In vitro controlled release of vinpocetine–cyclodextrin–tartaric acid multicomponent complexes...

www.elsevier.com/locate/jconrel

Journal of Controlled Releas

In vitro controlled release of vinpocetine–cyclodextrin–tartaric acid

multicomponent complexes from HPMC swellable tablets

Laura Ribeiroa,*, Domingos C. Ferreirab, Francisco J.B. Veigaa

aLaboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, 3000-004 Coimbra, PortugalbLaboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

Received 15 August 2004; accepted 2 December 2004

Available online 23 December 2004

Abstract

The objective of this study was to investigate the effect of multicomponent complexation (MCC) of vinpocetine (VP), a

poorly soluble base-type drug, with h-cyclodextrin (hCD), sulfobutylether h-cyclodextrin (SBEhCD), tartaric acid (TA),

polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), on the design of controlled release hydrophilic

HPMC tablets and to evaluate their in vitro release profiles by a pH gradient method. Multicomponent complexation led to

enhanced dissolution properties of VP both in simulated gastric and intestinal fluids, and became possible the development of

HPMC tablet formulations with more independent pH dissolution profiles. Drug release process was investigated

experimentally using USP apparatus 3 and by means of model-independent parameters. Responses studied included similarity

of dissolution profiles, time for 60% of the drug to dissolve (T60%), percent of VP released after 7h (PD7 h) and the dissolution

efficiency parameter at 12 h (DE12 h). Influence of multicomponent complexation was proved to increase the release of VP from

HPMC tablets and superior PD7 h and DE12 h values were obtained in formulations containing VP–CD–TA complexes. Results

supported the use of HPMC matrices to provide a useful tool in retarding the release of VP and that dissolution characteristics of

the drug may be modulated by multicomponent complexation in these delivery systems, suggesting an improvement on VP

bioavailability.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Multicomponent complexation; Vinpocetine; HPMC swellable tablets; Controlled drug delivery; In vitro release studies

1. Introduction

Vinpocetine (VP) is a poorly water-soluble base-

type drug (water solubility valuec5 Ag/ml and pKa

0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.jconrel.2004.12.001

* Corresponding author. Tel.: +351 239855085; fax: +351

239855019.

E-mail address: [email protected] (L. Ribeiro).

value of 7.31), which shows a pH-dependent solubility

profile [1], and is usually available as immediate oral

dosage forms containing 5 mg of the active ingredient.

However, existing formulations exhibit poor bioavail-

ability and poor absorption, since VP absorption is

dissolution rate-limited and consequently slow and

irregular [2]. Because VP is characterized by a short

half-life time and requires chronic administration, a

e 103 (2005) 325–339

L. Ribeiro et al. / Journal of Controlled Release 103 (2005) 325–339326

controlled release dosage form could provide

increased clinical value over conventional formula-

tions, as a result of improved therapeutic effect and

patient compliance by reducing dosing frequency, a

more constant or prolonged therapeutic effect and

possible enhanced bioavailability [3,4]. However, it is

known that the aqueous solubility of base-type drugs,

as VP, or their salts, is much higher at low pH values,

whereas it is very poor at higher pH of the intestinal

tract. Therefore, the release site from formulations of

such drugs is restricted to the stomach or to the upper

part of the intestinal tract and such properties makes

difficult the preparation and use of these drugs in

controlled release formulations [5].

When designing extended-release dosage forms,

the solubility characteristics of the active must then be

taken into account as these can strongly influence the

overall release profile. In fact, the solubility and the

dissolution rate of VP at acidic pH values are very high

making difficult to control the release of VP in the

stomach and, in addition, it is necessary to ensure the

dissolution of the drug on the intestinal medium.

Consequently, all attempts to model drug release place

a particular importance on VP solubility. As the

difficulties originated from the low aqueous solubility

of certain drugs, such as low rate and percent of

dissolution, from pharmaceutical formulations

together with poor and variable bioavailability can be

overcome by cyclodextrin (CD) complexation [5,6],

we have previously attempted to improve the solubility

of VP by h-cyclodextrin (hCD) and sulfobutylether-h-cyclodextrin (SBEhCD) multicomponent complex-

ation (MCC) in the presence of water-soluble polymers

and tartaric acid (TA) [7–9]. In the present work,

controlled in vitro release of VP from VP–CD–TA

multicomponent systems have been considered.

Advanced controlled release can be achieved by a

pertinent combination of CDs and pharmaceutical

polymers [10]. Indeed, the use of hydrophilic polymers

is actually the most used method in controlling the

release of drugs in the formulation of oral pharma-

ceutical dosage forms. In particular, HPMC-based

hydrophilic matrix tablets offer several advantages

when developing an oral sustained-release formulation

such as flexibility of release modulation, simplicity of

preparation, low production costs and ease to scale up

point of view. Moreover, they can be used to control

the release of both water-soluble and water-insoluble

drugs, being the release behaviour of drugs variable

with the nature of the matrix as a consequence of the

complex interaction between swelling, diffusion and

erosion processes [11]. One of the most important

characteristics of HPMC is the high swellability, which

has a considerable effect on the release kinetics of

incorporated drug [12]. When HPMC comes in contact

with water or aqueous gastro-intestinal fluids, the

polymer absorbs water and undergoes swelling or

hydration. The rapid formation of a viscous gel layer

upon hydration has been regarded as the essential step

in achieving controlled drug release from HPMC

matrices. This process leads to relaxation of the

polymer chains with a reduction in the value of the

glass transition temperature of the polymer. Subse-

quently, the polymer undergoes a glassy to rubbery

phase transition, the chains disentangle and as a result

of increased distance separation between the chains,

the drug diffuses [13].

Thus, in an effort to achieve better solubility and

dissolution properties as well as controlled release rate

of VP, we have prepared VP–CD–TA MCC and an

optimal formulation was then designed by the

combination of these complexes into HPMC-based

hydrophilic tablet dosage forms. The in vitro release

profiles of VP MCC incorporated in HPMC tablets

was thoroughly evaluated since recent reports point to

the effectiveness of CD derivatives to modulate drug

release into these solid dosage forms by changing the

solubility of the drug and hence its diffusivity through

the HPMC swollen barrier [14–20]. Furthermore,

since the release characteristics of many extended-

release systems show some dependence on pH and

may be affected by other excipients within the

formulation to varying degrees, depending upon the

dissolution test conditions [21], we have studied the

release behaviour of VP MCC from HPMC matrix

tablets over the entire range of physiological pH found

in the fasted gastro-intestinal tract using the USP

apparatus 3, by a pH gradient method.

2. Materials and methods

2.1. Materials

VP (MW 350.5) was purchased from Covex

(Madrid, Spain). hCD (KleptoseR; MW 1135) and

L. Ribeiro et al. / Journal of Controlled Release 103 (2005) 325–339 327

SBEhCD (Captisolk; TDS 6.8, MW 2160) were

kindly offered by Roquette (Lestrem, France) and

Cydex (Kansas City, USA). HPMC 4000 cps, PVP

K30 and TA were purchased from Sigma Chemical

(St. Louis, USA). For the preparation of the matrix

tablets MethocelR HPMC K15M CR (Dow Chemical,

Michigan, USA), monohydrate lactose and magne-

sium stearate of pharmaceutical grade were used.

2.2. Preparation of VP–CD–TA multicomponent

systems

The solid MCC, VP–hCD–TA and VP–SBEhCD–TA, with and without water-soluble polymers (PVP

and HPMC), were prepared by the lyophilization

method as described in a previous work [8]. The

corresponding physical mixtures (PM) were prepared

in the same molar ratio as MCC for further

comparisons.

2.3. In vitro dissolution studies of VP–CD–TA

multicomponent systems

The dissolution profiles were collected using a

Vankel VK7000 apparatus, according to the USP

rotating basket method. The dissolution media (fil-

tered, degassed and maintained at 37 8C) consisted of

900 ml of enzyme-free simulated gastric (pH 1.2) and

intestinal (pH 6.8) fluids (USP XXV). Powdered

samples containing 10 mg of VP or its equivalent in

lyophilized or physically mixed form with hCD and

SBEhCD were used. The stirring speed was set at

100F2 rpm and the temperature was maintained at

37F0.2 8C. At settled time intervals for a period of 60

min, dissolved VP was automatically determined by

UV spectroscopy (UV-1603, Shimadzu, Kyoto,

Japan) at 316 nm. VP dissolution profiles were

evaluated by the percent of drug dissolved at 5 min

(DP5 min) and by the dissolution efficiency parameter

at 60 min (DE60 min), calculated from the area under

the dissolution curve, according to the method of

Khan [22]. Six replicates have been made for each

experience. Statistical comparisons of the dissolution

data were made by one-way analysis of variance

(ANOVA) and the significant level set at Pb0.05,

followed by Tukey’s multiple comparison test. The

statistical analysis was done using GraphPad PrismR

version 4.00 software.

2.4. Preparation of HPMC matrix tablets

HPMC-based hydrophilic matrix tablets were

manufactured by direct compression of the formula-

tion mixtures presented in Table 1 under a pressure of

4000 kg/cm2. The respective powders (VP, MCC, PM,

HPMC K15 MCR, lactose and magnesium stearate)

were blended thoroughly with a mortar and a pestle.

Formulation mixtures were weighed and fed manually

into the die of an instrumented single-punch tablet

press (Specac limited, Kent, UK) fitted with 8 mm

flat-faced punches The tablet weight was kept con-

stant, at 200 mg and 300 mg for the formulations

incorporating hCD and SBEhCD systems, respec-

tively, by adjusting the amount of lactose used in each

formula. All tablet formulations contained 20 mg of

VP, or its equivalent, and 30% of HPMC K15M CR,

and were lubricated with 1% of magnesium stearate.

2.5. In vitro dissolution studies of HPMC matrix

tablets

Dissolution tests were performed using USP

apparatus 3 (Bio-Dis III extended release tester,

Vankelk, Cary, NC), at various pH values to simulate

the conditions of fasted human gastro-intestinal tract

(GIT). According to published guidelines [23], the pH

of test medium used to study the dissolution of

extended release oral dosage forms should be set

within pH 1 to 6.8. To simulate the passage through

stomach and the small intestine, all dosage forms were

tested with a pH gradient method based on mean

physiological pH values in each gastro-intestinal

segment. The pH of the dissolution media and

corresponding dissolution durations were set as

follow: pH 1.2 (simulated gastric fluid without

enzymes, USP XXV) for 1 h, pH 4.5 (phosphate

buffer, Eur. Ph., 4th edition) for 0.5 h, pH 6.0

(phosphate buffer, Eur. Ph., 4th edition) for 2.5 h

and pH 6.8 (simulated intestinal fluid without

enzymes, USP XXV) for 8 h. The pH values and

residence times in each row were selected on the basis

of literature information of the pH values found in

different parts of the GIT in fasted state [24–27].

Dissolution testing was performed at 37F0.2 8C. Thevessels were fitted with 250 ml of media and matrices

were weighed and placed in the dipping tubes which

contained a polypropylene bottom screen of 420 Am

Table 1

Composition of controlled release hydrophilic matrix formulations of vinpocetine

Formulation

no.

MCC, PM or

pure VP (mg)

HPMC

(mg)

Lactose

(mg)

Mg stearate

(mg)

Total weight

(mg)

VP content in MCC

and PM (mg)

F1a 158.2 90.0 48.8 3.0 300.0 20.0

F2b 120.6 90.0 86.4 3.0 300.0 20.0

F3c 115.5 90.0 91.5 3.0 300.0 20.0

F4d 158.2 90.0 48.8 3.0 300.0 20.0

F5e 30.0 90.0 177.0 3.0 300.0 20.0

F6f 20.0 90.0 187.0 3.0 300.0 –

F7g 99.6 60.0 38.4 2.0 200.0 20.0

F8h 81.6 60.0 56.4 2.0 200.0 20.0

F9i 76.6 60.0 61.4 2.0 200.0 20.0

F10j 99.6 60.0 38.4 2.0 200.0 20.0

F11e 30.0 60.0 108.0 2.0 200.0 20.0

F12f 20.0 60.0 118.0 2.0 200.0 –

a VP/SBEhCD/TA MCC.b VP/SBEhCD/TA/PVP MCC.c VP/SBEhCD/TA/HPMC MCC.d VP+SBEhCD+TA PM.e VP+TA PM.f VP.g VP/hCD/TA MCC.h VP/hCD/TA/PVP MCC.i VP/hCD/TA/HPMC MCC.j VP.


mesh size. The mesh size of the top screens was also

fixed at 420 Am. A standard dip rate per minute (dpm)

of 10 and 15 were used in all experiments and dipping

tubes were drained for 1 min before moving to the

following media. These agitation rates were selected

on the basis of previous published works using the

USP apparatus 3 [28–31]. Sample solutions (3 ml)

were collected at specified time intervals from

dissolution vessels using a plastic syringe (BraunR)

coupled with a polypropylene tube which was inserted

inside the vessel and an equal volume of fresh test

medium was replaced. Samples were filtered through

membrane filters of 0.45 Am pore size (La-Pha-PackR,

Langerwehe, Germany) and analyzed for UV absorp-

tion (UV-1603, Shimadzu, Kyoto, Japan) at 316 nm.

The cumulative percent of drug released was calcu-

lated according to calibration curves for each pH

buffer solutions and a correction was applied for the

cumulative dilution caused by replacement of the

sample with an equal volume of fresh medium. All

experiments were made in triplicate and results for

each time point of the three dissolution curves are

registered as an average in figures.

2.6. Release profile comparison of matrix

formulations

Fit factors ( f1 and f2) proposed by Moore and

Flanner were used for comparing the dissolution

profiles. The f2 factor is a logarithmic reciprocal

square root transformation of the sum of squared

error and is a measurement of the similarity in the

percent dissolution between the curves. The f1factor calculates the percent difference between the

two curves at each time point and is a measure of

the relative error between the two curves. For

curves to be considered similar, f2 values should be

close to 0 and f2 values to 100. Generally, f1values V15 and f2 values z50, which means an

average difference of no more than 10% at the

sample time points, ensures equivalence of the

curves and thus of the performance of the test and

reference products [32]. Both f1 and f2 equations

were used as they are very popular methods used

to compare dissolution profile data, and recom-

mended for use in a number FDA guidance

documents [33].


2.7. Rate and extent of drug release from matrix

formulations

To quantify drug release curve as a measure

response, the following parameters were used: time

to release 60% of VP (T60%), percent of VP released at

7 h (PD7 h) and the dissolution efficiency parameter at

12 h (DE12 h). The first two parameters were extracted

directly from dissolution data and DE12 h was

calculated from the area under the dissolution curve

[22]. All values are expressed as means from separate

experiments. Statistical significance for the compar-

ison of T60%, PD7 h and DE12 h values was tested by

one-way ANOVA and the significant level set at

Pb0.05, followed by Tukey’s multiple comparison

test, using GraphPad PrismR version 4.00 software.

3. Results and discussion

3.1. In vitro dissolution studies of VP–CD–TA

multicomponent systems

The mean dissolution profiles of VP and corre-

sponding VP–CD–TA multicomponent systems, with

and without PVP and HPMC, at pH 1.2 and 6.8 are

presented respectively in Figs. 1 and 2. DP5 min and

DE60 min values are collected in Table 2 for all

products studied.

In acidic medium, due to basic nature of VP, there

were no significant differences between the dissolved

drug amounts (PN0.05), but differences in dissolution

rate were experienced. Pure drug has taken approx-

imately 20 min to disperse and dissolve entirely,

while its dissolution from VP–hCD–TA MCC was

practically immediate in the first 5 min. In general,

DP5 min was equivalent to DE60 min for those MCC

(PN0.05), but as the dissolution rate for PM was

slightly lower there was no equivalence between these

two parameters for PM (Pb0.001), excluding the case

of VP–hCD–TA PM. Furthermore, differences in the

dissolution rate were experienced for VP–CD–TA–

HPMC multicomponent systems (PM and MCC),

since a delayed release profile was clearly evident

over the 60 min of the dissolution studies. In fact, for

these systems, DE60 min was significantly lower than

for the corresponding systems without HPMC

(Pb0.001).

At pH 6.8, low dissolution rate of VP was

significantly improved by complexation. As a result,

dissolution profiles of VP MCC and PM exhibited

better dissolution properties than pure VP, namely a

clear enhancement on the dissolution rate and extent

of drug released from all VP–CD–TA products,

compared with pure drug (Pb0.001). This behaviour

was certainly due to the basic character of VP, whose

solubilization is not favoured at alkaline pH (only

11% of VP was dissolved after 60 min). The marked

increase in the dissolution properties of pure VP was

evident in all VP–CD–TA PMs, for which, as a

consequence of the mechanical treatment, the drug

carrier contact was increased, and also can be

explained on the basis of drug solubility in aqueous

CD solutions with TA. Since CDs and TA dissolve

more rapidly in the dissolution medium than pure

drug, it can be assumed that, in early stages of the

dissolution process, CD molecules will operate locally

on the hydrodynamic layer surrounding the particles

of VP, this action resulting in an in situ inclusion

process, which, in association with the ionisation of

the drug, produces a rapid increase on the amount of

dissolved drug [34,35]. There was no significant

variation between the dissolution profile of PM with

or without PVP and HPMC, being the DE60 min

parameter very similar for those products (PN0.05).

Oppositely to pure VP and PM, VP–CD–TA MCC,

with and without PVP and HPMC, dissolved almost

completely, being their resulting DE60 min signifi-

cantly higher than those obtained for pure drug and

PM (Pb0.001). The presence of TA in the complex

creates an acid environment, which facilitates the

dissolution of the drug also at high pH values, so that

dissolution characteristics of VP were less dependent

on the local pH [5]. The same trend was observed for

the values of DP5 min and DE60 min as in acidic media

for MCC, i.e., these parameters presented equivalent

values (PN0.05), once again excluding VP–CD–TA–

HPMC systems where DP5 min were significantly

lower than DE60 min (Pb0.001). The significant

improvement of DE60 min from VP–CD–TA MCC,

with and without PVP and HPMC, may be ascribed to

the formation of an acidic microenvironment in the

dissolution medium that facilitates dissolution of the

basic drug, to surfactant-like properties of CD

molecules that reduce the interfacial tension between

the water-insoluble drug and the dissolution media

0 10 20 30 40 50 60 700

20

40

60

80

100

Time (min)

VP

rel

ease

d (%

)

0 10 20 30 40 50 60 700

20

40

60

80

100

Time (min)

VP

rel

ease

d (%

)

VP

VP+βCD+TA (PM)VP+βCD+TA+PVP (PM)VP+βCD+TA+HPMC (PM)

VP:βCD:TA (MCC)VP:βCD:TA:PVP (MCC)VP:βCD:TA:HPMC (MCC)

A

VP

VP+SBEβCD+TA (PM)

VP+SBEβCD+TA+PVP (PM)

VP+SBEβCD+TA+HPMC (PM)

VP:SBEβCD:TA (MCC)

VP:SBEβCD:TA:PVP (MCC)

VP:SBEβCD:TA:HPMC (MCC)

B

Fig. 1. Dissolution profiles of vinpocetine at pH 1.2 from: (A) hCD products and (B) SBEhCD products.


and to enhanced drug solubility and high energetic

amorphous state following complexation, as con-

firmed previously by XRD studies [8,36–39].

A similar behaviour was observed for VP–CD–TA–

HPMCmulticomponent systems at pH 1.2 and 6.8, that

is, the same delayed effect on VP dissolution rate was

0 10 20 30 40 50 60 700

20

40

60

80

100

VP

VP+TA (PM)

VP+βCD+TA (PM)

VP+βCD+TA+PVP (PM)

VP+βCD+TA+HPMC (PM)

VP:βCD:TA (MCC)

VP:βCD:TA:PVP (MCC)

VP:βCD:TA:HPMC (MCC)

Time (min)

VP

rel

ease

d (%

)

0 10 20 30 40 50 60 700

20

40

60

80

100

VP

VP+TA

VP+SBEβCD+TA (PM)

VP+SBEβCD+TA+PVP (PM)

VP+SBEβCD+TA+HPMC (PM)

VP:SBEβCD:TA (MCC)

VP:SBEβCD:TA:PVP (MCC)

VP:SBEβCD:TA:HPMC (MCC)

Time (min)

VP

rel

ease

d (%

)

A

B

Fig. 2. Dissolution profiles of vinpocetine at pH 6.8 from: (A) hCD products and (B) SBEhCD products.


noticeable. This phenomenon may be associated to the

swelling effect of the polymer, and therefore to the

formation of a high viscosity gel layer around

powdered products, which could control the diffusivity

of dissolved drug to the dissolution media, resulting in

sustained drug release. In these products, the dissolu-

tion of VP reached nearly 100% after 60 min; however,

DE60 min were significantly reduced (Pb0.001).

Table 2

Dissolution parameters for VP in pure, complexed and physically mixed forms in simulated gastric and intestinal dissolution media

System pH 1.2 pH 6.8

DP5 min (%) DE60 min (%) DP5 min (%) DE60 min (%)

VP 87.7F3.2 96.6F0.7 0.3F0.1 4.9F0.6

VP+TA PM – – 48.5F2.1 49.8F2.3

VP–hCD–TA PM 97.8F0.8 96.8F0.7 51.6F2.2 51.7F1.3

MCC 99.3F1.6 98.5F1.0 99.9F1.7 99.9F1.3

VP–SBEhCD–TA PM 88.5F4.5 92.9F1.4 61.6F2.3 61.3F1.9

MCC 104.0F2.8 103.9F2.8 102.2F2.2 100.7F2.1

VP–hCD–TA–PVP PM 87.7F3.2 96.6F0.7 51.7F3.6 51.5F3.2

MCC 98.1F0.4 96.8F0.8 97.1F1.5 96.1F1.3VP–hCD–TA–HPMC PM 98.3F1.4 98.8F0.9 40.0F2.5 42.4F1.6

MCC 56.3F4.0 86.1F2.2 72.4F1.8 90.9F1.4

VP–SBEhCD–TA–PVP PM 72.9F4.5 93.2F1.6 53.9F2.2 55.2F1.2

MCC 99.0F0.9 98.7F1.7 100.7F1.3 99.8F1.0

VP–SBEhCD–TA–HPMC PM 58.3F4.2 77.9F3.4 48.0F2.2 51.5F1.2

MCC 76.4F3.4 90.6F2.0 75.6F7.5 91.6F4.0

All results are presented as mean valuesFS.D.


3.2. In vitro dissolution studies of HPMC matrix

tablets

The release of a drug from a prolonged release

dosage form and its absorption are inevitably affected

by physiological factors in the GIT. Prolonged release

dosage forms are more susceptible to these factors

than immediate release dosage forms. The physiolog-

ical characteristics of the GIT (volume, composition,

pH, surface tension and viscosity of the gastro-

intestinal content as well as its motility) vary greatly

from site to site. Moreover, prolonged release dosage

forms remain in the GIT longer than conventional

preparations. Therefore, physiological conditions of

the GIT can affect the release of active ingredients of

these prolonged release dosage forms much more than

release from conventional ones. Noteworthy, gastric

pH varies from acidic to neutral, and these variations

can affect the release of the active ingredient from the

dosage form. Thus, the travelling characteristics of the

dosage form through the GIT should be fully

considered in designing advantageous dosage forms.

In addition, in vitro release behaviours should be

investigated under as many conditions as possible to

understand possible effects of gastro-intestinal varia-

bles on in vivo release [40].

We studied VP release from HPMC tablets accord-

ing to a method which can simulate VP passage

through the GIT, by multiple levels of pH representing

typical gastro-intestinal pH variations. The use of a

physiological based pH gradient in the type 3

dissolution apparatus not only facilitates simulation

of the upper gastro-intestinal transit within one experi-

ment, but may also lead to more pertinent in vitro

results, since carryover effects can be detected [31].

Furthermore, as most extended-release dosage forms

are sensitive to agitation, the greater the agitation the

faster the release of drug from dosage forms, we

evaluated, if VP matrices were affected by agitation in

order to allow for varying gastric conditions [21].

Studies were done applying a pH gradient from pH 1.2

to 6.8, accurately simulating gastro-intestinal fasted

conditions of pH and residential time of the dosage

forms in different media, at 10 and 15 dpm. The release

profiles of all formulations are just presented at 10

dpm, in Figs. 3 and 4, because of the similarity of the

results obtained at both agitation rates.

All formulations tested, either with hCD or

SBEhCD systems, exhibited VP extended release

behaviour over a 12 h period, since HPMC hydro-

philic tablets swelled upon contact with the dissolu-

tion media and a gel layer was formed on tablet

surface. This gel retarded further ingress of fluid and

subsequent drug release. However, important differ-

ences in the release profiles of tablet formulations

were observed as a consequence of pH variation of the

dissolution media. Hydration of HPMC polymers is

not affected by natural variations in pH level

0 60 120 180 240 300 360 420 480 540 600 660 720 7800

20

40

60

80

100

F1F2F3F4F5F6

pH 1.2 pH 4.5 pH 6.0 pH 6.8

Time (min)

Cum

ulat

ive

% o

f V

P r

elea

sed

Fig. 3. Vinpocetine dissolution profiles from F1 to F6 matrix formulations at 10 dpm.


throughout the GIT. They hydrate rapidly to form a

gel layer in acid conditions of the stomach [12]. As

pH of the dissolution media was previously reported

0 60 120 180 240 300 360 420

20

40

60

80

100pH 1.2 pH 4.5 pH 6.0

Time (m

Cum

ulat

ive

% o

f V

P r

elea

sed

Fig. 4. Vinpocetine dissolution profiles from F

to affect drug release rate, the differences observed in

the dissolution profiles of tablet formulations were

primarily due to pH influence on VP solubility.

0 480 540 600 660 720 780

F7F8F9F10F11F12

pH 6.8

in)

7 to F12 matrix formulations at 10 dpm.


In the early stages of the dissolution process, VP

was released from matrix tablets at similar extent

from all formulations. However, as dissolution

progressed in time, the pH of the media changed

to higher values and this was reflected on the release

abilities of matrix formulations. We observed that the

presence of CDs, either in PM or MCC forms, had a

remarkable effect on the extent of VP release from

HPMC matrices. This effect was essentially ascribed

to the higher VP solubility in the presence of CDs,

namely at pH values that do not favour the ionized

form of VP, and hence was related to complexation

effect of CDs.

We found a lower extent of VP released in

matrices formulated with pure VP (F6 and F12) and

in matrix formulations having VP physically mixed

with TA (F5 and F11), comparatively with all

formulations containing CDs either in PM or MCC

forms. In tablet formulations having CDs in the

physical mixed form (F4 and F10), the improvement

of VP released was notable. As these formulations

presented higher extent of VP released than tablets

without CDs, their profiles could denote that the

increase of drug solubility was related to in situ

complexation of VP in the hydrated gel layer of

swelled matrices [14,18]. This phenomenon takes

place because the dissolved CD molecules in the gel

layer formed a complex with VP and improved its

apparent solubility [15]. Consequently, VP diffusion

through hydrated gel layer of HPMC tablets was

improved, and subsequently there was an improve-

ment on VP dissolution. Another mechanism that

might be contributing to the improvement of VP

released on these formulations could be associated to

the dissolution of CD molecules themselves, which

results in an increase in the amount of water inside

the matrix that may favour VP solubilization in the

presence of TA [16]. However, it should be

emphasized that after 12 h of the dissolution assay,

these formulations presented a lower extent of VP

released than the corresponding formulations with

MCC, owing to superior solubility of VP in MCC

than PM.

Complexation with CDs strongly increased VP

solubility and, consequently, this enhanced the release

process. This effect was particularly important in the

case of SBEhCD-containing matrices, reflecting the

different solubility performances of both CDs. As

previously mentioned, VP MCC dissolved easily in

the hydrated polymer environment comparatively to

equivalent PM, resulting in a higher diffusional

driving force and faster drug release [15]. This effect

was possibly due to the higher amorphous state of the

lyophilized MCC with relation to the corresponding

PM and therefore to higher solubility and faster

hydration rate of the swelling polymer in the presence

of the amorphous MCC [8,41].

The major explanation of the contributing effects

of CDs and TA on the release from HPMC swellable

tablets is presented on the basis of VP solubility and

is common for tablet formulations containing MCC

and PM. As a weak basic drug, we estimated the

solubility of VP to be in gastric simulated fluid (pH

1.2) 24.16F0.04 mg/ml, in pH 4.5 phosphate buffer

199.14F4.49 Ag/ml, in pH 6.0 phosphate buffer

24.23F0.25 Ag/ml and in intestinal simulated fluid

(pH 6.8) 5.38F0.53 Ag/ml. The effect of this change

on VP solubility, as a function of pH dissolution

media, is a decrease on the diffusion rate of drug

through the gel barrier. TA could preserve a low pH

inside the tablet and operate locally to overcome the

very low solubility of VP in higher pH dissolution

media, since it contributes to the formation of an

acidic microenvironment inside the tablet, which

results to a more independent VP release throughout

the pH of the dissolution media. Moreover, the

presence of CDs contributes for higher extent of VP

released and a less dependent profile on the pH of

the dissolution media, being this effect complemen-

tary to the contribution of TA. In addition, the high

release rate of CDs and TA from tablets might

favour the weakening of their structures through an

increased porosity created after their dissolution and

release.

Interestingly, tablet formulations containing

MCC (F1 and F7) presented an analogous extent

of VP released than tablets formulated with

equivalent complexes having PVP and HPMC at

the end of the dissolution process. This fact may

have relevant pharmaceutical potential, since MCC

containing polymers were obtained in the presence

of smaller amounts of CDs, due to the enhanced

complexation efficiency of CDs toward VP in the

presence of PVP and HPMC [7–9], thereby

contributing to the reduction of formulation bulks

and costs with CDs.


3.3. Release profiles comparison of matrix

formulations

To compare dissolution profiles between two drug

products model dependent, statistical analysis and

model independent methods can be used. Although

mathematical models have been used extensively to

characterize dissolution profiles, such methods are

more complicated and require greater caution in their

application relative to model independent methods

(fit factors). Ideally, acceptable fits show relatively

small differences between the fitted and the actual

data, present no systematic trends in this residual

error, and employ a relatively small number of

model parameters [42]. Therefore, we performed a

mathematical comparison by applying f1 and f2equations to VP dissolution data from matrix

formulations. Results are collected on Table 3 and

confirmed our previous findings that tablet formula-

tions with VP–CD–TA MCC and VP–CD–TA–

polymer MCC could be considered equivalent to

each other ( f1V15 and f2V50). We could also

conclude that the dissolution profiles of tablet

formulations without CDs were not similar to the

dissolution profiles of matrix formulations having

CDs, either in PM or MCC forms.

HPMC tablet formulations F1–F6 and F7–F12

revealed some variation on drug release performances.

Besides the different nature of CD, the main differ-

ences between these two groups of formulations

reside in distinct physical properties such as their

Table 3

Fit factors values for formulations F1 to F12, comparing the same group of

same formulation at different agitation rates (10 and 15 dpm)

Fit

factorsa10 dpm 15 dpm

F1/F2 F1/F3 F1/F4 F1/F5 F1/F6 F1/F2 F1/F3 F1/F4

f1 13.8 13.9 7.3 34.5 32.2 12.8 14.6 3.9

f2 51.3 52.2 66.0 31.2 33.5 55.4 51.3 77.3

10 dpm 15 dpm


f1 3.7 2.8 1.4 5.4 15.8 0.5 3.6 4.3

f2 79.6 85.2 79.6 64.1 46.2 92.6 82.4 72.2

Reference formulation set as F1 for F1–F6 group and F7 for F7–F12 groa Only one measurement was considered after 85% of dissolution of b

points were lesser than 10% (from the second to the last time point).

weight, thickness and diffusional area. Thus, the

divergence observed in some of these formulations

was attributed to different diffusional paths of VP to

be released on the dissolution medium, because of

differences on matrix thickness and area when

matrices were formulated with a final weight of 200

mg or 300 mg. The bigger matrix size (300 mg) for a

given drug quantity (20 mg) produces a greater release

restriction [43], and consequently, F5 and F6 for-

mulations gave rise to a lower amount of VP released

than F11 and F12 formulations at the end of the

dissolution process. Therefore, F5 and F6 formula-

tions reveal no equivalence with F1 and also no

equivalence was observed between F7 and F12

formulations ( f1z15 and f2V50), but similar dissolu-

tion profile was found between F7 and F11 formula-

tions ( f1V15 and f2z50).

Finally, there were no apparent differences

between the dissolution profiles of all formulations

studied at 10 and 15 dpm, except for formulation F6

that presented around 12% difference of VP released

after 12 h of dissolution test. This variation was

subsequently disclosed by f1 and f2 values confirming

no similarity between the dissolution profiles of F6

formulation at 10 and 15 dpm. This particular

situation may be ascribed to the smaller amount of

VP released from this formulation, as a result of the

limited solubility of VP at higher pH values in the

absence of CDs and TA and consequently to its

higher susceptivity to agitation rate than other

formulations.

formulations (F1–F6 and F7–F12) at the same agitation rate and the

10 dpm/15 dpm


27.2 21.4 2.4 5.4 5.5 1.2 3.6 15.6

38.3 41.4 82.7 74.9 66.2 92.9 83.2 48.4

10 dpm/15 dpm


5.3 15.7 1.1 4.0 5.1 2.7 2.9 4.8

52.3 45.1 95.7 77.8 74.9 77.0 80.5 75.5

up.

oth reference and test products and the coefficient of variation of all


3.4. Rate and extent of drug release from matrix

formulations

The influence of CD multicomponent complex-

ation on the rate and extent of VP released was

evaluated by the T60%, PD7 h and DE12 h parameters.

Data is collected in Table 4.

Data analysis revealed that all tablets containing

CDs either in PM or MCC forms had significantly

superior PD7 h and DE12 h values compared to

tablet formulations without CDs (F5, F6, F11 and

F12) at both agitation rates (Pb0.001), corroborat-

ing the importance of CDs ant TA on VP solubility

and consequently on its higher diffusion rate

through the hydrated gel layer of HPMC tablets.

Moreover, the formulations containing MCC pre-

sented significantly higher PD7 h and DE12 h values

compared to tablet formulations containing PM

(Pb0.05), reflecting the superior solubility of VP

in the former formulations.

In the case of F7–F12 formulations, exactly the

same results were obtained, namely equivalent PD7 h

and DE12 h values for F7, F8 and F9 (PN0.05), being

these values significantly different from F10, F11

(Pb0.05) and F12 (Pb0.001) at 10 dpm. These

observations supported the influence of CD multi-

component complexation in giving rise to better

dissolution performance of VP in MCC containing

Table 4

Mathematical analysis of VP release data from matrix formulations at 10

released after 7 h and dissolution efficiency at 12 h parameters

Formulations 10 dpm

T60% (min)a PD7 h (%)b DE12 h (

F1 c145 90.62F0.31 77.24F0

F2 c135 86.95F5.68 74.62F0

F3 c140 86.30F1.15 72.62F0

F4 c155 80.30F3.38 70.62F0

F5 c330 59.96F1.14 54.32F1

F6 c330 55.03F0.92 54.71F1F7 c170 82.70F2.95 71.74F0

F8 c165 82.48F0.42 73.45F2

F9 c175 85.11F0.26 71.18F0

F10 c165 78.32F1.44 67.26F0

F11 c200 76.29F0.94 67.32F0

F12 c240 64.69F1.11 57.88F1

a Approximate values extracted directly from dissolution data profilesb Results are presented as mean values of three replicatesFS.D.

formulations. However a few differences were

observed at 15 dpm, since F7, F8, F9, F10 and F11

presented similar values (PN0.05), being just signifi-

cantly different from F12 (Pb0.001). Such divergence

might be related to the higher susceptibility of F5 and

F6 to the agitation rate, in comparison with F11 and

F12, as a result of the differences on physical

properties of the tablets, as previously reported. Tablet

formulations containing MCC with or without water-

soluble polymers showed similar T60%, PD7 h and

DE12 h values (PN0.05), reinforcing the results

discussed in previous sections.

We also observed a significant improvement on the

release and extension rate of formulations having

SBEhCD in comparison with the equivalent formu-

lations with hCD (Pb0.05) and consequent lower

T60% values (Pb0.001). Since SBEhCD is a very

water-soluble polyionic material, it undergoes faster

leaching from HPMC swellable tablets compared

with hCD and therefore formulations containing

SBEhCD will present increased porosity and

increased desegregation of the gel layer that might

result on VP superior release rate from matrix

formulations.

As expected from previous findings, there were no

significant differences on T60 min, PD7 h and DE12 h

values of tablet formulations studied at different

agitations rates (PN0.05), except for T60 min value

and 15 dpm using the time to release 60% of VP, percent of VP

15 dpm

%)b T60% (min)a PD7 h (%)b DE12 h (%)b

.57 c140 90.04F0.78 79.26F0.32

.99 c145 85.30F1.26 74.53F4.62

.95 c140 88.34F0.29 76.10F0.19

.95 c155 80.95F1.13 69.94F3.14

.40 c260 62.11F1.48 52.35F0.92

.97 c270 62.82F3.84 48.98F0.77

.47 c170 83.19F0.34 71.38F2.84

.52 c165 86.36F2.84 71.13F0.22

.64 c165 86.16F0.89 73.55F0.38

.83 c160 78.75F1.94 71.54F0.32

.90 c180 80.91F0.39 68.88F1.25

.25 c220 64.94F0.34 60.51F0.40

.


of formulations that did not contained CDs. These

were more susceptible to reciprocating agitation rate

and therefore a significant decrease was observed for

T60 min values at 15 dpm (Pb0.001).

4. Conclusions

The present study was carried out to develop oral

controlled release delivery systems for VP using CD

multicomponent complexes and swelling controlled

systems as formulation strategies. The first obstacle

generated by the low aqueous solubility of VP was

overcome by multicomponent complexation of the

drug. The dissolution of VP MCC in both simulated

gastric and intestinal fluids gave rise to faster

dissolution than that of drug alone. Particularly, at

pH 6.8, the better dissolution properties of VP in

MCC were clearly evident. The hydrophilic HPMC-

based matrix formulations designed with resulting

VP–CD–TA MCC and PM exhibited controlled

release behaviour over a 12-h period. The extent of

VP released was lower in HPMC tablets formulated

with isolated VP in comparison with the ones

formulated with CDs, reflecting an improvement of

VP release in the presence of CDs. In fact,

incorporation of hCD and SBEhCD, either in MCC

or PM forms, promoted a change on VP release

profiles from tablet formulations, reflecting an

improvement of VP release as a consequence of VP

complexation. VP release profiles from tablet for-

mulations with VP–SBEBCD–TA and VP–hCD–TAMCC showed some variation on the extent and rate of

VP dissolved, as a result of different solubility

performances of both CDs, that was reflected on

higher PD7 h and DE12 h values for the former

formulations. Moreover, the comparison of the dis-

solution profiles of tablet formulations containing

MCC with or without water-soluble polymers

revealed a convergence of dissolution data and

demonstrated the equivalence of in vitro perform-

ances of formulations with both types of MCC,

suggesting the possibility to reduce the amount of

CDs in these dosage forms without deviation of their

pharmaceutical potential. Thus, the results suggest

that the use of HPMC swellable tablets can provide a

useful tool for retarding the release rate of VP. In

addition, the improvement of the dissolution proper-

ties of VP, in all MCC incorporated in these delivery

systems, is suggestive of a promising enhancement on

VP oral bioavailability.

Acknowledgements

This work was financially supported by a grant

(Praxis XXI/BD/21455/99) from FCT (Fundacao para

a Ciencia e a Tecnologia, Portugal). Authors acknowl-

edge Cydex L.C. (Kansas City, USA) and Roquette

(Lestrem, France) for their support providing

SBEhCD and hCD, respectively.

References

[1] P. Pudleiner, L. Vereczkey, Study on the absorption of

vinpocetine and apovincaminic acid, Eur. J. Drug Metab.

Pharmacokinet. 18 (1993) 317–321.

[2] T. Szakacs, Z. Veres, L. Vereczkey, In vitro–in vivo correlation

of the pharmacokinetics of vinpocetine, Pol. J. Pharmacol. 53

(2001) 623–628.

[3] Y. Qiu, J. Garren, E. Samara, G. Cao, C. Abraham, H.S.

Cheskin, K.R. Engh, Once-a-day controlled release dosage

form of dilvaproex sodium II: development of a predictive

in vitro drug release method, J. Pharm. Sci. 92 (2003)

2317–2325.

[4] A.R. Rabaji-Siahboomi, An overview of current oral modified

release technologies, Bus. Brief. Pharmatech. 2003 (2003)

181–184.

[5] P. Chiesi, P. Ventura, M. Pasini, J. Szejtli, M. Vikmon, E.

Redenti, Highly soluble multicomponent inclusion complexes

containing a base type drug, an acid and a cyclodextrin, USP

5,855,916 (1999).

[6] V.J. Stella, R.A. Rajewski, Cyclodextrins: their future in drug

formulation and delivery, Pharm. Res. 14 (1997) 556–567.

[7] L. Ribeiro, T. Loftsson, D. Ferreira, F. Veiga, Investigation and

physicochemical characterization of vinpocetine-sulfobutyl

ether h-cyclodextrin binary and ternary complexes, Chem.

Pharm. Bull. 51 (2003) 914–922.

[8] L. Ribeiro, D. Ferreira, F. Veiga, Physicochemical investiga-

tion of the effects of water-soluble polymers on vinpocetine

complexation with h-cyclodextrin and its sulfobutyl ether

derivative in solution and solid state, Eur. J. Pharm. Sci. 20

(2003) 253–266.

[9] L. Ribeiro, R.A. Carvalho, D.C. Ferreira, F.J.B. Veiga,

Multicomponent complex formation between vinpocetine,

cyclodextrins, tartaric acid and water-soluble polymers moni-

tored by NMR and solubility studies, Eur. J. Pharm. Sci.

(2004) (in press).

[10] Z. Wang, T. Horikawa, F. Hirayama, K. Uekama, Design and

in vitro evaluation of modified release oral dosage form of

nifedipine by hybridization of hydroxypropyl-h-cyclodextrin


and hydroxypropylmethylcellulose, J. Pharm. Pharmacol. 45

(1993) 942–946.

[11] P. Colombo, R. Bettini, G. Massimo, P.L. Catellani, P. Santi,

N.A. Peppas, Drug diffusion front movements is important in

drug release control from swellable matrix tablets, J. Pharm.

Sci. 84 (1995) 991–997.

[12] M.V. Velasco, J.L. Ford, P. Rowe, A.R. Rajabi-Siahboomi,

Influence of drug:hydroxypropylmethycellulose ratio, drug

and polymer particle size and compression force on the release

of diclofenac sodium from HPMC tablets, J. Control. Release

57 (1999) 75–85.

[13] S.R. Parakh, A.V. Gothoskar, M.T. Karad, A novel method for

the study of water absorption rates by swellable matrices,

Pharm. Technol. 5 (2003) 40–48.

[14] D.C. Bibby, N.M. Davies, I.G. Tucker, Mechanism by which

cyclodextrins modify drug release from polymeric drug

delivery systems, Int. J. Pharm. 197 (2000) 1–11.

[15] V.M. Rao, J.L. Haslam, V.J. Stella, Controlled and complete

release of a model poorly water-soluble drug, prednisolone,

from hydroxypropylmethylcellulose matrix tablets using SBE-

h-cyclodextrin as a solubilizing agent, J. Pharm. Sci. 90

(2001) 807–816.

[16] M.E. Sangalli, L. Zema, A. Maroni, A. Foppoli, A. Gazzaniga,

Influence of h-cyclodextrin on the release of poorly soluble

drugs from inert and hydrophilic heterogeneous polimeric

matrices, Biomaterials 22 (2001) 2647–2651.

[17] A.C. Jain, B.J. Aungst, M.C. Adeyeye, Development and in

vitro evaluation of buccal tablets prepared using danazol-

sulfobutylether7-h-cyclodextrin (SBE7) complexes, J. Pharm.

Sci. 91 (2002) 1659–1668.

[18] L.S. Koester, C.R. Xavier, P. Mayorga, V.L. Bassani, Influence

of h-cyclodextrin complexation on carbamazepine release

from hydroxypropyl methylcellulose matrix tablets, Eur. J.

Pharm. Biopharm. 55 (2003) 85–91.

[19] M. Jug, M. Becirevic-Lacan, Influence of hydroxypropyl-h-cyclodextrin complexation on piroxicam release from buc-

coadhesive tablets, Eur. J. Pharm. Sci. 21 (2004) 251–260.

[20] B. Pose-Vilarnovo, C. Rodrıguez, J.F. Rosa Dos Santos, J.

Vasquez-Doval, A. Concheiro, C. Alvarez-Lourenzo, J.J.

Torres-Labandeira, Modulating drug release with cyclodextrins

in hydroxypropyl methylcellulose gels and tablets, J. Control.

Release 94 (2004) 351–363.

[21] E.D. Jorgensen, D. Bhagwat, Development of dissolution tests

for oral extended-release products, Pharm. Sci. Technol. Today

1 (1998) 128–135.

[22] K.A. Khan, The concept of dissolution efficiency, J. Pharm.

Pharmacol. 27 (1975) 48–49.

[23] F.I.P., FIP guidelines for dissolution testing of solid oral

products (final drafts, 1995), Drug Inf. J. 30 (1996) 1071–1084.

[24] W.N. Charman, C.J.H. Porter, S. Mithani, J.B. Dressman,

Physicochemical and physiological mechanisms for the effects

of food on drug absorption: the role of lipids and pH, J. Pharm.

Sci. 86 (1997) 269–282.

[25] E. Galia, E. Nicolaides, D. Horter, R. Lobenberg, C. Reppas,

J.B. Dressman, Evaluation of various dissolution media for

predicting in vivo performance of class I and II drugs, Pharm.

Res. 15 (1998) 698–705.

[26] E. Nicolaides, E. Galia, C. Efthymiopoulos, J.B. Dressman, C.

Reppas, Forecasting the in vivo performance of four low

solubility drugs from their in vitro dissolution data, Pharm.

Res. 16 (1999) 1876–1882.

[27] E.S. Kostewicz, U. Brauns, P. Becker, J.B. Dressman,

Forecasting the oral absorption behavior of poorly soluble

weak bases using solubility and dissolution studies in

biorelevant media, Pharm. Res. 19 (2002) 345–349.

[28] P.P. Sanghvi, J.S. Nambiar, A.J. Shukla, C.C. Collins,

Comparison of three dissolution devices for evaluating drug

release, Drug Dev. Ind. Pharm. 20 (1994) 961–980.

[29] B.R. Rohrs, D.L. Burch-Clark, M.J. Witt, D.J. Stelzer,

USP dissolution apparatus 3 (reciprocating cyclinder):

instrument parameter effects on drug release from sus-

tained release formulations, J. Pharm. Sci. 84 (1995)

922–926.

[30] W. Sorasuchart, J. Wardrop, J.W. Ayres, Drug release from

spray layered and coated drug-containing beads: effects of pH

and comparison of different dissolution methods, Drug Dev.

Ind. Pharm. 25 (1999) 1093–1098.

[31] S. Klein, M.W. Rudolph, J.B. Dressman, Drug release

characteristics of different mesalazine products using USP

apparatus 3 to simulate passage through the GI tract,

Dissolution Technol. 9 (4) (2002) 6–13.

[32] J.W. Moore, H.H. Flanner, Mathematical comparison of curves

with an emphasis on in vitro dissolution profiles, Pharm.

Technol. 20 (6) (1996) 64–74.

[33] T. O’hara, A. Dunne, J. Butler, J. Devane, A review of

methods used to compare dissolution profile data, Pharm. Sci.

Technol. Today 1 (1998) 214–223.

[34] O.I. Corrigan, C.T. Stanley, Mechanism of drug dissolution rate

enhancement from beta-cyclodextrin-drug systems, J. Pharm.

Pharmacol. 34 (1982) 621–626.

[35] S.�Y. Lin, Y.H. Kao, Solid particulates of drug-h-cyclodextrininclusion complexes directly prepared by a spray-drying

technique, Int. J. Pharm. 56 (1989) 249–259.

[36] J. Szejtli, Preparation and characterization of cyclodextrins

complexes, in: K. Fromming, J. Szejtli (Eds.), Cyclodextrins in

Pharmacy, Kluwer Academic Plublishers, 1994.

[37] J.R. Moyano, M.J. Arias, J.M. Gines, F. Giordano, Solid-state

characterization and dissolution characteristics of glicazide-h-cyclodextrin inclusion complexes, Int. J. Pharm. 148 (1997)

211–217.

[38] G. Dollo, P. Le Corre, M. Chollet, F. Chevanne, M. Bertault,

J.L. Burgot, R. Verge, Improvement in solubility and

dissolution rate of 1,2-dithiole-3-thiones upon complexation

with h-cyclodextrin and its hydroxypropyl and sulfobuthyl

ether derivatives, J. Pharm. Sci. 88 (1999) 889–895.

[39] P. Mura, M.T. Faucci, G.P. Bettinetti, The influence of

polyvinylpyrrolidone on naproxen complexation with

hydroxypropyl-h-cyclodextrin, Eur. J. Pharm. Sci. 13

(2001) 187–194.

[40] Guidelines for the design and evaluation of oral prolonged

release dosage forms, Ministry of health and welfare of Japan,

1988.

[41] S.P. Duddu, M. Vakilynejad, F. Jamali, D.J.W. Grant, Stereo-

selective dissolution of propranolol hydrochloride from


hydroxypropyl methylcellulose matrices, Pharm. Res. 10

(1993) 1648–1653.

[42] J.E. Polli, G.S. Rekhi, L.L. Augsburger, V.P. Shah, Methods to

compare dissolution profiles and a rationale for wide dissolution

specifications for metoprolol tartrate tablets, J. Pharm. Sci. 86

(1997) 690–700.

[43] I. Martınez-Gonzalez, L. Villafuerte-Robles, Effect of varying

the restriction degree of 4-aminopyridine release from HPMC

matrices on the mechanism controlling the process, Int. J.

Pharm. 257 (2003) 253–264.

In vitro controlled release of vinpocetine–cyclodextrin–tartaric acid multicomponent complexes...

Documents

Transcript of In vitro controlled release of vinpocetine–cyclodextrin–tartaric acid multicomponent complexes...