the USP method for

propranolol extended release capsules (method B – section 3.5, page 65). The

release data obtained were plotted as a function of square root of time, to

- 75 -

determine the mechanism of drug release. A model independent approach using

similarity factor f2 was used to compare the dissolution profiles.

3.6.3.5. Testing of Inderal® LA capsules (reference listed drug product)

Inderal® LA (lot #9010268), the reference listed product, was tested for the drug

release in different media according to method A and method B (section 3.5,

page 65). This step was necessary because the reference listed product served

as comparison for some of the developed matrix tablet formulations.

3.6.3.6. Selection of propranolol 80mg formulation for pilot bioequivalence study

The release profiles (obtained according to method B – section 3.5, page 65) of

the developed matrix tablet formulations with 60 and 70% Kollidon® SR were

compared to Inderal® LA and it was decided to formulate and manufacture

tablets using an intermediate polymer level (65%).

3.6.3.7. Testing of propranolol 80mg tablets for the pilot bioequivalence study

For the selected formulation (65% Kollidon® SR), the following

characteristics/tests were performed: physical properties of the tablets, content

uniformity, propranolol release – method A and B (section 3.5, page 65),

reproducibility, effect of storage on tablet hardness and in vitro drug release.

- 76 -

Effect of storage on tablet physical properties and drug release

Propranolol 80mg tablets with 65% Kollidon® SR were stored in HDPE bottles in

the presence of desiccant under different storage conditions (FDA, 2001 ICH

Q1A, FDA, 1997 ICH Q1C). At predetermined time points, the tablets were

sampled and tested for physical properties and drug release (Table 9 – page 77).

Table 9. Stability study design

Study Storage condition

Frequency of testing Tests performed

Long-term 25 ± 2°C / 60± 5%RH

0, 1, 3, 6, 9 months Appearance, weight, thickness, hardness, drug release – method B

Accelerated 40 ± 2°C / 75± 5%RH

0, 3 and 6 months (9 months included, although not required by ICH

Appearance, weight, thickness, hardness, drug release – method B

3.6.4. Pilot bioequivalence study

3.6.4.1. Design and methodology

The relative bioavailabilities of the selected propranolol 80mg extended release

matrix tablets and reference listed drug product Inderal® LA 80mg were

evaluated in a pilot bioequivalence study, according to a protocol (# 01-6-19-1)

approved by the University of Cincinnati Institutional Review Board (Appendix 1-

page171). The study design was a randomized cross-over single-dose two-

period open-label two-treatment, with a wash out period of one week.

- 77 -

According to the 21 CFR 320.31 b., the study did not require an IND submission

because it was designed to assess the bioavailability / bioequivalence in humans

of single dose of an approved non-new chemical entity (propranolol

hydrochloride) and the dose did not exceed the maximum single dose specified

in the labeling of the drug product that is the subject of an approved new drug

application or abbreviated new drug application. Additionally, correspondence

with the Food and Drug Administration - Office of Generic Drugs was submitted

to the Institutional Review Board to support the protocol approval.

The pilot study was conducted in compliance with the requirements for IRB

review and informed consent (21 CFR parts 56 and 50, respectively) and with the

requirements concerning the promotion and sale of drug (21 CFR 312.7). The

study did not invoke 21 CFR 50.24. It was performed under medical supervision

at the University of Cincinnati and Veterans Affairs Hospital facilities in

Cincinnati.

Ten volunteers underwent a screening procedure 2-6 days prior to the first

testing period and 8 subjects who met inclusion criteria, provided written consent

were enrolled in the study and randomized to one of the two dosing sequences

(SAS software).

Inclusion Criteria

• Healthy, male and female subjects between the ages of 18 – 65 years

inclusive

• Subjects must be outpatients at the time of screening

- 78 -

• Subjects must be on no chronic medications (prescription or OTC) and must

be medication-free for a period of at least one week prior to the first test day

and throughout the duration of the study

• Subjects must be off any investigational drug for a period of at least 3 months

prior to the entry in the study

• Subjects must be in good health as determined by medical history, routine

physical examination, ECG and clinical laboratory tests

• Subjects must be free of significant psychiatric illness

• Subjects must be willing and able to provide written informed consent.

Exclusion Criteria

• Subjects with a history or evidence of clinically significant and currently

relevant hematological, renal, hepatic, gastrointestinal, endocrine,

pulmonary, dermatological, oncological or neurological illness, and

alcoholism.

• Subjects with a history of cardiovascular disease, including hypotension,

hypertension, heat block, congestive heart failure, angina pectoris, bypass

surgery, or myocardial infarction

• Subjects with clinically significant abnormalities on the electrocardiogram at

screening

• Pregnant and breast-feeding women were not eligible

• Subjects using concomitant drugs

• Subjects with known allergy to propranolol

• Subjects with clinically significant emotional problems

- 79 -

• Subjects unable and/or unlikely to comprehend and follow the study protocol.

Screening examinations

• Routine physical examination and medical history

• Safety examination – ECG before the treatment, blood pressure, pulse and

temperature

• Laboratory examination – complete blood count with differential, hepatic and

renal profiles.

Treatments

♦

♦

Test product - propranolol 80mg developed extended release matrix tablets.

Reference product - Inderal® LA 80mg capsules (reference listed product,

innovator product).

Methodology

Subjects were admitted as outpatients in the morning (7.30 am) of the first day of

each period and after the insertion of the catheter, they received a single dose of

the drug (test or reference product) at 8.00am (0 hour of the test). Subjects were

in the facility until 8.00pm (after the 12-hour blood sample was withdrawn).

Subjects returned the second day of each period at 8.00 am and 2.00pm for the

24-hour and 30-hour blood sample withdrawal.

Meals and Food Restrictions. Subjects fasted for at least 12 hours prior to the

dose administration. Prior to and during each study phase subjects were allowed

water as desired except for one hour before and after drug administration.

Subjects received lunch at 1.00pm. Subjects abstained from alcohol for 24 hours

- 80 -

prior to each study period and until after the last sample from each period was

collected. Use of tobacco and caffeine was not allowed for 24 hours prior to each

study period and until after the last sample from each period was collected.

Subject monitoring. The blood pressure and pulse rate were monitored prior to

dosing and at the sampling times. The treatment effects on blood pressure and

pulse rate at every time point were tested by one-way ANOVA. Subjects had

their weight measurements taken and recorded at each period. Subjects were

advised to avoid the use of prescription and OTC medications.

Blood samples

During each period, 12 venous blood samples were taken from the antecubital

veins in heparinized vacutainers as follows:

• Day 1 - at 0 (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post-dose

(using catheter hep-lock)

• Day 2 - at 24, 30 hours post-dose (by direct venipuncture).

The plasma was separated by centrifugation (3000g x 15minutes) and then,

transferred to the labeled tubes and promptly frozen. The samples were stored at

–70°C, until analyzed.

3.6.4.2. Analysis of propranolol in plasma

Propranolol was analyzed in plasma by a reverse phase HPLC - fluorescence

detection method, developed based on published data (Drummer et al., 1981,

Braza et al., 2000, Rekhi et al., 1995). The method parameters are presented in

– page 82. Table 10

- 81 -

To 1.0ml spiked plasma or sample, 0.1ml 1M NaOH, 0.1 ml Pronethalol 600ng/ml

(internal standard) and 5ml ethyl acetate were added. The mixture was vortexed

for 15sec and then centrifuged at 3000 rpm for 3 minutes. 4ml of the supernatant

were transferred to disposable vials and evaporated to dryness at 40°C using

nitrogen steam. The residue was reconstituted in 0.5ml mobile phase, vortexed

for 10sec and 100µl were injected on the column.

Table 10. Analytical method for analysis of propranolol in plasma

Column Metachem Inertsil ODS-3 5µm 250x4.6mm HPLC Column with MetaGuard 4.6mm Inertsil ODS-3 5µm

Mobile phase Acetonitrile : Water with 1.2% (w/v) triethylamine and pH adjusted to 3 with 85% orthophosphoric acid =30 : 70

Flow rate 1.0ml/min

Injection volume 100µl

Detection Method Fluorescence detection excitation wavelength 280nm, emission wavelength 333nm

Linearity. Daily standard curves were prepared by spiking plasma with

propranolol HCl solution in water to obtain the following final concentrations: 2, 4,

10, 20, 40, 100ng/ml. Calibration curves were generated by plotting the ratio of

areas of propranolol / internal standard versus ratio of the concentrations of the

two components. The calibration curve was considered linear for values of the

correlation coefficient above 0.99.

- 82 -

Accuracy. Three concentrations within the linearity range (2, 20, 100ng/ml) were

prepared by spiking the plasma with the corresponding amount of propranolol

solution and internal standard and analyzed. Accuracy was calculated as

percentage of measured (recovered) concentration to theoretical values.

Intra- and inter-day variability. The intra-day variability was determined by

analyzing three replicates of spiked plasma at three different concentrations (2,

20, 100ng/ml). For inter-day variability, the samples were prepared and injected

into the column on two consecutive days.

3.6.4.3. Pharmacokinetic and statistical analysis

The values of the concentrations were natural log-transformed and a non-

compartmental pharmacokinetic model was applied to calculate Cmax, area

under the concentration time curves from 0-24h (AUC 0-24h) and 0-∞ (AUC 0-∞)

for each subject and formulation (WinNonlin). The resulting data were statistically

analyzed by a non-parametric test (Wilcoxon) for carry-over (residual) effects,

sequence and treatment effects (SAS software).

The bioequivalence of the two formulations was tested using the following model

(WinNonlin software - bioequivalence wizard):

Y = intercept + sequence + treatment + period

Random effect = subject (sequence).

- 83 -

4. Results and Discussions

4.1. Propranolol 10 mg tablets


tablets manufactured by direct compression

Propranolol 10mg tablets were manufactured with different concentrations of

Kollidon® SR, (10, 20, 30, 40 and 50% of tablet weight) – section 3.6.1.1, page

68. Tablets were uniform in weight and thickness and their hardness increased

as the concentration of polymer in the formulation increased (Table 11 – page

84).

Table 11. Effect of Kollidon® SR on physical properties of propranolol 10mg tablets manufactured by direct compression

Kollidon® SR Weight (mg) Thickness (mm) Hardness (kP)

Average RSD Average RSD Average RSD

10% KSR 131.49 0.577 3.897 0.172 4.14 14.324

20% KSR 132.75 0.725 3.923 0.173 6.47 7.252

30% KSR 132.78 0.001 4.007 0.407 8.91 11.524

40% KSR 133.87 1.264 4.152 1.077 11.54 10.024

50% KSR 133.68 0.001 4.224 0.488 13.12 10.300

- 84 -

It was found that increasing polymer concentration up to 40%, significantly

decreased the drug release rate in water, sustaining the release of the highly

water soluble drug incorporated at low dose for a longer period of time

(dissolution data for all the experimental batches were reproducible n=6,

RSD<3% and hence only the average values were plotted). There was no

significant difference between the formulations containing 40% and 50% of the

polymer content f2>50 (Figure 5 – page 86).

The regression parameters of the drug release curves for formulations with 30-

50% polymer content are indicated in – page 85 and the plot of percent

drug released versus square root of time is illustrated in Figure 6 – page 87. The

high correlation coefficient (above 0.99) obtained indicates a square root of time

dependent release kinetics. Thus, as the data fitted the Higuchi model, it

confirmed a diffusion drug release mechanism.

Table 12

Table 12. Regression parameters of the diffusion drug release curves for propranolol 10mg tablets manufactured by direct compression

Kollidon® SR %a Slope (n) Intercept (l) r2

30 45.582 -7.771 0.999

40 23.404 3.356 0.997

50 22.947 -2.099 0.999 (Q=n*t1/2+l) aKollidon® SR as percentage of total tablet weight

- 85 -

0

10

20

30

40

50

60

70

80

90

100

110

0 4 8 12 16 20 24

time (hr)

%re

leas

ed

10% KSR20% KSR30% KSR40% KSR50% KSR

Figure 5. Effect of Kollidon® SR on drug release in water from propranolol 10mg tablets manufactured by direct compression

- 86 -

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4

√t (√hr)

%re

leas

ed

30% KSR40% KSR50% KSR

Figure 6. Effect of Kollidon® SR on diffusion controlled drug release in water from propranolol 10mg tablets manufactured by direct compression

- 87 -

It is suggested that the main driving force for the drug release in case of water-

soluble drug like propranolol hydrochloride from the matrix tablets is the

infiltration of release medium. As the tablet is introduced into the medium, water

penetrates into the matrix and povidone leaches out to form pores through which

the drug may diffuse out. Also, as observed in Figure 6 – page 87, as the

polymer level in the formulation is increased, drug diffusion is slowed due to the

lower porosity and higher tortuosity of the matrix. Thus polyvinylacetate, which is

a very plastic material, produces a coherent matrix, sustaining the drug release

from the tablet matrix. Similarly, Ruchatz et al 1999 reported that caffeine was

released from Kollidon® SR matrix tablets by diffusion over more than 16 hours.

The matrix remained intact during the dissolution test due to the water-insoluble

polyvinylacetate.


tablets manufactured by wet granulation

The application of Kollidon® SR for tablets manufactured by wet granulation

using distilled water as granulating medium, was studied (section 3.6.1.2 – page

69). Tablets were uniform in weight, thickness and hardness (

Table 13 – page 89).

- 88 -

Table 13. Effect of Kollidon® SR on the physical properties of Propranolol 10mg tablets manufactured by wet granulation

Kollidon® SR Weight (mg) Thickness (mm) Hardness (kP)

Average RSD Average RSD Average RSD

10% KSR 135.96 1.065 3.998 0.105 8.37 4.141

20% KSR 134.84 1.419 4.029 0.273 9.40 6.784

30% KSR 134.80 0.001 4.079 0.270 11.11 8.055

40% KSR 135.49 1.570 4.133 0.511 12.81 11.709

50% KSR 133.30 0.002 4.207 0.663 11.40 7.725

- 89 -

0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12

time (hr)

%re

leas

ed

10% KSR20% KSR30% KSR40% KSR50% KSR

Figure 7. Effect of Kollidon® SR on drug release in water from propranolol 10mg tablets manufactured by wet granulation

- 90 -

0

10

20

30

40

50

60

70

80

90

100

110

0 1 2 3 4

√t (√hr)

%re

leas

ed


Figure 8. Effect of Kollidon® SR on diffusion controlled drug release in water from propranolol 10mg tablets manufactured by wet granulation

- 91 -

The drug release in water is shown in Figure 7 – page 90 and the Higuchi plots in

– page 91. Figure 8

By comparing the slopes of Higuchi plots as an indicator for release rate, it can

be seen that wet granulation (Table 14 – page 92) produced a faster release than

direct compression (Table 12– page 85).

Table 14. Regression parameters of the diffusion drug release curves for propranolol 10mg tablets manufactured by wet granulation


30 42.438 -7.037 0.999

40 37.774 -5.167 0.999

50 53.380 -16.238 0.994 (Q=n*t1/2+l) aKollidon® SR as percentage of total tablet weight

In contrast to the direct compression method, in tablets manufactured by wet

granulation, increasing the polymer concentration from 30 to 50%, produced a

faster rate of drug release from the matrix. The regression parameters for

Higuchi model are presented in Table 14 – page 92 and the change in release

profiles is indicated by the varying slope values for the square root of time plots.

This behavior could be attributed to a faster penetration of waterfront into the

matrix, leading to a formation of more porous structure in the matrix. The

povidone in the polymer would have deposited on the polyvinylacetate particles

during granulation, thus localizing as discrete granules between polyvinylacetate

particles, leading to a faster channeling action. The lower tortuosity and higher

- 92 -

water penetration due to an increase in the volume of povidone at 50% polymer

content, could also lead to a faster drug release rate. As Kollidon® SR was not

studied before for wet granulation applications, no literature data were available

for comparison purposes.

4.1.3. Effect of external binder on drug release from propranolol

10mg tablets manufactured by wet granulation

The effect of the addition of an external binder in the granulating medium, on the

drug release rate from formulations containing 30 and 50% Kollidon® SR content

was evaluated and the release profiles are as shown in Figure 9 – page 94. The

two binders studied at 5% concentration levels were water-soluble Kollidon® 30

and Kollicoat® SR30D aqueous dispersion with hydrophobic properties.

No significant change in drug release profiles (f2 >50) was observed at 30%

Kollidon® SR level. At a concentration of 50% Kollidon® SR, additional external

binder did not slow the release as expected. None of the two binders used could

compensate for the reduced interaction of the hydrophobic polyvinylacetate with

the other hydrophilic components from the tablets (reduced interaction caused by

exposure of the polymer during the wet granulation process) (Mulye and Turco,

1994). The results indicated that Kollidon® SR was primarily controlling the drug

release rate.

- 93 -

0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12

time (hr)

%re

leas

ed 30% KSR / water

30% KSR / 5% Kollidon 30

30% KSR / 5% Kollicoat SR30D

50% KSR / water

50% KSR / 5% Kollidon 30

50% KSR / 5% Kollicoat SR30D

Figure 9. Effect of external binder on drug release in water from propranolol 10mg tablets with 30% and 50% Kollidon® SR

- 94 -


10mg matrix tablets

Drug release from tablets with 30, 40 and 50% Kollidon® SR was tested in three

different dissolution media: distilled water, USP pH 6.8 phosphate buffer and

0.1N hydrochloric acid (Figure 10 - Figure 15, pages 96 - 101).

On applying the similarity factor, f2, to compare the dissolution in 0.1N HCl or pH

6.8 buffer to the release in water, values of above 50 were obtained indicating

the similarity of the release profiles (Table 15 – page 102).

Drug release from matrix systems is influenced by the aqueous solubility of the

drug and matrix behavior at different pH. Propranolol has a pKa=9.5 (Avdeef et

al., 2000) and an acceptable solubility over the physiologic pH range: 220 mg/ml

in 0.1 N HCl and 254 mg/ml in pH 7.4 phosphate buffer (Siepmann and Kranz,

2000). Kollidon® SR contains no ionic groups, hence it is inert to drug

substances and its solubility and hydration are not influenced by pH. As a result,

the drug release was pH-independent and it was concluded that Kollidon® SR is

suitable for the manufacturing of pH-independent extended release matrix

tablets, on the condition that drug solubility does not drastically change with the

pH.

- 95 -

0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12 14 16 18 20 22 24

time (hr)

% re

leas

ed

water0.1N HClpH 6.8 buffer

Figure 10. Effect of dissolution medium on drug release from propranolol 10mg tablets with 30% Kollidon® SR manufactured by direct compression

- 96 -

0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12

time (hr)

% re

leas

ed


Figure 11. Effect of dissolution medium on drug release from propranolol

10mg tablets with 30% Kollidon® SR manufactured by wet granulation

- 97 -

0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12 14 16 18 20 22 24

time (hr)

% re

leas

ed



- 98 -

0

10

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40

50

60

70

80

90

100

110

0 2 4 6 8 10 12

time (hr)

% re

leas

ed


Figure 13. Effect of dissolution medium on drug release from propranolol 10mg tablets with 40% Kollidon® SR manufactured by wet granulation

- 99 -

0

10

20

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40

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80

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100

110

0 2 4 6 8 10 12 14 16 18 20 22 24

time (hr)

% re

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ed



- 100 -

0

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100

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0 2 4 6 8 10 12

time (hr)

% re

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ed


Figure 15. Effect of dissolution medium on drug release from propranolol 10mg tablets with 50% Kollidon® SR manufactured by wet granulation

- 101 -

Table 15. f2 values - effect of dissolution medium on drug release from propranolol 10mg tablets

Formulation f2 (0.1N HCl – water) f2 (pH 6.8 buffer – water)

30% Kollidon® SR direct compression

86.62 82.81

30% Kollidon® SR wet granulation

72.99 53.77


94.30 72.33


82.06 55.45


72.10 88.77


75.44 84.31

- 102 -

4.1.5. Drug release profiles from matrix tablets with Eudragit® RSPO

Kollidon® SR was replaced in direct compression with a polymethacrylate

polymer, Eudragit® RSPO. Tablets with 30, 40 and 50% polymer levels were

manufactured and the drug release profiles in distilled water were compared. The

drug release was faster (Figure 16 – page 104), with about 80-100% of

propranolol released in the first 1-2 hours, which was attributed to a rapid and

complete erosion of the matrix (disintegration time for all Eudragit® RSPO

formulations tested was less that 10 minutes). This was a result of a low

cohesiveness of the powder during compression, the maximum hardness which

could be achieved (under maximum compression force) was between 4-6kP.

- 103 -

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Eudragit RSPO 30%Eudragit RSPO 40%Eudragit RSPO 50%

Figure 16. Effect of Eudragit® RSPO on drug release in water from propranolol 10mg tablets

- 104 -

4.2. Buspirone 10mg tablets


properties and drug release of buspirone 10mg tablets

Buspirone tablets were found uniform in weight and thickness and had high

mechanical strength, even under the lowest applied compression force (Table 16

– page 107). Increasing the compression force from 1000lbs to 2000lbs

significantly increased the hardness of the tablets, but further increase above

2000lbs did not significantly change the hardness of the tablets with 40 - 60%

Kollidon® SR (p>0.05). Increasing the polymer concentration increased the

hardness, mainly due to the polyvinylacetate component, which is a very plastic

material (Figure 17 – page 106).

Increasing the compression force from 1000lbs to 2000 lbs reduced the release

rate in water, but compression forces above 2000 lbs did not significantly change

the drug release profile f2>50 ( - , pages 106 - 109; Table 17

– page 110).

Figure 17 Figure 19

- 105 -

0

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Compression force (lbs)

Har

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P)

0% KSR10% KSR20% KSR30% KSR40% KSR50% KSR60% KSR

Figure 17. Effect of Kollidon® SR concentration and compression force on the hardness of buspirone 10mg tablets

- 106 -

Table 16. Physical properties of buspirone 10mg tablets

Compression Weight (mg) Thickness (mm) Hardness (kP)

Force Average RSD Average RSD Average RSD

0% KSR 1000lbs 160.74 0.995 3.102 0.204 4.41 5.286

2000lbs 160.20 1.196 2.811 0.615 9.15 4.349

3000lbs 160.73 0.855 2.748 0.537 11.27 5.751

10% KSR 1000lbs 158.40 0.710 3.037 0.222 7.12 8.551

2000lbs 162.51 0.551 2.919 0.441 11.71 2.744

3000lbs 162.24 0.844 2.863 0.595 13.86 2.102

20% KSR 1000lbs 161.08 0.901 3.127 0.905 11.00 4.791

2000lbs 161.22 0.584 2.996 0.322 12.56 11.624

3000lbs 158.39 0.563 2.914 0.289 14.94 2.913

30% KSR 1000lbs 159.31 1.358 3.218 0.353 9.80 5.931

2000lbs 161.10 0.482 3.101 0.238 15.16 3.381

3000lbs 162.22 0.735 3.083 0.485 18.44 2.387

40% KSR 1000lbs 161.82 0.720 3.588 0.729 8.08 5.887

2000lbs 160.03 0.374 3.194 0.219 17.63 2.593

3000lbs 157.94 1.477 3.128 0.795 18.07 5.250

50% KSR 1000lbs 158.77 0.463 3.621 0.087 9.07 2.801

2000lbs 160.86 0.544 3.314 0.432 20.87 3.873

3000lbs 159.14 1.082 3.262 0.853 21.70 4.334

60% KSR 1000lbs 161.47 0.714 3.739 0.320 12.02 2.280

2000lbs 158.90 0.843 3.376 0.348 22.14 2.998

3000lbs 156.03 0.69 3.325 0.622 21.73 5.079

- 107 -

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10% KSR - 1000lbs10% KSR - 2000lbs10% KSR - 3000lbs20% KSR - 1000lbs20% KSR - 2000lbs20% KSR - 3000lbs30% KSR - 1000lbs30% KSR - 2000lbs30% KSR - 3000lbs

Figure 18. Effect of compression force on drug release from buspirone 10mg tablets with 10 - 30% Kollidon® SR

- 108 -

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40% KSR - 1000lbs40% KSR - 2000lbs40% KSR - 3000lbs50% KSR - 1000lbs50% KSR - 2000lbs50% KSR - 3000lbs60% KSR - 1000lbs60% KSR - 2000lbs60% KSR - 3000lbs

Figure 19. Effect of compression force on drug release from buspirone 10mg tablets with 40 - 60% Kollidon® SR

- 109 -

Table 17. f2 values - effect of compression force on drug release from buspirone 10mg tablets

Formulation f2 value (2000 lbs – 3000 lbs)

30% Kollidon® SR 94.45




Consequently, further testing was carried out for tablets compressed at 2000 lbs.

By increasing Kollidon® SR concentration in the tablets, drug diffusion was

slowed down due to the lower porosity and higher tortuosity of the matrix.

Consequently, the drug release rate significantly decreased, prolonging the

release of the buspirone up to 24 hours (Figure 20 – page 111). A minimum

Kollidon® SR concentration of 30% was necessary in order to achieve a

coherent matrix and an extended drug release.

The release of drug dispersed in the matrix systems fitted the Higuchi model

(Table 18 – page 113), which denoted a diffusion-controlled mechanism (

– page 112).

Figure

21

- 110 -

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KSR 0%KSR10%KSR20%KSR30%KSR40%KSR50%KSR60%

Figure 20. Effect of Kollidon® SR on drug release from buspirone 10mg tablets

- 111 -

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30% KSR40% KSR50% KSR60% KSR

Figure 21. Effect of Kollidon® SR on diffusion controlled drug release from buspirone 10mg tablets

- 112 -

Table 18. Regression parameters of the diffusion drug release curves for buspirone 10mg tablets


30 32.702 -1.262 0.969

40 18.086 7.598 0.972

50 15.387 8.571 0.985

60 10.774 7.859 0.986 (Q=n*t1/2+l) aKollidon® SR as percentage of total tablet weight

4.2.2. Effect of dissolution medium on drug release from buspirone

10mg tablets

Although Kollidon® SR is a non-ionic polymer, buspirone release rate at each

polymer level in the three dissolution media varied (Table 19 – page 118); the

fastest release was obtained in 0.1N HCl and the slowest in pH 6.8 phosphate

buffer (Figure 22 - Figure 25, pages 114 - 117). This was attributed to the pH-

dependent solubility of buspirone, which is a basic drug (pKa1=4.12, pKa2=7.32).

It was concluded that although Kollidon® SR can promote a pH-independent

release, the drug release is also a function of drug solubility.

- 113 -

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0.1N HClwaterpH 6.8

Figure 22. Effect of dissolution medium on drug release from buspirone 10mg tablets with 30% Kollidon® SR

- 114 -

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- 115 -

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- 116 -

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0.1N HClwaterpH 6.8


- 117 -

Table 19. f2 values – effect of dissolution medium on drug release from buspirone 10mg tablets

Formulation f2 (0.1N HCl – water) f2 (pH 6.8 buffer – water)

30% Kollidon® SR 51.03 41.16

40% Kollidon® SR 48.50 44.31

50% Kollidon® SR 48.80 46.41

60% Kollidon® SR 47.24 57.04 (Q=n*t1/2+l) aKollidon® SR as percentage of total tablet weight

4.3. Propranolol 80mg tablets


properties and drug release from propranolol 80mg tablets

Previous results suggested a minimum Kollidon® SR concentration of 30% is

necessary for a coherent matrix, able to extend the drug release. Considering

this previous finding and the higher drug dose to be used (80mg) the minimum

concentration of Kollidon® SR for this set of experiments was 40%. Tablet

formulations with 80mg propranolol and 40-60% Kollidon® SR were evaluated

with regard to the robustness of the release to variations in compression forces,

which may occur during manufacturing. The resultant tablets were uniform in

weight, thickness and hardness, as shown in Table 20 – page 119.

- 118 -

Table 20. Effect of compression force and Kollidon® SR concentration on physical properties of propranolol 80mg tablets

Compression Weight (mg) Thickness (mm) Hardness (kP)

force Average RSD Average RSD Average RSD

40% KSR

1000lbs 222.62 0.800 5.075 0.104 5.79 8.824

2000lbs 223.40 0.534 4.761 0.459 10.62 4.587

3000lbs 223.92 0.797 4.576 0.537 16.80 5.383

50% KSR

1000lbs 222.77 0.325 5.339 0.399 6.12 8.035

2000lbs 223.08 0.905 4.820 0.366 16.28 5.005

3000lbs 223.02 0.726 4.722 0.676 20.12 4.036

60% KSR

1000lbs 224.07 1.196 5.616 0.172 5.53 11.690

2000lbs 224.62 1.198 4.941 0.544 18.90 5.918

3000lbs 222.97 0.842 4.873 0.774 21.27 5.323

A change in the drug release due to variation in the compression force during the

manufacturing process is a significant disadvantage. It is the formulator’s task to

assure that minor changes in the formulation and process variables that may

occur during the manufacturing process will not result in alteration of the product

performance.

- 119 -

For tablet formulations containing 40 - 60% Kollidon® SR, it was observed that

while changes in the compression forces from 1000 to 2000 lbs produced an

increase in tablet hardness ( – page 121) and a slight decrease in

dissolution rate (not significant according to the f2 similarity factor, Table 21 –

page 123), further increase to 3000 lbs did not affect the drug release profiles

(Figure 27 – page 122). Therefore a robust delivery system was attained at

compression force above 2000 lbs and this represented a definite advantage of

these formulations.

Figure 26

Increasing the Kollidon® SR concentration in the tablet led to an increase in

tablet hardness, as shown in Figure 26 – page 121.

Release profiles of the tablets that were formulated with 40-60% Kollidon® SR

and compressed under 2000 lbs are shown in Figure 28 – page 124. It was found

that the drug release was faster at 40% polymer levels, and further increase from

50 to 60% did not significantly change the release rate.

- 120 -

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Compression force (lbs)

Har

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Figure 26. Effect of Kollidon® SR and compression force on the hardness of propranolol 80mg tablets

- 121 -

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40% KSR 1000lbs40% KSR 2000lbs40% KSR3000lbs50% KSR 1000lbs50% KSR 2000lbs50% KSR 3000lbs60% KSR 1000lbs60% KSR 2000lbs60% KSR 3000lbs

Figure 27. Effect of Kollidon® SR and compression force on drug release in water from propranolol 80mg tablets

- 122 -

Table 21. f2 values – effect of compression force on drug release from propranolol 80mg tablets

Formulation f2 (1000lbs – 2000lbs) f2 (2000lbs – 3000 lbs)

40% Kollidon® SR 53.24 57.91

50% Kollidon® SR 44.96 86.19

60% Kollidon® SR 40.92 84.72

The release was diffusion controlled (Higuchi mechanism) as confirmed by the

data presented in Table 22 – page 125. When porous hydrophobic polymers

drug delivery systems are placed in contact with a dissolution medium, the

release of the drug must be preceded by the drug dissolution in water filled pores

and by diffusion through the water filled channels. The geometry and the

structure of the pore network are important to the drug release process (Gurny et

al., 1982). The insoluble polyvinylacetate component of the Kollidon® SR is

considered to give a coherent matrix in which the drug is dispersed and the

release occurred by diffusion through the pore formed by gradually dissolving

povidone. Consequently, the release rate is dependent on the porosity and

tortuosity of the tablets. At lower polymer levels, the diffusion occurred faster due

to lower porosity of the matrix, while increasing the polymer concentration led to

a slower release until the matrix achieved its maximum tortuosity and minimum

porosity. All the tablets remained intact during the 24-hour dissolution test.

- 123 -

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Figure 28. Effect of Kollidon® SR on diffusion controlled drug release from propranolol 80mg tablets

- 124 -

Table 22. Regression parameters of the diffusion drug release curves in water from propranolol 80mg tablets

Kollidon® SR %* Slope (n) Intercept (l) r2

40 49.336 1.7028 0.998

50 33.329 3.3383 0.995

60 32.245 2.4016 0.997 (Q=n*t1/2+l) aKollidon® SR as percentage of total tablet weight


80mg tablets

Drug release from matrix systems is influenced by the aqueous solubility of the

drug and matrix behavior at different pH. Propranolol has a pKa=9.5 (Avdeef et

al., 2000) and an acceptable solubility over the physiologic pH range: 220 mg/ml

in 0.1 N HCl and 254 mg/ml in pH 7.4 phosphate buffer (Siepmann and Kranz,

2000). Kollidon® SR contains no ionic groups and is therefore inert to drug

substances and pH of the dissolution medium. The release rates at every

polymer level were virtually pH independent, as confirmed by the almost super-

imposable release curves in pH 6.8 buffer and 0.1N HCl ( – page 126)

and f2 values greater that 50 (66.51, 73.38 and 64.95 for Kollidon® SR 40%,

50% and respectively 60%). This confirmed the findings in case of propranolol

10mg tablets, regarding the ability of Kollidon® SR to provide a pH-independent

release, depending on the drug solubility (Draganoiu et al., 2001).

Figure 29

- 125 -

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40% KSR 0.1N HCl40% KSR pH 6.850% KSR 0.1N HCl50% KSR pH 6.860% KSR 0.1N HCl60% KSR pH 6.8

Figure 29. Effect of dissolution medium on drug release from propranolol 80mg tablets

- 126 -

4.3.3. Effect of Kollidon® SR – Eudragit® L100-55 combination on

drug release from propranolol 80mg tablets

Addition of an anionic polymer to matrix tablets is a widely used approach to

modulate the drug release and /or to promote a pH independent release

(Streubel et al., 2000). In acidic medium, the enteric polymer is insoluble and

acts as a part of the matrix thus contributes to the retardation of the drug release.

In buffer media, the enteric polymer dissolves and loosens the matrix structure,

thus increasing the porosity and permeability of the dosage form and

compensating for the reduction in the diffusion rate.

The effect of partial replacement (5 or 10% of the tablet weight) of Kollidon® SR

with Eudragit® L100-55, while keeping constant the total matrix forming agent

concentration (70% of the tablet weight) was investigated.

Eudragit® L100-55 is a methacrylic acid copolymer insoluble at pH below 5.5. As

expected, the release rates in water and 0.1N HCl were slightly reduced (

– page 129, – page 130). This was because Eudragit® L100-55 is

insoluble in water or 0.1N HCl, so it acted as a diffusion barrier.

Figure

30 Figure 31

Surprisingly, the same phenomenon was observed in pH 6.8 buffer (Figure 32 –

page 131). Possible explanations reside in a hindered dissolution of the enteric

polymer due to the polyvinylacetate network (Streubel et al., 2000) and also in

cationic drug - anionic polymer interaction (Takka et al., 2001, Streubel et al.,

2000, Chang and Bodmeier, 1997, Feely and Davis, 1988).

- 127 -

A 48-hour dissolution test was performed in distilled water for the formulation

containing 70% Kollidon® SR to verify the hypothesis that the non-released

propranol at the end of the first 24 hours was still present in the matrix. 100% of

the label claim was released at the end of the 48-hour interval, compared to 7%

released after 24 hours and thus confirming the hypothesis.

- 128 -

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70%KSR

65%KSR+ 5%Eudragit

60%KSR+ 10%Eudragit

Figure 30. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in water from propranolol 80mg tablets

- 129 -

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70%KSR

65%KSR+ 5%Eudragit

60%KSR+ 10%Eudragit

Figure 31. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in 0.1N HCl from propranolol 80mg tablets

- 130 -

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70%KSR

65%KSR+ 5%Eudragit

60%KSR+ 10%Eudragit

Figure 32. Effect of Kollidon® SR and Eudragit® L100-55 combination on drug release in pH 6.8 buffer from propranolol 80mg tablets

- 131 -

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Figure 33. Propranolol release in water over 48 hours from tablets manufactured with 70% Kollidon® SR

- 132 -

4.3.4. Comparison of the propranolol 80 mg tablet formulations with

the reference listed capsule product

Currently all extended release propranolol products available in the United States

are capsules and Inderal® LA is the reference listed product (RLD, innovator).

The product is formulated as capsules containing coated pellets. Although the

condition for pharmaceutical equivalence is not met (due to difference in dosage

forms capsules versus tablets), Inderal® LA was used as reference product in

developing matrix tablet formulations.

By evaluating the release profiles obtained according to the USP dissolution

method (method B – section 3.5, page 65) for propranolol 80mg tablets with 60

and 70% Kollidon® SR and the reference listed capsule product (Figure 34 –

page 134), it was found that the initial release was faster for the tablets than for

the capsules, while at the later dissolution stages the release profile for the

innovator product was intermediate to the tablet profiles. Thus, it was decided to

formulate and manufacture tablets using an intermediate polymer level (65%)

and this formulation was used in the pilot bioequivalence study.

- 133 -

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70%KSR60%KSRInderal LA

Figure 34. Comparison of drug release from propranolol 80 mg tablets with 60 and 70% Kollidon® SR and Inderal® LA

- 134 -

The composition of the selected formulation (65% Kollidon® SR) is presented in

– page 135. Table 23

Table 23. Composition of the propranolol 80mg tablets formulation used in the pilot bioequivalence study

Ingredient Manufacturer / Lot # Amount (mg) / tablet

Percent / tablet

Propranolol HCl (BP) BASF C20011001 80.000 29.0

Kollidon® SR BASF16-9006 179.309 65.0

Emcompress® Penwest A20E 6.8965 2.5

Emcocel® 90M Penwest 9D5H1 6.8965 2.5

Aerosil® 200 DegussaD10221D 1.3793 0.5

Magnesium stearate Malinckrodt C19408 1.3793 0.5

Total 275.86 100.0 *all the materials were certified by the manufacturers for human use.

An example of the compression and ejection forces recorded during the

manufacturing is shown in Figure 35 - page136.

- 135 -

Compression Force [lb] Average: 1967.17 lb St. Dev. 113.87 lb Rel. SD 5.79 %

1967.17 1934.57 1901.96 2108.46 2206.28 1978.04 1858.49 1880.23 1847.62 1988.91

Ejection Force [lb] Average 111.95 lb

St. Dev. 3.03 lb Rel. SD. 2.71 %

115.02 115.02 109.97 108.11 116.22 114.75 111.16 111.30 108.64 109.30

Figure 35. Compression and ejection forces recorded during manufacturing

of propranolol 80 mg tablets with 65% Kollidon® SR

- 136 -

The resulting tablets were uniform in weight, thickness and hardness and passed

the USP criteria for the Content Uniformity (Table 24 – page 137).

Table 24. Characteristics of propranolol 80mg tablets used in the pilot bioequivalence study

Characteristics Average RSD

Tablet weight (mg) 277.91 0.861

Tablet thickness (mm) 4.884 0.308

Tablet hardness (kP) 14.12 4.847

Content uniformity 95.194 2.534

Compared to the reference-listed product, the drug release from the matrix

tablets was faster in the initial stage (Figure 36 – page 138). This can be

attributed to differences in the formulation and release mechanism

(multiparticulate versus monolithic system). The burst effect observed with the

tablets could be explained by the propranolol trapped on the surface of the matrix

and released immediately upon activation in the dissolution medium. This is a

common reported phenomenon for matrix systems (Krajacic and Tucker, 2003,

Huang and Brazel, 2001, Bodea and Leucuta, 1997). During the buffer stage, the

developed product met the USP requirements for propranolol release (Table 25 –

page 139) and was similar to the innovator product, as determined with the

similarity factor (f2=60.60).

- 137 -

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Figure 36. Comparison of the drug release profiles from propranolol 80mg tablets with 65% Kollidon® SR and Inderal® LA

- 138 -

Table 25. Drug release from the propranolol 80 mg tablets with 65% Kollidon® SR (used for the pilot bioequivalence study)

Time (hr) Propranolol 80mg tablets

(65% Kollidon® SR)

USP requirements

1.5 32.69% NMT 30%

4 49.64% 35-60%

8 63.23% 55-80%

14 77.74% 70-95%

24 91.22% 81-110%

The formulation was robust and reproducible, as shown by the drug release

profiles from batches manufactured on different days (Figure 37 – page 140).

This formulation was used in the pilot bioequivalence study and was tested for

stability of the dissolution profiles under different storage conditions.

- 139 -

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batch 1batch 2batch 3

Figure 37. Reproducibility of propranolol 80 mg tablets formulation with 65% Kollidon® SR

- 140 -

4.3.5. Effect of storage conditions on propranolol 80 mg tablets

physical properties and drug release

Propranolol 80 mg tablets with 65% Kollidon® SR were tested to see the effect of

storage conditions (long term or accelerated ICH testing conditions) on tablet

physical properties and drug release (method B – section 3.5, page 65).

No change in the dissolution profile was observed for tablets stored under long-

term stability conditions for a period of up to nine months. A change in the

dissolution profile was observed for tablets stored at 40°C/75% RH for more than

3 months. The reduction in the dissolution rate continued after six months, the

time period recommended for conducting accelerated stability studies; it was also

observed at nine months testing point. The change in the dissolution profile

observed just in case of the tablets stored under accelerated conditions could be

attributed to the amorphous nature of polyvinylacetate coupled with its unusually

low glass transition temperature of 28–31°C, which imparts certain unique

characteristics to the matrix. Such a change in dissolution profile is usually

indicative of polymer structural relaxation. These results are in agreement with

published data. Shao et al. (2001) observed a reduction in the dissolution rate for

the diphenhydramine - Kollidon® SR formulation stored at 40°C/75%RH, as a

result of polyvinylacetate relaxation. A post-compression curing step (1-18 hours

at 60°C) was found to be critical in stabilizing the release rates of tablets

containing high levels (≥47 %w/w) of Kollidon® SR.

- 141 -

The change in the dissolution rate of propranolol tablets was accompanied by an

increase in tablet hardness. The increase in hardness was significantly higher for

accelerated conditions compared to the long term conditions (p<0.05), as seen in

– page 142. Tablets stored under accelerated conditions became

yellow after 6 months storage.

Table 26

Table 26. Effect of storage on the hardness of propranolol 80 mg tablets

Time 25°C/60%RH 40°C/75%RH

Initial 14.12±0.68 14.12±0.68

1 month 15.54±0.43 20.06±0.46 * **

3 months 16.39±0.99 * 21.06±0.70 * **

6 months 16.57±0.63 * 29.51±0.32 * **

9 months 16.97±0.59 * ND

(*) significantly different from the initial at 0.05 level (Tukey procedure) (**) significantly different from the long term conditions at 0.05 level (Tukey procedure) ND – could not be determined (above the hardness tester maximum capacity); tablets were plastically deformed.

- 142 -

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initial1 month3 months6 months9 months

Figure 38. Effect of storage on drug release from propranolol 80 mg tablets – ICH long term stability conditions

- 143 -

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Figure 39. Effect of storage on drug release from propranolol 80 mg tablets – ICH accelerated stability conditions

- 144 -

4.4. Evaluation of bioequivalence of propranolol 80 mg matrix

tablets to Inderal® LA capsules

4.4.1. Analysis of propranolol in plasma

The calibration curves generated by plotting the ratio of areas of propranolol to

internal standard (pronethalol) versus concentration ratio of the two components

were linear over the concentration range of 2 - 100ng/ml, (correlation coefficient

> 0.99).

Accuracy calculated as percentage of measured (recovered) concentration to

theoretical values for three concentrations within the linearity range (2, 20,

100ng/ml) was in the range of 89-115%.

The intra- and inter-day variability determined by using three replicate analyses

of spiked plasma at three different concentrations (2, 20, 100ng/ml) were 9.60,

6.29, 3.94%, respectively 10.46, 6.68, 2.82%.

4.4.2. Subjects monitoring during the pilot bioequivalence study

Subjects enrolled in the study had their body weight recorded each period and

their vital signs were monitored at each blood drawing (Appendix 2 – page 197).

It was found that at each time point the treatment effects on blood pressure and

pulse rate were not significant (p>0.05), as tested by one-way ANOVA

procedure. No significant adverse effects were reported during and post - study.

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4.4.3. Pharmacokinetic and statistical analysis

Based on FDA recommendation for assessing the bioequivalence for a

previously approved molecular entity, a cross-over single dose non-replicate

fasting study was performed for propranolol 80mg developed tablets and the

reference listed product Inderal® LA (FDA, 2002). The single dose study is

considered to be more sensitive in addressing the primary question of

bioequivalence, i.e. release of the drug substance from the product into the

systemic circulation. The multiple dose study is not recommended by the FDA

even in the instances where nonlinear kinetics is present. The parent drug

propranolol was measured in plasma (rather than the metabolites) because the

concentration-time profile of the parent drug is more sensitive to changes in

formulation performance than a metabolite, which is more reflective of metabolite

formation, distribution and elimination (FDA, 2002).

Propranolol plasma concentrations obtained after administration of the developed

matrix tablets and Inderal® LA are graphically displayed for each subject in

Figure 40 - Figure 47, pages 147 - 154. The mean results are shown in Figure 48

page 155.

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0

10

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0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30time (hr)

Prop

rano

lol (

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Inderal LA 80mg

Propranolol 80mg tablets

Figure 40. Plasma levels of propranolol following administration – subject #1

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0

5

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15

20

25

30

35

40

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30time (hr)

Prop

rano

lol (

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l)Propranolol 80 mg tablets

Inderal LA 80 mg

Figure 48. Plasma levels of propranolol following administration (mean ± SEM)

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A good agreement was found between the in vitro drug release and propranolol

plasma concentration for the first twelve hours post-dosing, as may be seen in

– page 86 and Figure 48 – page 155. The developed matrix tablets

which had faster initial release produced higher plasma concentrations compared

to the reference listed product. The difference in plasma concentrations was

significant at 2, 3, 4 and 5 hours post dosing (P<0.05). These results confirm

those of McAinsh et al. (1981) who reported for different extended release

propranolol formulations that the peak blood level and AUC decreased as the

dissolution was slower. McAinsh et al. (1981) explained the lowering of the

systemic bioavailability as the dissolution time increases by an increased

metabolism of propranolol.

The calculated AUC0-24h, AUC0-∞ and Cmax for each subject are presented in

Table 27 – page 157.

Testing the AUC0-24h, AUC 0-∞ and Cmax by non-parametric Wilcoxon two-

sample test – NPAR1WAY procedure for variable SUM, showed no significant

carry over (residual) effect (p= p=0.8852, p=0.8852 and p=1.000 respectively).

Testing for period effect by Wilcoxon two-sample test – NPAR1WAY procedure

for variable XOVERDIF proved that the period did not significantly affect the

responses, i.e. AUC 0-24h, AUC 0-∞ and Cmax (p=0.6650, p=1.000, respectively

p=0.3123).

Figure 5

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Table 27. Pharmacokinetic parameters after administration of propranolol 80mg tablets and Inderal® LA 80mg

Subject Propranolol 80mg tablets Inderal® LA

AUC 0-24h AUC 0-∞ Cmax AUC 0-24h AUC 0-∞ Cmax

1 210.91 239.21 18.47 187.00 467.26 17.99

2 284.84 346.27 20.59 257.78 495.71 19.28

3 393.99 404.06 66.92 358.41 694.92 28.09

4 398.29 433.93 28.75 166.35 259.14 10.91

5 241.12 251.82 23.89 237.32 1659.82 15.98

6 812.39 1064.99 54.94 360.21 900.28 33.24

7 604.80 830.07 74.30 677.34 880.97 50.45

8 502.18 830.90 62.76 315.18 659.68 20.36

Analysis of variance was carried out to test for the treatment effect. The

treatment effect was not significant with regard to AUC 0-24h and 0-∞ (p=0.1070,

p=0.3094) at a 5% level of significance. Tablets and capsules produced similar

24 hour- and total drug exposure. Analysis of Cmax showed significant difference

between the two treatments at a 5% level of significance (p=0.0107).

According to the FDA two products are considered bioequivalent if the 90%

confidence interval for the ratio of the averages (population geometric means) of

the measures for the test and reference (Cmax, AUC) falls within a BE limit,

usually 80-125% for the ratio of the product averages (FDA 2001). By applying

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this criterion, the two products tested (propranolol 80mg matrix tablets and

Inderal® LA) were not bioequivalent with regards to Cmax, AUC0-24h, AUC 0-∞

(Table 28 – page 158). The tablets produced higher Cmax and 24-hour drug

exposure than the capsules.

Table 28. Results of the bioequivalence testing using WinNonlin software Cmax AUC 0-24h AUC 0-∞

Probab. < 80 0.1317 0.0296 0.8465

Probab. > 125 0.8674 0.9677 0.1530

Maxim probability 0.8674 0.9677 0.8465

Total probability 0.9991 0.9974 0.9995

AH p value 0.7357 0.9381 0.6934

Power 0.0999 0.1 0.0999

Thus, Cmax was higher for the tablets than the capsules as tested by both

ANOVA and FDA criterion for bioequivalence. Testing by ANOVA for the area

under the curve did not show a significant treatment effect, while testing

according to the FDA criterion revealed that the two products were not

bioequivalent. This difference in results could be explained by the high variability

of propranolol plasma concentration and the reduced number of subjects

included in the pilot study. The variability of propranolol plasma concentrations is

known to be due to the high intersubject variability in the hepatic metabolism of

the drug (Bottini et al., 1983, Flouvat et al., 1989, Lalonde et al., 1987, Perucca

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et al., 1984). As the study could not be performed on a larger number of subjects

because of the limited resources, it was designated as a pilot study. Similar

sample size (6-9 subjects) was used in other studies on the bioavailability /

bioequivalence of propranolol extended release formulations (Bottini et al., 1983,

Lalonde et al., 1987, Perucca et al., 1984, Rekhi et al., 1996). To account for the

variability, a non-parametric test was used for the analysis of variance.

It is concluded that according to the FDA criteria the two products were not

bioequivalent and the tablets had higher bioavailability as shown by Cmax and

AUC 0-24h than the capsules. This conclusion applies for the mean results and

for each subject. The initial faster release observed in vitro in case of the

developed matrix tablets was reflected in vivo by the higher plasma

concentrations for up to 12 hours (statistically significant for up to 5 hours).

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5. Conclusions

A minimum concentration of 30% polymer was necessary to achieve a coherent

matrix, able to extend the release of the incorporated drugs. Increasing the

Kollidon® SR concentration in the tablet led to an increase in the tablet hardness

and a slower drug release. Drug release followed square root of time dependent

kinetics, thus indicating a diffusion-controlled release mechanism. Although

Kollidon® SR promoted pH-independent drug release, the drug release was

dependent on the solubility at various pHs.

The drug release rate was faster for wet granulation than for direct compression,

thus making direct compression the method of choice for manufacturing

Kollidon® SR extended release systems.

Kollidon® SR was the main release controlling agent in the presence of an

external binder or enteric polymer in the matrix.

A significant reduction in the dissolution rates associated with an increase in

tablet hardness was observed during stability testing under accelerated

conditions, but not under long term conditions. Based on this finding, the

recommended storage conditions are at 25°C / 60%RH or lower.

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The developed propranolol 80mg extended release formulation was found to

have higher bioavailability than the reference listed product capsules, as shown

by higher Cmax and AUC 0-24h. For the developed tablet formulation, the higher

initial plasma concentration was correlated with the faster initial release observed

in vitro. Thus, according to the FDA bioequivalence criteria, the two products

were not bioequivalent.

Based on the above, it is concluded that Kollidon® SR is a potentially useful

excipient for the production of pH-independent extended release matrix tablets.

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Streubel, A., Siepmann, J., Dashevsky, A., Bodmeier, R., 2000. pH independent release of a weakly basic drug from water insoluble and soluble matrix tablets. J. Contr. Rel. 67, 101-110.

Sung, K.C., Nixon, P.R., Skoug, J.W., Ju, T.R., Patel, M.V., et al., 1996. Effect of formulation variables on drug and polymer release from HPMC-based matrix tablets. Int. J. Pharm. 142, 53-60.

Takacs-Novak, K., Avdeef, A., 1996. Interlaboratory study of log P determination by shake-flask and potentiometric methods J. Pharm Biomed Anal. 14, 1405-13.

Takahashi, H., Ogata, H., Warabioka, R., Kashiwada, K., Someya, K., et al. 1990. Decreased absorption as a possible cause for the lower bioavailability of a sustained-release propranolol. J. Pharm. Sci. 79, 212-215.

Takka, S., Rajbhandari, S., Sakr, A., 2001. Effect of anionic polymerws on the release of propranolol hydrochloride from matrix tablets. Eur. J. Pharm. Biopharm. 52, 75-82.

United States Pharmacopeia&National Formulary 25th Ed. The United States Pharmacopeial Convention Inc., 2002.

Upadrashta, S.M., Katikaneni, P.R., Hileman, G.A., Keshary, P.R., 1993. Direct compression controlled release tablets using ethylcellulose matrices. Drug Dev. Ind. Pharm. 19, 449-460.

US Patent 4, 138, 475.

US Patent 6, 066, 334.

Velasco, M.V., Ford, J.L., Rowe, P., Rajabi-Siahboomi, A.R., 1999. Influence of

compression force on the release of diclofenac sodium from HPMC tablets. J. Contr. Rel. 57, 75-85.

Venkatraman, S., Davar, N., Chester, A., Kleiner, L., 2000. An Overview of Controlled-Release Systems in Handbook of Pharmaceutical Controlled Release Technology (Wise, D. L. Edt), Marcel Dekker Inc.

Walle, T., Walle, U.K., Olanoff, L.S., Conradi, E.C., 1986. Partial metabolic clearances as determinants of the oral bioavailability of propranolol. Br. J. Clin. Pharm. 22, 317-323.

Wan, L.S., Heng, P.W., Wong, L.F., 1995. Matrix swelling: simple model describing extent of swelling of HPMC matrices. Int. J. Pharm. 116, 159-168.

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7. Appendix 1

Study of the Bioavailability of Two Extended Release Propranolol HCl

Dosage Forms – Research Protocol # 06-19-01

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Research Protocol - page 1

To:

UCMC Institutional Review Board Chairperson

From:

Principal Investigator Bernadette D’Souza, M.D. Associate Director of Clinical Affairs, Associate Professor

[email protected] Phone (513) 475-6326 Fax (513) 475-6379 Mail Location 116A Department of Veterans Affairs, Medical Center Mental Health Care Line 3200 Vine Street, Cincinnati OH 45220

Coinvestigators: Adel Sakr, Ph.D., Professor & Director, Industrial Pharmacy

Graduate Program, College of Pharmacy, University of Cincinnati Thomas Geracioti, Jr., M.D., Associate Professor and Vice Chair, Department of Psychiatry, College of Medicine, University of Cincinnati Elena Draganoiu, Graduate Student, Industrial Pharmacy Graduate Program, College of Pharmacy, University of Cincinnati

Study of the Bioavailability of Two Extended Release Propranolol HCl Dosage Forms

Department Chair Approval: Daniel Acosta Jr., Ph.D. Dean College of Pharmacy

06/11/2001 Revised 11/07/01

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RESEARCH PROTOCOL

OUTLINE A. Specific aims 3 B. Significance 3

Background Information 4 C. Preliminary Studies 7 D. Experimental Design and Methods 9

1. Subjects 9 a. Criteria for subject selection 9

Inclusion Criteria 9 Exclusion Criteria 9

b. Screening examinations 10 2. Source of subject population 10 3. Research Protocol 11

a. Methodology 11 • Study design 11 • Products studied 11 • Drug assignment 11 • Study visits 12 • Screening 12 • Study test days 12 • Drug administration 12 • Blood samples 13 • Meals and food restrictions 13 • Subject monitoring 13

b. Analysis 14 • Method of analysis 14 • Pharmacokinetic and statistical analysis 14

c. Setting and laboratory facilities 14 E. Human subjects 15

1. Recruitment 15 2. Risks and benefits 15 3. Payment 15 4. Subject costs 15 5. Consent form 15

F. Estimated period of time to complete the study 16 Study schedule 16

G. Funding 16 H. References 17 J. Consent form 19

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RESEARCH PROTOCOL

A. Specific aims As part of a Ph.D. Dissertation Research (E. Draganoiu – College of Pharmacy,

University of Cincinnati), a systematic pharmaceutical technology research

resulted into an in vitro extended release tablet formulation for Propranolol HCl.

The specific aim of this protocol is to compare the bioavailability of the developed

Propranolol HCl extended release (ER) tablets with the leading commercial

brand in the US market.

This will validate and complete the research objectives of the Ph.D. Dissertation

of E. Draganoiu.

B. Significance All the Propranolol extended release formulations currently in use are hard

gelatin capsules, containing small spheroids each containing Propranolol

hydrochloride dispersed in an insoluble matrix. The drug containing spheroids

are in turn coated with a semipermeable membrane, which allow drug to diffuse

at a controlled rate.

This study is an attempt to formulate and deliver Propranolol as directly

compressed extended release tablets. The drug is homogenously dispersed

through the Polyvinylacetate-Povidone matrix and the drug release follows the

diffusional mechanism (Jantzen, Robinson 1996, Draganoiu et al, 2001).

Compared to capsule manufacturing (spheronization followed by coating) the

tablet manufacturing technology by direct compression is easier and more

efficient. The in vitro dissolution test conducted for tablet in different media

should provide an extended release of the drug over 24 hours.

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Research Protocol - page 4 Background Information Propranolol is almost completely absorbed from the gastrointestinal tract, but it is subjected to an extensive and highly variable hepatic first pass metabolism, with a reported systemic bioavailability between 15 and 23% (Cid et al, 1986, Walle et al, 1986). Peak effect occurs after 1-2 hours and can vary up to seven fold after oral administration due to individual variations in hepatic metabolic activity (Shand et al, 1970). The biologic half-life is approximately four hours. Due to relatively short plasma half-life, Propranolol conventional tablets are administrated at 6 to 8 hours intervals. Such frequent drug administration may reduce patient compliance and thus therapeutic efficacy (Serlin et al, 1983). Several sustained release systems have been developed in order to enable daily administration of the drug and a 24 hours maintained beta-adrenoceptor blockade. Propranolol extended release systems should fulfill two objectives. Firstly to achieve an effective plasma concentration through the dosing interval, while avoiding potentially toxic peak concentration or ineffective plasma concentration that might occur with conventional formulations and secondly to produce a pharmacological effect as effective, at least, as the conventional drug given at more frequent dosing interval. Different formulations have been tested in vitro and in vivo in comparison to conventional tablets for these claims. (Serlin et al, 1983) However there are some problems associated with Propranolol ER formulations. Besides the variable Propranolol bioavailability (first pass degradation, influence of food, ethnic factor, other medication), ER formulations exhibit a significantly lower systemic bioavailability than the conventional tablets. This is due to a slower absorption and higher first pass effect. Pharmacokinetic Properties of Propranolol (Frishman and Jorde, 2000) Formulation Extent of

absorption (%of dose)

Bioavailability (%of dose)

Interpatient variation in plasma level

β-Blocking plasma concentration

Protein binding (%)

Immediate release

>90% 30 20 fold 50-100ng/ml 93

Extended release

>90% 20 10-20 fold 20-100ng/ml 93

In a crossover single oral dose study (Takahashi et al, 1990) on healthy subjects who received 60 mg Propranolol as sustained release capsules (Inderal LA) or as conventional tablets, significant differences (parallel decreases for Inderal LA release compared to conventional tablets) were observed in area under the curve of Propranolol hydrochloride, Propranolol glucuronide and naphtoxylactic acid and in the amounts of all metabolites excreted in urine. Therefore it was

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Research Protocol - page 5 concluded that the hepatic metabolism of Propranolol would not be affected by the slower absorption at a single dose of 60mg. Bioavailability of a 160mg slow release formulation following single dose administration was about one third that of the conventional preparation (Drummer et al, 1981) Garg et al (1987) showed that for two Propranolol long-acting formulation (80mg and 160mg) the area under the curve and the peak concentration were significantly less compared to the conventional tablets; in addition the elimination half-life was longer (9 hours) than for conventional Propranolol (4hours). In a crossover study on healthy subjects with Propranolol 160mg daily for 7 days mean bioavailability of sustained release capsules relative to regular tablet formulation was 52% for single doses and 54% for steady state (Straka et al, 1987). For one-day therapy with sustained release Duranol capsules (single dose in the morning) and Inderal conventional formulation (two doses morning and evening) it was found that the relative bioavailabilities were similar despite prolonged absorption time for the sustained action capsules (Bottini et al, 1983) In a study with sustained release Propranolol (Elanol 120mg, Inderal LA 160mg) and conventional Inderal (40mgx3/day) single doses of controlled release preparations produced a smoother serum level profile with lower and delayed peak times (dose corrected AUC lower for Inderal LA than for Elanol). At steady state all regimen ensured relatively sustained serum levels and a stable degree of pharmacological effect. Dose corrected AUC decreased in order Elanol>Inderal>Inderal LA. These results demonstrated that long acting formulations of Propranolol can be developed which are not necessarily associated with reduced bioavailability secondary to enhanced first pass metabolism (Perucca et al, 1984). The bioavailability of Inderal LA (80, 160 and 240mg once daily for 4 days) was proportional to the dose administrated as sustained action capsules. Steady state was attained after 2 doses. (Dvornik et al, 1983) For two different sustained release formulations (Dociton retard and Propranolol 160 Stada) there were found analogous associations between in vitro and in vivo dissolution after 4 hours (Moller, 1983). For different sustained release formulation, the peak blood level and AUC decrease as the dissolution time increase; the half-life are inversely proportional to the dissolution rate. The lowering of the systemic bioavailability as the dissolution time increases is thought to be due to an increased metabolism of Propranolol (McAinsh et al, 1981)

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Research Protocol - page 6 An attempt to develop plastic matrix tablets was done in 1974 by Grundy et al. The matrix consisted on Propranolol 125 mg embedded in an insoluble matrix of Pevikon D-42-P (polyvinyl chloride, 273 mg). The formulation had a satisfactory in vitro release profile (50% of the dose in 3 hours, at 100rpm). However when administered in dogs, the in vivo release profile was unsatisfactory (the drug was not completely released from the matrix) (Grundy et al, 1974). Single entity extended release formulations of Propranolol were therefore abandoned in favor of multiparticulate systems. *Sustained release, Extended release, Controlled release, Long-acting forms are alternative terms used by various researchers to describe the modified release dosage forms (excluding delayed release).

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C. Preliminary Studies

The dissolution test is the best in vitro predictor for in vivo product performance. Among the dissolution test specifications, the dissolution profile comparison seems to be more precise than single point estimate approach to characterize the drug product (O’Hara et al, 1998). For extended release formulation FDA recommends that the dissolution profile should be evaluated by using a multipoint profile, with adequate sampling at different time points (for example at 1, 2 and 4 hours and every two hours after, until either 80% of the drug is release or an asymptote is reached). The regulatory accepted method for comparison of the dissolution profiles is a model independent mathematical approach described by Moore and Flanner (1996), which is know as f2 (similarity factor) equation.

}])TtRt()n/(log{[fn

t

. 100115021

502 ⋅−+⋅= ∑=

−

Where Rt and Tt are the cumulative percentage dissolved at each of the selected

n time points of the reference and test product respectively. Factor f2 is inversely proportional to the average squared difference between the

two profiles, with emphasis on the larger difference among all the time-points. The transformation is such that the f2 equation takes values less or equal to 100.

The value of f2 is 100 when the test and reference mean profiles are identical. The factor f2 measures the closeness between the two profiles.

When the two profiles are identical, f2=100. An average difference of 10% at all measured time points results in an f2 value of 50 (Shah et al, 1998). FDA has set a public standard of f2 value between 50-100 to indicate similarity between two dissolution profiles. In vitro release data of the Propranolol tablets and reference Inderal LA capsules in different media (0.1N HCl and pH 6.8 buffer) are shown.

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0

10

20

30

40

50

60

70

80

90

100

110

0 2 4 6 8 10 12 14 16 18 20 22 24

Inderal LA cps 0.1N HClInderal LA cps pH 6.8Propranolol Tb 0.1N HClPropranolol Tb pH 6.8

Propranolol release from Inderal LA cps and Propranolol Tb

The dissolution profiles in 0.1N HCl for the two formulations are almost super imposable. The similarity is confirmed by f2 values at all tested points greater than 50. In case of using pH 6.8 USP phosphate buffer as dissolution medium, the dissolution profiles meet the FDA criteria for similarity (f2 values greater than 50 at all tested points). For the developed tablet formulation the release is slighter slower than for the marketed product. This difference of in vitro release should be tested for in vivo significance, knowing that in some cases formulation with significantly different in vitro release rates exhibit equal bioavailability (Sakr, Andheria 2001)

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D. Experimental Design and Methods

1. Subjects

A total number of 8 subjects capable of giving informed consent will be studied.

Subjects will be healthy male and female volunteers and will be studied as

outpatients. All samples from all subjects will be analyzed.

Informed consent written will be obtained from each subject prior to entry into the

study.

Criteria for subject selection

Inclusion Criteria

• Healthy, male and female subjects between the ages of 18 – 65 years

inclusive

• Subjects must be outpatients at the time of screening

• Subjects must be on no chronic medications (prescription or OTC) and must

be medication-free for a period of at least one week prior to the first test day

and throughout the duration of the study

• Subjects must be off any investigational drug for a period of at least 3 months

prior to the entry in the study

• Subjects must be in good health as determined by medical history, routine

physical examination, ECG and clinical laboratory tests

• Subjects must be free of significant psychiatric illness

• Subjects must be willing and able to provide written informed consent.

Exclusion Criteria

• Subjects with a history or evidence of clinically significant and currently

relevant hematological, renal, hepatic, gastrointestinal, endocrine, pulmonary,

dermatological, oncological or neurological illness, and alcoholism.

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Research Protocol - page 10 • Subjects with a history of cardiovascular disease, including hypotension,

hypertension, heat block, congestive heart failure, angina pectoris, bypass

surgery, or myocardial infarction

• Subjects with clinically significant abnormalities on the electrocardiogram at

screening

• Pregnant and breast-feeding women are not eligible

• Subjects using concomitant drugs

• Subjects with known allergy to Propranolol

• Subjects with clinically significant emotional problems

• Subjects unable and/or unlikely to comprehend and follow the study protocol

Screening examinations: Routine physical examination and medical history Safety examination – ECG before the treatment, blood pressure, pulse and temperature Laboratory examination – complete blood count with differential, hepatic and renal profiles 2. Source of subject population Normal healthy volunteers who meet all inclusion criteria.

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Research Protocol - page 11 3. Research Protocol a. Methodology

Study design

This study will be a cross-over single-dose two-period open-label study which will

compare the absorption of Propranolol from two dosage forms: Propranolol 80mg

extended release capsules (InderalLA) and Propranolol 80mg extended release

tablets, administrated oral, under fasting conditions.

Subjects will undergo a screening procedure 2-6 days prior to the first test day. If

all inclusion and exclusion criteria are met, subjects will be randomized to one of

the two dosing sequence. Subjects will report to the outpatient facility in the

morning of the first day of each period and will receive a single dose of the drug

(capsule or tablet).

Products studied

A) Propranolol ER tablet formulation - test product (Industrial Pharmacy

Laboratory, UC)

B) Propranolol ER capsule formulation – reference product (Inderal LA,

Manufacturer Ayerst Laboratories Inc., lot # 9010268, expiration date 07/2003)

Drug Assignment: The subjects will be assigned to two dosing sequence as

follows:

Period 1 Period 2

4 subjects A B

4 subjects B A

The administration sequence will be assigned randomly.

Subjects will be monitored for 30 hours after each dose. There will be 2 test

periods separated by one-week washout.

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Research Protocol - page 12 Study visits

Screening

Routine physical examination and medical history; body weight will be recorded

Vital signs – blood pressure (100-140 mm Hg systolic /70-90 mm Hg diastolic),

pulse 60-100 beats/min

Electrocardiogram before the treatment

Laboratory examination – complete blood count with differential, hepatic and

renal profiles

Study test days

Period 1 Day 1

Day2

Time between periods: One week

Period 2 Day 1

Day 2

Subjects will be admitted in the morning (7.30 am) of the first day of each period

and after the insertion of the catheter, they will receive a single dose of the drug

(treatment A or B) at 8am (0 hour of the test). Subjects will be in the facility until

8pm (after the 12 hours blood sample is withdrawn). Subjects will return the

second day of each period at 7.30 am for the 24h and 30h blood sample

withdrawal. There will be 2 test periods separated by one-week washout.

Drug Administration

Treatment A: Propranolol 80mg ER tablet (1 tablet) oral at 0 hour with 240ml of

room temperature water

Treatment B Propranolol 80mgER capsule (1 capsule) oral at 0 hour with 240ml

of room temperature water

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Blood samples:

During each period, 12 venous blood samples will be taken in heparinized

vacutainers as follows:

Day 1 - at 0 (predose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12h (using catheter hep-lock)

after drug administration

Day 2 - at 24, 30h (by direct venipuncture) after drug administration (Singh,

Jambhekar, 1996).

The plasma will be separated, transferred to the labeled tubes and promptly

frozen. The samples will be stored frozen at –20C, until analyzed.

Meals and Food Restrictions: Subjects shall fast for at least 12 hours prior to the

dose administration. Prior to and during each study phase subjects are allowed

to water as desired except for one hour before and after drug administration After

drug administration, subjects will receive lunch at 1pm. Subjects should abstain

from alcohol, for 24 hours prior to each study period and until after the last

sample from each period is collected (alcohol increases plasma clearance rate).

Abuse of tobacco, caffeine is not allowed for 24 hours prior to each study period

and until after the last sample from each period is collected.

Subject monitoring

The blood pressure and pulse rate will be monitored prior to dosing and at the

sampling times.

Subjects will have their weight measurements taken and recorded at check-in,

each period.

Subjects will be advised to avoid the use of prescription and OTC medications

and alcohol

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Method of analysis: All Propranolol samples obtained from the test and reference

product will be analyzed by the same HPLC method coupled with fluorescence or

UV detection. The measurement of only the Propranolol concentration is

performed, assuming that the concentration-time profile of the parent drug is

more sensitive to changes in formulation than a metabolite (FDA Guidance on

Bioequivalence). The validation, linearity and sensitivity of the method will be

conducted before the study is started.

Pharmacokinetic and statistical analysis:

Cmax, tmax – obtained direct from the data,

t1/2 (terminal half-life)

AUC 0-t and AUC 0-∞

Bioavailability of the test and reference product will be tested by two one-sided t-

test, by computing a 90% CI for the ratio of the mean response (AUC and Cmax).

c. Setting and laboratory facilities

The study will be sponsored by the University of Cincinnati and conducted at the

Veterans Affairs Medical center (VAMC), Outpatient Clinic facilities.

The screening procedure will be conducted at the investigator’s office and

laboratory at the VAMC.

The Propranolol plasma analysis will be performed in the laboratories of the

College of Pharmacy

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E. Human subjects

1. Recruitment

Advertisement for study enrollment will be posted in the News Record and on

boards within the East Campus (see attached advertisement). Healthy volunteers

responding to the advertisement will be recruited, after explaining the purpose

and protocol of the study and given the informed consent. A screening procedure

will be done before enrolment in the study.

2. Risks and benefits

After administration of Propranolol adverse effects have been rare, mild and

transient: bradycardia, insomnia, weakness, fatigue, nausea, vomiting, epigastric

distress, abdominal cramping, diarrhea, constipation. 80mg is a relatively low

dose (the usual maintenance dose is 120-240mg/day and it may be increased in

some cases up to 640mg/day).

3. Payment – subjects will not be directly remunerated for the participation in

the study, but compensation consisting of educational materials (up to

$200/participant) will be available for each qualified participant

4. Subject costs:

Funds are not available to cover the costs of any ongoing medical care and the

subjects remain responsible for the cost of non-research related care. Tests,

procedures and other costs incurred solely for purposes of research will be the

financial responsibility of the sponsor.

5. Consent form – is attached as a separate document

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F. Estimated period of time to complete the study (approximately 6

weeks):

Subject recruitment – 14days

Pre-study screening – 7 days

First treatment – 2 days

Wash-out period – 7 days (during this time the samples from the first treatment

will be analyzed)

Second treatment - 2 days

Analysis of the samples – 2 days

Data analysis – 7 days

Study schedule

Screen Period 1 Wash-out Period 2 Days -6 0 1-2 7 1-2 Consent x Screening History Physical examination Weight check Electrocardiogram Lab exams

x x x x x

Vital signs x x x Administration Study Drug x x Propranolol plasma analysis x x

G. Funding

Industrial Pharmacy Graduate Program, University of Cincinnati through its funds (Industrial Pharmacy Account), will support the costs of this study.

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REFERENCES

Bottini, P. B.; Caulfield, E. M.; Devane, J. G.; Geoghegan, E. J.; Panoz, D. E. 1983. Comparative oral bioavailability of conventional Propranolol tablets and a new controlled absorption Propranolol capsule. Drug Dev. Ind. Pharm. (9) 1475-1493 Cid, E.; Mella, F.; Lucchini, L.; Carcamo, M.; Monasterio, J., 1986. Plasma concentrations and bioavailability of Propranolol by oral, rectal and intravenous administration in man. Biopharm. Drug Disp (7) 559-566 Draganoiu, E., Andheria, M., Sakr, A. Evaluation of a New Polyvinyl acetate/ Povidone Excipient for Matrix Sustained Release Dosage Forms. Accepted for publication in Pharm. Ind. Drummer, O. H.; McNeil, J.; Pritchard, E.; Louis, W. J. 1981. Combined high performance liquid chromatographic procedure for measuring 4-hydroxyPropranolol and Propranolol in plasma: pharmacokinetic measurements following conventional and slow-release Propranolol administration. J. Pharm. Sci. (70) 1030-1032 Dvornik, D.; Kraml, M.; Dubuc, J.; Coelho, J.; Novello, L. A.; et al. 1983. Relationship between plasma Propranolol concentrations and dose of long-acting Propranolol (Inderal LA). Curr. Ther. Res. (34) 595-605 Frishman, W.H., Jorde, U. 2000 β-Adrenergic Blockers in Oparil, S., Weber, M.A. Hypertension: A Companion to Brenner and rector’s The Kindey, pp.590-594, W.B. Saunders Company Garg, D.G., Jallad, N.S., Mishriki, A., Chalavarya, G., Kraml, M. et al 1987. Comparative Pharmacodynamics and Pharmacokinetics of Conventional and Long-Acting Propranolol J. Clin. Pharmacol. (27) 390-396 Grundy, R. U., McAinsh, J., Taylor, D.C. 1974 The effect of food on the in vivo release of Propranolol from a PVC matrix tablet in dog, J.Pharm. Pharmacol. (26 Suppl.), 65P Jantzen, G.M., Robinson, J.R. Sustained and Controlled Release Drug Delivery Systems in Banker, G.S., Rhodes, C. (eds.) Modern Pharmaceutics, 3rd ed., pp 575-610, Marcel Dekker (1996). McAinsh, J., Baber NS Holmes BF Young J Ellis SH 1981. Bioavailability of sustained release Propranolol formulations. Biopharm Drug Disp. (2) 39-48. Moller, H. 1983. Release in vitro and in vivo and bioavailability of Propranolol from sustained release formulations. Acta Pharm. Technol. (29) 287-294 Moore, J.W., Flanner, H.H., 1996. Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm. Tech. 20(6), 64-74. O’Hara, T, Dunne, A, Butler, J., Devane, J., 1998. A review of methods used to compare dissolution profile data. Pharm. Sci. Tech. Today. (5) 214-223.

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Research Protocol - page 18 Perucca, E.; Grimaldi, R.; Gatti, G.; Caravaggi, M.; Frigo, G. M. et al. 1984. Pharmacokinetic and pharmacodynamic studies with a new controlled release formulation of Propranolol in normal volunteers: comparison with other commercially available formulations. Br. J. Clin. Pharm. (18) 37-43 Rekhi, G.S., Jambhekar, S.S. 1996. Bioavailability and In-vitro-/in-vivo Correlation for Propranolol Hydrochloride Extended-release Bead Products Prepared Using Aqueous Polymeric Dispersions. J. Pharm. Pharmacol. (48) 1276-1284 Sakr, A., Andheria, M. 2001. Pharmacokinetics of Buspirone Extended Release Tablets: A Single Dose Study. Accepted for publication in J. Clin Pharmacol. Serlin. M.J., Orme, M. L’E., MacIver, M., Sibeon, R.G., Breckenridge, A.M. 1983. The Pharmacodynamics and pharmacokinetics of conventional and long-acting Propranolol in patients with moderate hypertension. Br. J. Clin. Pharm. (15) 519-527 Shah, V.P., Tsong, Y., Sathe, P., 1998. In vitro dissolution profile comparison - statistics and analysis of the similarity factor, f2. Pharm. Res. (15) 889-896. Shand, D.G., Nuckolls, E.M., Oates, J.A. 1970. Plasma Propranolol levels in adults with observations in four children. Clin. Pharm. Ther. (11) 112-120 Straka, R. J.; Lalonde, R. L.; Pieper, J. A.; Bottorff, M. B.; Mirvis, D. M. 1987. Nonlinear pharmacokinetics of unbound Propranolol after oral administration. J. Pharm. Sci. (76) 521-524 Takahashi, H.; Ogata, H.; Warabioka, R.; Kashiwada, K.; Someya, K.; et al 1990. Decreased absorption as a possible cause for the lower bioavailability of a sustained-release Propranolol. J. Pharm. Sci. (79) 212-215 Walle, T.; Walle, U. K.; Olanoff, L. S.; Conradi, E. C. 1986. Partial metabolic clearances as determinants of the oral bioavailability of Propranolol. Br. J. Clin. Pharm. (22) 317-323 ***FDA 1997 Guidance for Industry Modified Release Solid Oral Dosage Forms Scale-Up and Postaproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation. Guidance for Industry. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. ***FDA 1997 Guidance for Industry Extended Release Solid Oral Dosage Forms Development, Evaluation And Application Of In Vitro-In Vivo Correlation. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. *** Martindale - The Extra Pharmacopoeia 32nd Ed. The Royal Pharmaceutical Society London, 1999 *** Physicians' Desk Reference 49th Ed. Medical Economics, 2000. *** United States Pharmacopeia&National Formulary 24th Ed. The United States Pharmacopeial Convention, Inc., 1999.

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Consent to participate in a Research Study Study of the Bioavailability of Two Extended Release Propranolol HCl

Dosage Forms College of Pharmacy, University of Cincinnati Sponsor

Bernadette D’Souza, M.D. (513) 475-6326 Principal Investigator Phone number Adel Sakr, Ph.D Thomas Geracioti, Jr., M.D. Elena Draganoiu Coinvestigators

INTRODUCTION Before agreeing to participate in this study, it is important that the following

explanation of the proposed procedures be read. It describes the purpose,

procedures, benefits, risks, discomforts and precautions of the study. It also

describes alternative procedure available and the right to withdraw from the study

at any time. I have been told that no guarantee or assurance can be made as to

the results. I have also been told that refusal to participate in this study will not

influence standard treatment available to me.

I, have been asked to participate in the research

study under the direction and medical supervision of Dr. Bernadette D’Souza.

Other professional persons associated with the study may assist or act for

him/her.

This research is sponsored by the College of Pharmacy, University of Cincinnati.

I will be one of 8 subjects to participate in this trial.

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PURPOSE The purpose of this research study is to evaluate how a new preparation of an

extended release Propranolol tablet behaves in the body when taken by healthy

volunteers who are under fasting conditions and to compare the blood

concentrations of Propranolol when taken as a once-a-day tablet versus a

marketed once-a-day capsule. Propranolol is a beta-adrenergic blocker that is

currently used for the treatment of high blood pressure, anginal chest pain, some

types of heart beat irregularities, and post heart attacks. It is approved for use in

the United States

DURATION My participation in this study will last for approximately 14days.

PROCEDURE I have been told that during the course of the study, the following will occur:

Initially a physician will take my medical history, perform a physical examination,

check my body weight and record my electrocardiogram. For testing purposes,

approximately two teaspoons of blood will be drawn from a vein in my arm. The

results of my tests and physical examination will be kept confidential and

disclosed only as required by law. All procedures will be completed within a

seven day timeframe to determine my eligibility for the study.

The study consists of two periods separated by one week. On Day One of each

period I will come to the outpatient facility at 7.30 am and I will remain there for at

least 12 hours after dosing. Because this study is performed under fasting

conditions, I will be required not to eat anything after 8 pm of the evening before

the test day. I will be able to eat lunch at 1 pm on Day One. I may drink water as

desired except within one hour before and after receiving the study medication.

A catheter with a lock (hep-lock) will be inserted into a vein in my arm before the

drug administration and will be kept at site for 12 hours after administration.

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During each period I will be given 80 mg of Propranolol either in the form of a

capsule or in the form of a tablet with 240 ml of water. During each period I will

have twelve (12) blood samples drawn, each sample being about 5 ml or 1

teaspoon. Ten samples will be drawn on Day One through the hep-lock catheter

from 8 am to 8 pm. The other two samples will be drawn by direct venipuncture

on Day Two at 8 am and 2 pm.

EXCLUSION I should not participate in this study if any of the following apply to me:

I am under 18 or over 65 years of age.

I have a medical condition (hematological, renal, hepatic, gastrointestinal,

endocrine, pulmonary, dermatological, oncological or neurological, alcoholism),

requiring medical treatment, medications or care

I have a history of cardiovascular disease

I take concomitant drugs

I am allergic to Propranolol

I am a pregnant or lactating woman

I have participated in another drug study or any other study using the same drug

within the last three months.

I have also been informed and understand that:

I should be free of all over the counter preparations for one week before starting

the study and during the entire study

I should not drink alcoholic beverages for 24 hours prior to dosing at each period

I am not allowed to smoke from 1 hour prior to until 12 hours after dosing

I should refrain to from eating or drinking any caffeine-containing products

(chocolate, tea, coffee, cola) for at least 12 hours prior and 12 hours after dosing.

RISKS / DISCOMFORTS I have been told that the study described above may involve certain risks and

discomforts, as well as the possibility for unforeseen risks. The 80 mg daily dose

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of Propranolol which I will be taking is relatively low as compared to the normal

maintenance dose of 120 to 240mg/day.

The most frequently reported adverse events with Propranolol have been

gastrointestinal discomfort, loss of appetite, nausea, vomiting, diarrhea, and

abdominal pain. Other less frequently reported adverse events are: decreased

circulation to the extremities, congestive heart failure, sleep disturbances,

dizziness, fatigue and breathing problems.

On rare occasions, rash and allergic reactions to Propranolol have been

reported.

There is a risk of bruising on my arm at the intravenous sites used for drawing

blood samples.

In case I experience any adverse effects, I will contact Dr. D’Souza at (513) 475-

6326 to obtain necessary medical treatment.

PREGNANCY If I am a woman of childbearing potential, I will not participate in this research

study unless I have a negative pregnancy test and am using an approved form of

birth control. I agree to inform the investigator immediately if: 1) I have any

reason to suspect pregnancy; 2) I find that circumstances have changed and that

there is now a risk of becoming pregnant; or 3) I have stopped using the

approved form of birth control.

BENEFITS I have been told that I will receive no payment from my participation in this study,

but my participation may help health care practitioners better understand the

release and absorption of the study drugs after administration. I will also receive

educational materials up to a value of $200.

ALTERNATIVES The study will evaluate the rate of absorption of the studied drugs in healthy

volunteers and it is not intended for treatment of a medical condition. As such,

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there are no alternative treatments or procedures that are advantageous to me,

the study participant.

NEW FINDINGS I have been told that I will receive any new information during the course of the

study concerning significant findings that may affect my willingness to continue

participating in the study.

CONFIDENTIALITY Every effort will be made to maintain the confidentiality of my study records.

Agents of the United States Food and Drug Administration, representatives of the

UCMB – IRB, the investigator and coinvestigators or sponsor will be allowed to

inspect sections of my medical and research records related to this study. The

data from the study may be published; however I will not be identified by name.

My identity will remain confidential unless disclosure is required by law.

FINANCIAL COSTS TO THE SUBJECT Funds are not available to cover the costs of any ongoing medical care and I

remain responsible for the cost of non-research related care. Tests, procedures

and other costs incurred solely for purposes of research will not be my financial

responsibility.

COMPENSATION IN CASE OF INJURY If I am injured as result of research, I will contact Dr. D’Souza at (513) 475-6326

or the Chairman of the Institutional Review Board at (513) 558-5259. The

University of Cincinnati Medical Center makes decisions concerning

reimbursement for medical treatment for injuries occurring during, or caused by

participation in biomedical or behavioral research. In the event I become ill or

injured as a direct result of my participation in the research study, necessary

medical care will be available to me and the University, at its discretion, will pay

medical expenses necessary to treat such injury (1) to the extent I am not

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otherwise reimbursed by my medical or hospital insurance or by third party or

governmental programs providing such coverage and (2) provided I have used

the study drug as directed by the study doctor in accordance with the study

protocol. Financial compensation for such things as lost wages, disability or

discomfort due to injury during research is not routinely available.

PAYMENT TO PARTICIPANTS I have been told that I will be compensated for my participation in this study with

educational materials up to a value of $200

RIGHT TO REFUSE OR WITHDRAW It has been explained to me that my participation is voluntary and I may refuse to

participate, or may discontinue my participation AT ANY TIME, without penalty or

loss of benefits to which I am otherwise entitled. I have also been told that the

investigator has the right to withdraw me from the study AT ANY TIME. I have

been told that my withdrawal from the study may be for reasons solely related to

me (e.g. not following study-related directions from the investigator; a serious

adverse reaction) or because the entire study has been terminated. I have been

told that the sponsor has the right to terminate the study or the investigator’s

participation in the study at any time.

OFFER TO ANSWER QUESTIONS This study has been explained to my satisfaction by and

my questions were answered. If I have any others questions about this study, I

may call Dr. D’Souza at (513) 475-6326.

If I have any questions about my rights as a research subject, I may call UCMC -

IRB Chairperson at (513) 558-5259.

If research related injury occurs, I will call Dr. D’Souza at (513) 475-6326.


LEGAL RIGHTS Nothing in this consent form waives any legal rights I may have nor does it

release the investigator, the sponsor, the institution or its agents from liability for

negligence.

I HAVE READ THE INFORMATION PROVIDED ABOVE, I VOLUNTARILY AGREE TO PARTICIPATE IN THIS STUDY. AFTER IT IS SIGNED, I WILL RECEIVE A COPY OF THIS CONSENT FORM.

Subject Signature Date

Signature and Title of Person Obtaining Consent and Date

Identification of Role in the Study

Principal Investigator Signature Date

Revised 11/07/01

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8. Appendix 2

Subjects monitoring during the pilot bioequivalence study - period 1 (blood

pressure and heart rate)

Time post-dosing (hr)

Subject (treatment)

1 (CPS) 2 (CPS) 3 (TB) 4 (TB) 5 (TB) 6 (CPS) 7 (CPS) 8 (TB) 0 149/80

74 148/83

86 114/68

69 140/70

68 113/70

72 121/68

75 114/66

59 111/72

86 1 146/87

66 126/71

72 113/68

62 129/58

61 113/66

78 116/67

66 126/66

55 99/71

80 2 134/78

63 128/78

66 106/52

64 116/71

61 97/69

54 113/71

60 101/61

55 87/64

74 3 155/80

56 127/69

51 106/53

56 128/75

55 106/65

60 112/62

62 101/61

49 99/64

74 4 146/83

61 118/65

50 103/63

58 115/60

58 110/68

62 98/60

61 104/58

49 86/57

67 5 156/82

56 131/64

60 104/64

62 137/56

54 119/76

76 98/74

66 102/61

50 96/61

70 6 141/77

72 131/69

85 109/57

64 131/63

75 121/71

84 94/56

73 95/54

58 96/57

74 8 143/73

68 134/66

66 107/57

73 142/51

62 91/48

76 103/61

70 142/118

53 94/57

74 10 138/75

65 136/68

61 112/56

66 142/64

59 98/78

86 123/70

73 114/70

56 86/58

72 12 131/72

63 145/72

62 109/55

71 145/58

65 104/64

73 112/65

74 116/67

54 96/61

76 24 149/78

62 136/68

65 103/64

68 137/66

61 112/68

76 103/64

72 119/72

61 94/62

83 30 146/69

79 149/73

83 115/62

57 149/70

67 127/70

90 129/77

80 122/65

58 93/61

90 Weight 197 164 170 217 117 163 155 116

TB – Propranolol 80mg matrix tablets with 65% Kollidon® SR

CPS - Inderal® LA 80mg capsules

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Subjects monitoring during the pilot bioequivalence study - period 2 (blood

pressure and heart rate)

Time post-dosing (hr)

Subject (treatment)

1 (TB) 2 (TB) 3 (CPS) 4 (CPS) 5 (CPS) 6 (TB) 7 (TB) 8 (CPS) 0 136/83

62 129/66

73 107/62

65 130/58

65 112/70

67 114/69

77 126/65

62 105/62

91 1 144/76

60 100/75

74 113/74

64 130/67

60 118/72

86 106/70

72 113/73

60 94/58

76 2 120/66

52 133/69

59 112/64

64 134/67

57 111/77

68 105/68

64 124/71

50 94/67

80 3 124/71

52 130/75

70 116/65

61 136/77

62 108/64

62 98/69

67 115/70

49 94/60

74 4 127/74

55 124/72

60 110/64

58 147/69

57 107/69

69 95/58

66 111/68

51 92/59

74 5 119/55

55 124/62

57 107/76

62 127/62

60 108/69

67 106/67

66 102/67

48 82/56

76 6 140/70

67 138/68

76 108/64

72 112/59

76 105/61

70 102/58

73 112/65

66 96/60

86 8 140/78

71 137/63

79 117/61

65 136/52

65 117/62

67 96/53

72 105/52

60 83/49

81 10 136/76

71 140/75

73 122/69

68 150/65

61 114/65

70 105/75

71 119/61

57 92/61

80 12 145/73

71 132/64

71 110/62

68 146/56

67 110/63

63 92/74

68 105/59

58 105/68

85 24 155/70

70 122/76

68 134/67

62 128/64

62 100/60

70 115/70

70 125/76

57 92/57

80 30 152/76

71 140/75

96 110/60

75 160/61

72 115/59

66 122/59

69 123/67

62 96/55

87 weight 201 165 169 218 125 166 156 117

TB – Propranolol 80mg matrix tablets with 65% Kollidon® SR

CPS - Inderal® LA 80mg capsules

DRAGANOIU ELENA SIMONA

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