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Chapter 1 Introduction Page no. 1 to 42

Chapter 1 Introduction

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Chapter 1

Introduction 1.1. INTRODUCTION TO DRUG DELIVERY SYSTEM

In recent years, drug discovery program has dramatically undergone changes from

“empirical-based” to “knowledge-based” rational drug design. Advances in biotechnology

and combinatorial synthetic approaches, clubbed with high throughput screening (HTS)

for pharmacological activity, have resulted in increasing number of diverse new chemical

entities (NCEs). However, this rational design of molecules does not necessarily mean

rational drug delivery, since the drug molecules do not always deliver themselves (Davis

and Illum, 1998). Drug development in the past used to be initiated after identification of

most active molecule. However this approach lead to a number of drawbacks with the

problems being that many molecules which are put into development had poor

physicochemical (solubility, stability) and biopharmaceutical (permeability and enzymatic

stability) properties, as a consequence of which about 40% of NCEs fail to reach the

market place (Prentis et al., 1988). Many investigational new drugs (INDs) fail during

preclinical and clinical development, with an estimated 46% of compounds entering

clinical development are dropped due to unacceptable efficacy and 40% due to safety

reasons (Kennedy 1997). Oral delivery of such drugs is also frequently associated with

low bioavailability, high intra- and inter-subject variability, and a lack of dose

proportionality (Kommuru et al., 2001).

Currently a number of technologies are available to deal with the poor solubility,

dissolution rate and bioavailability of insoluble drugs. Various formulation strategies

reported in the literature include, incorporation of a drug in oils (Burcham et al., 1997),

solid dispersions (Serajuddin et al., 1988), emulsions (Myers and Stella 1992b), liposomes

(Schwendener and Schott 1996), use of cyclodextrins (Perng et al., 1998), coprecipitates

(Nazzal et al., 2002), micronization (McInnes et al., 1982; Vogt et al., 2008), nanoparticles

(Shabouri 2002), permeation enhancers (Aungst 2000) and lipid-based vehicles

(Chakrabarti and Belpaire, 1978; Tokumura et al., 1987; Trull et al., 1995).

1.2. LIPID-BASED DRUG DELIVERY SYSTEM

Lipid-based drug delivery systems are experiencing a resurgence of interest lately (Hauss,

2007; Humberstone and Charman, 1997; Kreilgaard, 2002; Lawrence and Rees, 2000;


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Strickley, 2004; Wasan and Constantinides, 2004) since their introduction in 1974 by

Attwood et al.

However, much attention has been focused on lipid-based formulations, with particular

emphasis on self-emulsifying drug delivery systems or SEDDS, which were shown to

improve the oral bioavailability of many drugs, viz. halofantrine (Khoo et al., 1998),

ontazolest (Hauss et al., 1998), cyclosporine (Klauser et al., 1997), and progesterone

(MacGregor et al., 1997).

Lipid formulations are a diverse group of formulations with a wide variety of properties

and usually consist of a mixture of excipients, ranging from triglyceride oils through

mixed glycerides, lipophilic surfactants, hydrophilic surfactants and co-solvents (Pouton,

2000). Lipid-based formulations can decrease the intrinsic limitations of slow and

incomplete dissolution of poorly water soluble drugs by facilitating the formation of

solubilised phases from which absorption takes place. The achievement of such phases

will not essentially take place from the formulation itself, but alternatively from taking the

advantage of the intra luminal processing to which lipids are subjected (Humberstone and

Charman, 1997). The extent of drug absorption from lipid vehicles is significantly affected

by the dispersibility of the administered lipid and drug. On the other hand, because of the

inherent physical instability, the large volume of the two phase emulsion, and the poor

precision of dose, the use of conventional emulsions is problematic. A formulation

approach for avoiding such restrictive problems is the use of microemulsions or self-

emulsifying drug delivery systems (SEDDS). The most famous example of a

microemulsion based system is the Neoral® formulation of Cyclosporine, which result in

replacement of Sandimmune® (Choc, 1997; Postolache et al., 2002).

1.3. CLASSIFICATION OF LIPID-BASED DRUG DELIVERY SYSTEM

Lipid system includes triglycerides, mono and diglycerides, lipophilic surfactants,

hydrophilic surfactants and co-solvents; excipients with a wide variety of physicochemical

properties. A classification system was introduced in 2000 to help identify the critical

performance characteristics of lipid systems (Pouton, 2000). Table 1.1 is an updated

version of what could reasonably be called the lipid formulation classification system

(LFCS). Briefly, Type I formulations are oils which require to be digested, Type II

formulations are water-insoluble self-emulsifying drug delivery systems (SEDDS), Type


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III systems are SEDDS or self-microemulsifying drug delivery systems (SMEDDS) which

contain some water-soluble surfactants and/or co-solvents (Type IIIA) or a greater

proportion of water soluble components (Type IIIB). Table 1.1 includes an additional

category (Type IV) to represent the recent trend towards formulations which contain

predominantly hydrophilic surfactants and co-solvents. Type IV formulations contain no

oils and represent the most extremely hydrophilic formulations. The advantage of blending

a surfactant with a co-solvent to give a Type IV formulation is that the surfactant offers

much greater good solvent capacity on dilution (as a micellar solution) than the co-solvent

alone. The co-solvent is useful to facilitate dispersion of the surfactant, which is likely to

reduce variability and irritancy caused by high local concentrations of surfactant. A Type

IV formulation is useful for drugs which are hydrophobic but not lipophilic, though it is

necessary to bear in mind that Type IV formulations may not be well-tolerated if the drug

is to be used on a chronic basis. An example of a Type IV formulation is the current

capsule formulation of the HIV protease inhibitor amprenavir (Agenerase, GSK)

(Strickley, 2004). For this clinical indication the benefit clearly outweighs the risk. The

general characteristics, advantages and disadvantages of each type of lipid formulation are

shown in Table 1.2.

The performance of lipid formulations, and the fate of the drug in the gastrointestinal tract,

depends on the physical changes that occur on dispersion and dilution of the formulation,

and the influence of digestion on drug solubilisation. The main advantage of lipid

formulation is that the drug can remains in solution form throughout its period in the

gastrointestinal tract. However, if precipitation occurs at any stage the advantage of a lipid

formulation is lost. Precipitation of drug is more prevalent from lipid systems which

contain more hydrophilic excipients. Therefore, utmost care is needed with lipid

formulation because such excipients are often used to improve the solvent capacity of the

formulation, to increase the dose that can be administered in a single capsule.


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Table 1.1: The proposed lipid formulation classification system (LFCS) showing typical composition of various types of lipid formulations

Droplet size (nm) / Increasing hydrophilic content → Excipient composition (%) Type I Type II Type IIIA Type IIIB Type IV

Oils: triglycerides or mixed mono and diglycerides

100 40-80 40-80 < 20 -

Water-insoluble surfactants (HLB < 12) - 20-60 - - 0-20

Water-soluble surfactants (HLB > 12) - - 20-40 20-50 30-80

Hydrophilic co-solvents (e.g. PEG, propylene glycol, transcutol

- - 0-40 20-50 0-50

Particle size of dispersion Coarse 100-250 100-250 50-100

Significance of aqueous dilution Limited importance Solvent capacity

unaffected Some loss of

solvent capacity

Significant phase changes and

potential loss of solvent capacity

Micellar solution

Significance of digestibility

Crucial requirement

Not crucial but likely to occur

Not crucial but may be inhibited

Not required and not likely to occur Limited digestion

Table 1.2: Characteristic features, advantages and disadvantages of the various types of ‘lipid’ formulations LFCS type Characteristics Advantages Disadvantages

Type I Non-dispersing, requires digestion

GRAS status; simple; excellent capsule compatibility

Formulation has poor solvent capacity unless drug is highly lipophilic

Type II SEDDS without water-soluble components

Unlikely to lose solvent capacity on dispersion

Turbid o/w dispersion (0.25-2 µm particle size)

Type IIIA SEDDS/SMEDDS with water-soluble components

Clear or almost clear dispersion; drug absorption without digestion

Possible loss of solvent capacity on dispersion; less easily digested

Type IIIB SMEDDS with water-soluble components and low oil content

Clear dispersion; drug absorption without digestion

Likely loss of solvent capacity on dispersion

Type IV Oil-free formulation based on surfactants and co-solvents

Good solvent capacity for many drugs; disperses to micellar solution

Loss of solvent capacity on dispersion; may not be digestible

1.4. DIGESTION AND SOLUBILISATION OF LIPID-BASED FORMULATIONS

IN THE SMALL INTESTINE

The solubilization capacity of the digestive system is considerable and its presence has an

effect on the dissolution and absorption of lipophilic drugs from all formulations

(Embleton and Pouton, 1997). The solubilising power is greater after a fatty meal, hence,

food often has a positive effect on bioavailability of dissolution rate-limited BCS class II

drugs. Bile salt concentrations in the gut are 3–5 mM on a fasted stomach and

approximately 15 mM after food. Formulae for simulation of intestinal fluids in a fasted

subject (FaSSIF) and fed subject (FeSSIF) have been used as alternative dissolution media

(Dressman and Reppas, 2000), indicating that the dissolution of lipophilic drugs from

conventional tablets is correlated with the availability of bile salt micelles (for example


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Figure 1.1). A well-designed amorphous or lipid formulation presents the drug as a

molecular dispersion, so the corresponding issue is whether the drug can be transferred to

the mixed micellar system as the formulation is diluted into the aqueous phase. The

surfactant components would be expected to interact with mixed bile salt micelles, which

may result in a change in its structure and solubilization capacity (Lim and Lawrence,

2004). There are a few reports which shed light on the structures that result from

interaction of non-ionic surfactants with mixed micelles.

Figure 1.1: Dissolution profile of Romazin tablets (troglitazone 200 mg) (Nicolaides et al., 1999). An example of how the rate and extent of dissolution from solid dosage forms is influenced by the likely components in the gut lumen. The presence of bile salt micelles in FaSSIF and FeSSIF increase both rate and extent. The higher concentrations of bile salt micelles in FeSSIF, representing the fed intestine, have a profound effect.

1.5. SELF EMULSIFYING DRUG DELIVERY SYSTEM

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants,

ideally isotropic, and sometimes containing co-solvents, which emulsify spontaneously to

produce fine oil-in-water emulsions when introduced into aqueous phase under gentle

agitation (Gershanik and Benita 2000; Gursoy and Benita, 2004; Shah et al., 1994; Craig

et al., 1993). Recently, SEDDS have been formulated using medium chain triglyceride oils

and non-ionic surfactants, the latter being less toxic. Upon peroral administration, these

systems form fine emulsions (or micro-emulsions) in gastro-intestinal tract (GIT) with

mild agitation provided by gastric mobility (Shah et al., 1994). Fine oil droplets would

pass rapidly from the stomach and promote wide distribution of the drug throughout the

GI tract, thereby minimizing the irritation frequently encountered during extended contact


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between bulk drug substances and the gut wall. The basic difference between self

emulsifying drug delivery systems (SEDDS) also called as self emulsifying oil

formulation (SEOF) and SMEDDS is SEDDS typically produce opaque emulsions with a

droplet size between 100 and 300 nm while SMEDDS form transparent micro emulsions

with a droplet size of less than 50 nm also the concentration of oil in SMEDDS is less than

20 % as compared to 40-80% in SEDDS. Potential advantages of these systems include

enhanced oral bioavailability enabling reduction in dose, more consistent temporal profiles

of drug absorption, selective targeting of drug(s) toward specific absorption window in

GIT, and protection of drug(s) from the hostile environment in gut (Patil et al., 2004;

Pouton and Charman, 1997).

Advantages

1) SMEDDS is a novel approach to improve water solubility and ultimate bioavailability

of drugs for which water is a rate-limiting step. They have the ability to present the drug to

GIT in 1-100 nm globule size and the subsequent increase in specific area enables more

efficient drug transport through the intestinal aqueous boundary layer leading to

improvement in bioavailability.

2) Many drugs show large inter-subject and intra-subject variation in absorption leading to

fluctuation in plasma profile. Food is a major factor affecting therapeutic performance of

the drug in the body. SMEDDS produce reproducible plasma profile.

3) Fine oil droplets empty rapidly from the stomach and promote wide distribution of the

drug through the intestinal tract and thereby minimizing irritation frequently encountered

with extended contact of drugs with gut wall.

4) Ease of manufacture and scale up is one of the most important advantages that make

SMEDDS unique, when compared to other drug delivery system like solid dispersion,

liposomes, nanoparticles etc; dealing with improved bioavailability. SMEDDS require

very simple and economical manufacturing facility like mixture with agitator and

volumetric liquid filing equipment for large-scale manufacturing. This is of interest to

pharmaceutical industry.

5) SMEDDS has potential to deliver peptides that are prone to enzymatic hydrolysis in

GIT.

6) When polymer is incorporated in the composition of SMEDDS, it gives prolonged

release of medicaments.

7) Enhanced oral bioavailability results in dose reduction.


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8) Selective targeting of drugs towards specific absorption window in GIT.

Limitations

One of the obstacles for the development of self emulsifying drug delivery systems

(SEDDS) and other lipid-based formulations is the lack of good predicative in vitro

models for assessment of the formulations (Tang et al., 2008; Zhang et al., 2008).

Traditional dissolution methods do not work, because these formulations potentially are

dependent on digestion in the gut, prior to release of the drug. To mimic this, an in vitro

model simulating the digestive processes of the duodenum has been developed. This in

vitro model needs further refinement and validation before its strength can be evaluated.

Further development will be based on in vitro - in vivo correlations and therefore different

prototype lipid based formulations need to be developed and tested in vivo in a suitable

animal model (Patil et al., 2007; Tang et al., 2007).

Few other drawbacks are chemical instabilities of drugs and high surfactant concentrations

in formulations (approximately 30-60%) which irritate GIT. Moreover, volatile co-

solvents in the conventional self-microemulsifying formulations are known to migrate into

the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic

drugs. The precipitation tendency of the drug on dilution may be higher due to the dilution

effect of the hydrophilic solvent. At the same time, formulations containing several

components become more challenging to validate.

Mechanism of self-emulsification

The process by which self-emulsification takes place is not well understood. Self-

emulsification occurs when the entropy change that favors dispersion is greater than the

energy required to increase the surface area of the dispersion. In addition, the free energy

of a conventional emulsion formation is a direct function of the energy required to create a

new surface between the two phases and can be described by equation as given below

(Reiss, 1975).

Where ∆G is the free energy associated with the process (ignoring the free energy of

mixing), N is the number of droplets of radius, r, and s represents the interfacial energy.


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With time, the two phases of the emulsion will tend to separate, in order to reduce the

interfacial area, and also, the free energy of the systems. Therefore, the emulsions

resulting from aqueous dilution are stabilized by conventional emulsifying agents, which

form a monolayer around the emulsion droplets, and hence, reduce the interfacial energy,

as well as providing a barrier to coalescence. In the case of self-emulsifying systems, the

free energy required to form the emulsion is either very low and positive, or negative

(then, the emulsification process occurs spontaneously) (Craig et al., 1995). Emulsification

requiring very little input energy involves destabilization through contraction of local

interfacial regions. For emulsification to occur, it is necessary for the interfacial structure

to have no resistance to surface shearing (Dabros et al., 1999).

It has been suggested that the ease of emulsification could be associated with the ease by

which water penetrates into the various liquid crystalline (LC) or gel phases formed on the

surface of the droplet (Rang and Miller, 1999). According to Wakerly et al (1986), the

addition of a binary mixture (oil/non-ionic surfactant) to water results in interface

formation between the oil and aqueous-continuous phases, followed by the solubilization

of water within the oil phase owing to aqueous penetration through the interface. This will

occur until the solubilization limit is reached close to the interface. Further aqueous

penetration will result in the formation of the dispersed LC phase. As the aqueous

penetration proceeds, eventually all material close to the interface will be LC, the actual

amount depending on the surfactant concentration in the binary mixture. Once formed,

rapid penetration of water into the aqueous cores, aided by the gentle agitation of the self-

emulsification process, causes interface disruption and droplet formation. The high

stability of these self-emulsified systems to coalescence is considered to be due to the LC

interface surrounding the oil droplets. The involvement of the LC phase in the emulsion

formation process was extensively studied by Pouton et al. (Rang and Miller, 1999;

Wakerly et al., 1986). Later, Craig et al. used the combination of particle size analysis and

low frequency dielectric spectroscopy (LFDS) to examine the self-emulsifying properties

of a series of Imwitor 742 (a mixture of mono- and diglycerides of capric and caprylic

acids)/Tween 80 systems (Craig et al., 1993; Craig et al., 1995). The dielectric studies

have provided evidence that the formation of the emulsions may be associated with LC

formation, although the relationship was clearly complex (Craig et al., 1995).


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1.6. COMPONENTS OF SEDDS

Natural product oils

A number of natural product oils, derived primarily from plant sources and processed to

remove impurities or to isolate various fractions of the original product, are available and

suitable for use in encapsulated oral formulation products. Naturally occurring oils and

fats are comprised of mixtures of triglycerides which contain fatty acids of varying chain

lengths and degrees of unsaturation. The melting point of particular oil increases in

proportion to the fatty acid chain length and decreases with increasing degree of

unsaturation. However, unsaturation can make it susceptible to oxidation. Triglycerides

are classified as short (< 5 carbons), medium (6–12 carbons), or long chain (> 12 carbons)

and may be synthetically hydrogenated to decrease the degree of unsaturation, thereby

conferring resistance to oxidative degradation. Separation of natural product oils into their

component glyceride fractions is used to prepare excipients that maximize desirable

physical and drug absorption-promoting properties (Greenberger et al., 1966) while

minimizing susceptibility to oxidation.

Semi-synthetic lipid excipients

Several semi-synthetic liquid and thermo-softening (semisolid) excipients, most

commonly prepared by chemically combining medium-chain saturated fatty acids or

glycerides derived from natural product plant oils, with one or more hydrophilic chemical

entities are currently available as pharmaceutical excipients for oral formulation

development (Gibson, 2007). These excipients find application as drug-solubilizing

vehicles, surfactants and wetting agents and as emulsifiers and co-emulsifiers in SEDDS

and self-microemulsifying drug delivery systems (SMEDDS). They are generally well-

suited for filling into both soft and hard gelatin or into HPMC capsules. Thermo-softening

excipients, which melt in the range of 26-70 °C and exist as waxy semi-solids at ambient

room temperatures, are typically filled into capsules in the molten state, with the excipient

melting temperature limiting their use to hard gelatin capsules.

Fully-synthetic excipients

A number of fully-synthetic, monomeric and polymeric liquid and semi-solid excipients,

most of which are glycolic in nature and relatively non-toxic, are used as solvents for

formulating poorly water-soluble drugs. These excipients can be used alone or in


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combination with other lipid excipients to improve the overall solubilizing power of the

formulation. However, their pronounced water miscibility can compromise formulation

performance due to uncontrolled precipitation of the drug substance following dilution in

the aqueous contents of the GIT. This results in dose-dependent bioavailability

enhancement. A few examples of the most commonly applied excipients in this class and

their applications follows. Among the polymeric glycol-based excipients finding

pharmaceutical application, the polyethylene glycols (PEGs) are a versatile, well-

characterized and widely applied class of solubilizers which are available as both liquids

and thermo-softening semi-solids. The physical state of these excipients at ambient room

temperature is determined by their molecular weights (Rowe and Sheskey, 2003a). PEGs

ranging from 200 to 600 in molecular weight are liquid at ambient room temperature

whereas those possessing molecular weights of 1000 or greater exist as thermo-softening

semi-solids. In comparison to natural product oils, PEGs have the following

disadvantages: they tend to be more chemically reactive; they can be more irritating to the

GI mucosa than oils. PEGs are also known to contain varying levels of peroxide impurities

and secondary products formed by auto-oxidation, which can contribute to chemical

instability of the incorporated drug substance. These excipients are widely used in soft

gelatin capsule formulations but find only limited use in conjunction with hard gelatin

capsules due to their hygroscopicity and resultant effects on gelatin moisture content,

which can compromise capsule physical integrity. Propylene glycol, a pharmaceutically-

acceptable, monomeric solvent possessing humectant and plasticizing properties, finds

application for soft gelatin capsule formulations of poorly water-soluble drugs (Rowe and

Sheskey, 2003b). The poloxamers, which are co-polymers of polyoxyethylene and

polyoxypropylene, possess both solvent and surfactant properties and thus find application

in the oral delivery of poorly water-soluble drugs (Rowe and Sheskey, 2003c). As with the

PEGs, they are available in a range of molecular weights which control the physical state

of the excipient at room temperature. In addition to improving the bioavailability of poorly

water-soluble drugs, they have found application in modified release formulations

(Anderson et al., 2001).

Surfactants

Non-ionic surfactants with a relatively high hydrophilic - lipophilic balance (HLB) have

been suggested for the design of self-dispersing systems, where the various liquid or solid


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ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80) are the

most frequently used excipients (Table 1.3). Emulsifiers derived from natural sources are

expected to be safer than synthetic ones and are recommended for self dispersing liquid

formulation (SDLF) use, despite their limited ability to self-emulsify (Hauss et al., 1998;

Yuasa et al., 1994). Non-ionic surfactants are known to be less toxic compared to ionic

surface-active agents, but they may cause moderate reversible changes in intestinal wall

permeability (Swenson et al., 1994; Wakerly et al., 1986). Amemiya et al. have proposed a

new vehicle based on a fine emulsion using minimal surfactant content (3%) to avoid the

potential toxicological problems associated with high surfactant concentration (Amemiya

et al., 1998). The usual surfactant concentration in self-emulsifying formulations required

to form and maintain an emulsion state in the GI tract ranged from 30 to 60% w/w of the

formulation. A large quantity of surfactant may irritate the GI tract. Thus, the safety aspect

of the surfactant vehicle should be carefully considered in each case. The high HLB and

subsequent hydrophilicity of surfactants is necessary for the immediate formation of o/w

droplets and/or rapid spreading of the formulation in the aqueous environment, providing a

good dispersing/self-emulsifying performance. The surface-active agents are amphiphilic

by nature, and they are therefore usually able to dissolve and even solubilize relatively

high quantities of the hydrophobic drugs. The latter is of prime importance for preventing

precipitation within the GI lumen and for the prolonged existence of the drug molecules in

the soluble form, vital for effective absorption (Serajuddin et al., 1988; Shah et al., 1994).

The lipid mixtures with higher surfactant and co-surfactant/oil ratios lead to the formation

of self-microemulsifying formulations (SMEDDS) (Constantinides, 1995). Formulations

consisting only of the surfactant mixture may form emulsions or microemulsions (when

surfactants exhibit different low and high HLB) (Farah et al., 1994), micelle solution

(Aungst et al., 1994) or, in some particular cases, niosomes, which are non-ionic,

surfactant-based bilayer vehicles (Uchegbu and Vyas, 1998).

Co-solvents

Relatively high surfactant concentrations (usually more than 30% w/w) are required to

produce an effective self-emulsifying system (Gershanik and Benita, 2000). Organic

solvents, suitable for oral administration (ethanol, propylene glycol (PG), polyethylene

glycol (PEG), etc.) may help to dissolve large amounts of either the hydrophilic surfactant

or the drug in the lipid base. These solvents sometimes play the role of the co-surfactant in


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the microemulsion systems, although alcohol- free self-emulsifying microemulsions have

also been described in the literature (Constantinides, 1995). Such systems may exhibit

some advantages over the previous formulations when incorporated in capsule dosage

forms, since alcohol and other volatile co-solvents comprised in the conventional self-

emulsifying formulations are known to migrate into the shells of soft gelatin, or hard,

sealed gelatin capsules, resulting in the precipitation of the lipophilic drug. On the other

hand, the lipophilic drug dissolution ability of the alcohol free formulation may be limited.


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Table 1.3: Composition of SDLFs that led to oral bioavailability enhancement of lipophilic drugs in in-vivo models Delivery system Oil Surfactant(s) %w/w Solvent(s) Model Drug Drug content (%) Reference SEDDS Mixture of mono-

and di-glycerides of oleic acid

Solid, polyglycolized mono-, di- and triglycerides (HLB = 14)

80 or 20

- Ontazolast 7.5 Hauss et al., 1998

Surfactant/Solvent dispersion

- Tween 80 (HLB = 15) NA Ethanol PG Retinol (Vitamin A), riboflavin (Vitamin B2)

NA Bateman & Uccellini, 1984

Surfactant dispersion - Solid, polyglycolized mono-, di- and triglycerides (HLB = 14)

81 - Α-pentyl-3-(2-quinolinyl-methoxy)-benzenemethanol

19 Serajuddin et al., 1988

Sandimmune® (SEDDS)

Olive oil Polyglycolyzed glycerides (HLB = 3/4)

30 Ethanol Cyclosporin A 10 Grevel et al., 1986

Lipid dispersion Medium chain monacyl glycerol

Soybean phosphatidyl choline

30 - Hexarelin 11.8 Fagerholm et al., 1998

SEDDS Medium chain saturated fatty acids, peanut

Medium chain mono- and di-glycerides, Tween 80, PEG-25 glyceryl trioleate, Polyglycolyzed glycerides (HLB = 6-14)

5-60 - Ro 15-0778, a naphthalene derivative

5 Shah et al., 1994

SEDDS Medium chain fatty acids

PEG-25 glyceryl trioleate 25 - WIN 54954 (5-(5-(2,6- dichloro-4-(dihydro-2-oxazolyl)phentoxy)pentyl)-3-methylisoxazole

35 Charman et al., 1992

SMEDDS - Polyglycolyzed glycerides (HLB = 1-14)

96 - Indomethacin 4 Farah et al., 1994

Surfactant dispersion - Polyglycolyzed glycerides (HLB = 14)

79.5 PEG-400 DMP 323 (HIV protease inhibitor)

7.5 or 12.5 Aungst et al., 1994

Neoral® formulation (SMEDDS)

Hydrolyzed corn oil

Polyglycolyzed glycerides, POE-castor oil derivative

NA Glycerol Cyclosporin A 10 Constantinides, 1995

Neoral® formulation (SMEDDS)

Hydrolyzed corn oil

Polyglycolyzed glycerides, POE-castor oil derivative

NA Ethanol Cyclosporin A 10 Vonderscher & Meinzer, 1994

Positively charged SEDDS

Ethyl oleate Tween 80 25 Ethanol Cyclosporin A 10 Rang & Miller, 1999


Ethyl oleate Tween 80 25 Ethanol Progesterone 2.5 Tarr & Yalkowsky, 1989


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1.7. BIOPHARMACEUTICAL ISSUES AND CHOICE OF A FORMULATION

Dose of drug

The optimum formulation for each drug will depend on a number of factors; on the

required dose, on which types of formulation have sufficient solvent capacity to allow for

formulation of a unit dose, and in particular on the fate of the drug after these formulations

have been administered to the gut. In many instances the choice of formulation will be

limited by solvent capacity, and in others the drug will not be sufficiently soluble in any

lipid formulations. Generally the most difficult drugs are those which have limited

solubility in both water and lipid (typically with log P values of approximately 2). It is

unlikely that lipid formulation will be of value for such drugs. In contrast, more

hydrophobic drugs may permeate lipid bilayers freely but dissolve very slowly in the

lumen of the gut. It has been common in the past for formulators to be presented with the

challenge of formulating a high dose oral product for a new hydrophobic drug, in

circumstances when the dose has been estimated using the results of early pre-clinical

animal studies, Such studies may have been conducted with an inadequate formulation,

such as a crude aqueous suspension, from which bioavailability is poor. In these

circumstances it is wise to anticipate that bioavailability may be much greater from a lipid

system, which may allow pharmacological activity to be achieved with a lower dose. This

is particularly important for drugs with high log P, when in the first instance the solvent

capacity of lipid formulations appear to fall short of the required dose.

If the drug is potent and is sufficiently soluble in Type I, Type II or Type III systems then

a choice will need to be made between these options. The most important consideration

should be to avoid the precipitation of a drug, but secondary consideration is whether or

not rapid absorption is desirable. Typically Type II or Type III systems will undergo

gastric emptying earlier and will be in a colloidal state earlier than Type I systems. An

emulsifying system is likely to result in more rapid absorption and higher peak

concentrations of drug. If the drug has a low therapeutic index this may be undesirable,

which argues in favour of a Type I formulation.

Significance of droplet size

Tarr and Yalkowsky (1989) were able to demonstrate in a gut perfusion experiment that

emulsion droplet size affected the rate of absorption of cyclosporine A. Absorption was


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more rapid from the finer of two emulsions, though the emulsions compared were both

relatively coarse. The situation is very different when a small volume of a lipid

formulation is administered in a capsule. The contents of the capsule will be emptied into

the digestive environment of the upper small intestine, so that the most important factor

may not be the size of the particles in the initial dispersion, but rather their susceptibility to

digestion and/or solubilisation by mixed micelles of bile salts and phospholipids. One

consequence of reducing the oil content and including surfactants and co-solvents is that

the droplets become less susceptible to digestion. This means that self-emulsifying

systems are dependent on the initial emulsification process to produce a colloidal

dispersion. It is assumed that the droplet size should be as fine as possible, and there is

some evidence that this assumption holds in the case of cyclosporine A. The drug was

more available from the ‘Neoral’ formulation than the earlier ‘Sandimmune’ formulation,

which was a coarsely emulsifying system (Mueller et al., 1994). One possible explanation

for this observation may be that the coarse emulsion produced by the ‘SandimmuneTM’

formulation could not be reduced to colloidal dimensions, due to limited digestion. Type

IIIB formulations generally produce the finest dispersions, due to their high content of

water-soluble solubilising agents (Constantinides, 1995).

The risk of precipitation

Consider the example of a hydrophobic drug dissolved in a pure co-solvent such as

polyethylene glycol or propylene glycol. When the formulation is added to water, the

solvent capacity of the mixture falls, approximately, logarithmically as the formulation is

diluted into water. The result is precipitation of the drug. It is much more difficult to

predict the fate of the drug on dispersion of a Type IIIA lipid formulation; perhaps

consisting of a drug dissolved in 30% medium chain triglycerides, 40% mixed partial

glycerides, and 30% hydrophilic surfactant. The hydrophilic surfactant will be

substantially separated from the oily components, forming a micellar solution in the

continuous phase. Does this lower the overall solvent capacity for the drug? That will

depend on the log P of the drug, and to what extent the surfactant was contributing to its

solubilisation within the formulation.


Page 16

Role of lipolysis and solubilisation in bile

Digestion of dietary triglycerides in the small intestine is very rapid, and many other non-

ionic esters, such as mixed glycerides and surfactants will be substrates for pancreatic

lipase (Embleton and Pouton, 1997). Digestion of formulations will inevitably have a

profound effect on the state of dispersion of the lipid formulation, and the fate of the drug

(MacGregor et al., 1997). The natural process of digestion offers the possibility that very

hydrophobic drugs could be taken up into the lymphatic system by partitioning into

chylomicrons in the mesentery (Porter and Charman, 1997). This is expected to be a

mechanism of absorption for drugs with log P values greater than 6, and has been

demonstrated for the anti-malarial compound halofantrine (Porter et al., 1996).

However, it is possible that digestion of a lipid formulation could reduce the solubility of

the drug in the gut lumen, which would result in precipitation of the drug and a decrease in

the absorption rate. More work needs to be carried out to establish which drugs are

precipitated on digestion. For such compounds Type II or Type III systems might be

preferable, since the presence of surfactants can inhibit digestion of the oil within the

formulation (MacGregor et al., 1997). Type III systems such as ‘Neoral’ have been shown

to act independently of bile, which suggests that they are not necessarily digested before

the drug is absorbed (Trull et al., 1995).

Drug absorption from SDLFs

Numerous bioavailability studies carried out in animals suggested that hydrophobic drugs

are better absorbed when administered as o/w emulsions (Hauss et al., 1994; Myers and

Stella, 1992b; Palin et al., 1986; Stella et al., 1978; Toguchi et al., 1990a; Toguchi et al.,

1990b). The improvement of the plasma profile reproducibility of WIN 54954 following

administration in SEDDS compared to PEG solution was emphasized by Charman et al.

(Charman et al., 1992), while others reported a higher bioavailability of the hydrophobic

drugs after administration as SEDDS (Fischl et al., 1997; Hauss et al., 1998; Shah et al.,

1994). In in-vivo absorption studies in non-fasting dogs for a lipophilic drug, RO15-0778,

a naphthalene derivative (Shah et al., 1994), SEDDS gave at least a three-fold greater Cmax

and AUC than the drug in any other liquid or solid oral dosage form (Table 1.4) (Shah et

al., 1994). The absorption in rats of ontazolast, a poorly water-soluble, lipophilic anti-

inflammatory compound (a potent calcium ionophore A23187-stimulated leukotriene B4


Page 17

inhibitor), as a function of lipid-based delivery system composition was investigated by

Hauss et al (1998). The bioavailability of this drug was significantly enhanced by all lipid-

based formulations: the emulsion, glyceryl oleate (Peceol) solution and both semisolid

SEDDS, containing either 20/80 or 50/50 Peceol/Gelucire 44/14 (PEG-32 glyceryl laurate)

compared to suspension formulation. The absorption of the poorly water-soluble

experimental drugs REV 5901 (a-pentyl-3-(2-quinolinylmethoxy)- benzenemethanol) and

DMP 323 (HIV protease inhibitor) in dogs from capsules containing solid dispersion with

Gelucire 44/14 was higher than that from PEG-based formulations (Serajuddin et al.,

1988). In multiple dosage studies carried out in HIV-infected patients, the administration

of SEDDS formulation resulted in a larger AUC, and a higher Cmin and Cmax, of the HIV

protease inhibitor SC-52151 (a urea-based peptide-mimetic compound) than the

corresponding elixir formulation (Fischl et al., 1997). A recently designed freeze-dried

formulation, consisting of olive oil and egg albumin, was shown to markedly enhance the

oral bioavailability of several hydrophobic drugs (Tsuji et al., 1996).

Table 1.4: Pharmacokinetic parameters of a lipophilic naphthalene derivative (Ro 15 0778) from different formulations in non-fasting dogs Formulation Cmax

(mg/mL) Tmax (h)

AUC (µg.h/mL)

Relative bioavailability (%)

SEDDS 5.57 2.50 29.77 389.0 Drug solution in PEG 400 (Control)

1.44 2.00 7.64 100.0

Capsule formulation of wet-milled spray dried powder

0.78 3.00 2.69 35.3

Tablet of micronized drug 0.58 2.00 1.32 17.2

Influence of the lipid vehicle

Effect of the oil vehicle on lipophilic drug pharmacokinetic parameters may be discussed

with respect to the effect of lipid composition and the efficiency of the carrier system. The

effect of lipids on the bioavailability of orally administered drugs is highly complex due to

numerous mechanisms by which the lipids can alter the biopharmaceutical characteristics

of the drug. They include a decreased rate of gastric emptying, an increased dissolution

rate of the drug and solubility in the intestinal fluid, and the formation of lipoproteins

promoting the lymphatic transport of highly lipophilic drugs (Hauss et al., 1998; Hauss et

al., 1994).


Page 18

Factors such as the acid chain length of a triglyceride, the saturation degree and the

volume of lipid administered may affect the drug absorption profile and its blood/lymph

distribution. Three major processes can occur in the intestine: large fat droplets are further

emulsified by bile salts, monoglycerides, cholesterol, lecithin and lysolecithin to produce

droplets with a mean diameter of 0.5-1 mm. These droplets are then metabolized by

pancreatic lipase, an enzyme with a molecular weight of about 40 000 Da (Maio and

Carrier, 2011). The dispersed oil droplet fragments form mixed micelles with bile salts

(Senior, 1964).

Lymphatic absorption pathway

Charman et al (1992 and 1986) proposed that drug candidates for lymphatic transport

should have a log P >5 and, in addition, a triglyceride solubility >50 mg/ml. The

importance of lipid solubility was illustrated by a comparing the lymphatic transport of

dichloro diphenyl trichloroethane (DDT, log P 6.19) with hexachlorobenzene (HCB, log P

6.53). While both compounds have similar log P values, the difference in lymphatic

transport on administration in oleic acid, 33.5% of the dose in the case of DDT and 2.3%

with HCB, was attributed to the 13-fold difference in triglyceride solubility (Charman et

al., 1986). However, combination of a high log P and high triglyceride solubility does not

always guarantee significant lymphatic transport. Penclomedine, an experimental

cytotoxic agent with a log P of 5.48 and a triglyceride solubility of 175 mg/ ml, was

poorly transported in the intestinal lymph, ~3% of the dose (Myers and Stella, 1992a).

Khoo et al. showed significant lymphatic transport of the poorly lipid soluble (~1 mg/ml)

HCl salt of halofantrine (Hf-HCl), following oral post-prandial administration to dogs. The

authors suggest that the high level of lymphatic transport of Hf-HCl (43.7% of dose),

which was similar to that of the lipid soluble Hf base, was due to conversion of Hf-HCl in

the intestinal lumen, during lipolysis, to the more lipophilic free base, which then becomes

associated with chylomicron production (Khoo et al., 1999).

Partitioning of the absorbed drug into the lymph is hindered by the low rate of lymph fluid

transport relative to that of blood, which is approximately 500-fold greater in the rat.

Nevertheless, this way may be contributive for highly lipophilic drugs with a log P of

more than 5, and high triglyceride solubility (Hauss et al., 1998; Hauss et al., 1994;

Toguchi et al., 1990a). The extent of lymphatic absorption may be altered by the lipid


Page 19

vehicle (Hauss et al., 1998; Hauss et al., 1994; Porter et al., 1996; Toguchi et al., 1990a).

The rank order effect of the vehicles for the promotion of the lymphatic transport of

halofantrine hydrochloride, a highly lipophilic anti-malarial agent, was micelles >

emulsion > lipid solution (Porter et al., 1996). In another study, the soybean-based

emulsion formulation produced significantly greater drug (ontazolast) transport into the

lymph than Peceol/Tween 80 SEDDS formulations (Hauss et al., 1998). Evidently, the

lipid composition of the vehicle, more so than the vehicle type, is the decisive factor for

lymphatic transport promotion. It was shown that enhanced lymphatic transport is not

necessarily reflected by proportionally elevated plasma AUC (Hauss et al., 1998; Hauss et

al., 1994). The amount of ontazolast transported by the lymph with only Peceol solution

was as high as that for the emulsion formulation, but the overall drug bioavailability from

oil was lower than that with SEDDS or emulsion formulations. In the other study, the total

quantity of CI-976 (2,2-dimethyl-N-(2,4,6-trimethoxyphenyl) dodecanamide), a poorly

water-soluble lipid regulator, transported in the lymph and accumulated in the peripheral

fat as a percentage of the dose administered, was much greater for the emulsion compared

to the surfactant dispersion formulation, although the plasma AUC was higher for the

dispersion formulation (Hauss et al., 1994).

Drug release

The release of a drug occurs following its partitioning to aqueous intestinal fluids during

droplet transport and disintegration along the GI tract. Shah et al. (1994) proposed that the

effective delivery of a drug from SEDDS is governed by two main factors: small particle

size and the polarity of the resulting oil droplets, which permits a faster rate of drug

release into the aqueous phase. The optimal polarity of the formulation is achieved by the

appropriate combination of oil and surfactants. In o/w microemulsion formulations, the

polarity of the oil phase is a less dominant factor, since the drug can reach the capillaries

while still incorporated within the microemulsion droplets (Constantinides, 1995;

Georgakopoulos et al., 1992; Vonderscher and Meinzer, 1994). Excess surfactant in a

formulation may also promote the effective dispersion of drug in the lumen by the

solubilisation process, in addition to drug spreading in oil droplets (Toguchi et al., 1990b).

The solubilized drug does not precipitate in the lumen, and undergoes rapid absorption

which is independent of the lipid digestion process. The presence of the lipid core in the

dispersed system is not a prerequisite for achieving the best solubilization effect. In some


Page 20

cases, therefore, the surfactant-based vehicle may be preferable, due to relative ease of

formulation design compared to SEDDS/microemulsion formulations (Serajuddin et al.,

1988). It was shown that the drug loading improvement of an o/w microemulsion over a

micellar system appears to depend on the solubility of the drug in the dispersed oil phase,

and is significant only for very lipophilic drugs (Malcolmson and Lawrence, 1993; Naylor

et al., 1993).


Multiple physiological studies have proved that the apical potential of absorptive cells, as

well as that of all other cells in the body, is negatively charged with respect to the mucosal

solution in the lumen (Aungst et al., 1988; Corbo et al., 1990). It was recently shown that

positively charged emulsion droplets formed by appropriate SEDDS dilution undergo

electrostatic interaction with the Caco-2 monolayer and the mucosal surface of the everted

rat intestine (Gershanik et al., 1998; Gershanik et al., 2000). This formulation enhanced

the oral bioavailability of progesterone in young female rats (Gershanik and Benita, 1996)

and exhibited higher blood levels of Cyclosporine A (CsA) in perfused rats in comparison

to the corresponding negatively charged formulation. Many aspects of these formulations

are still unclear. Positively charged formulations differ from negatively charged

formulations with respect to their interaction with biological components in the GI

environment. Positively charged droplets should be attracted to the negatively charged

physiological compounds naturally occurring in lumen (Gershanik et al., 1998). It was

already shown by these authors that larger droplets (a few microns in size range) are less

neutralized by mucin solutions of different concentrations than smaller droplets

(submicron size range) formed by the same formulation (Gershanik et al., 1998).

1.8. REGULATORY STATUS OF LIPID EXCIPIENTS

Historically, excipients were considered inert substances that would be used mainly as

diluents, fillers, binders, lubricants, coatings, solvents, and dyes, in the manufacture of

drug products (Handbook of Pharmaceutical Excipients, 1986). Over the years, however,

advances in pharmaceutical science and technology have facilitated the availability of a

wide range of novel excipients. In some cases, known and/or unknown interactions can

occur between an excipient and active ingredient, other inactive ingredient(s), biological

surroundings, or even container closure system (Adkin et al., 1995; Aungst, 2000; Basit et


Page 21

al., 2002; Bernkop-Schnurch and Kast, 2001; Chen et al., 2007; Hermeling et al., 2006;

Hermeling et al., 2003; Martin-Facklam et al., 2002; Rege et al., 2001; Sharma et al.,

2004; Tayrouz et al., 2003; Villalobos et al., 2005; Yu et al., 1999). Accordingly, it is now

recognized that not all excipients are inert substances and some may be potential toxicants

(http://www.fda.gov/cder/guidance/5544fnl.pdf.). The U.S. Food and Drug Administration

(FDA) has published listings in the Code of Federal Regulations (CFR) for GRAS

substances that are generally recognized as safe (USFDA, Title 21, Code of Federal

Regulations, Part 182, 184, 186.). Over the years, the Agency also maintains a list entitled

Inactive Ingredient Guide (IIG) for excipients that have been approved and incorporated in

the marketed products (http://www.fda.gov/cder/drug/iig/default.htm;

http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm). This guide is helpful in that it

provides the database of allowed excipients with the maximum dosage level by route of

administration or dosage form for each excipient. Both GRAS listings and IIG information

can be used by industry as an aid in developing drug products.

For new drug development purposes, once an inactive ingredient has appeared in an

approved drug product for a particular route of administration, the inactive ingredient is

not considered new and may require a less extensive review the next time it is included in

a new drug product. For example, if a particular inactive ingredient has been approved in a

certain dosage form with certain potency, a sponsor could consider it safe for use in a

similar manner for a similar type of product. In general, nonclinical and clinical studies are

required to demonstrate the safety of a new excipient before use. In this context, the U.S.

FDA has recently published a guidance document for industry on the conduct of

nonclinical studies for the safety evaluation of new pharmaceutical excipients

(http://www.fda.gov/cder/guidance/5544fnl.pdf.). This guidance not only provides the

types of toxicity data to be used in determining whether a potential new excipient is safe,

but also describes the safety evaluations for excipients proposed for use in over-the-

counter and generic drug products. The document also depicts testing strategies for

pharmaceuticals proposed for short-term, intermediate, and long-term use. More

importantly, this guidance highlights the importance of performing risk-benefit

assessments on proposed new excipients in the drug products while establishing

permissible and safe limits for the excipients. As illustrated, with proper planning, it is

often possible to assess the toxicology of an excipient in a relatively efficient manner

(http://www.fda.gov/cder/guidance/5544fnl.pdf.). Existing human data for some excipients


Page 22

can substitute for certain nonclinical safety data. In addition, an excipient with

documented prior human exposure under circumstances relevant to the proposed use may

not require evaluation with a full battery of toxicology studies (http://www.fda.gov/cder/

guidance/5544fnl.pdf.).

There is no process or mechanism currently in place within the FDA to independently

evaluate the safety of an excipient. Instead, for a drug or biological product subject to pre-

marketing approval, their excipients are reviewed and approved as ‘components’ of the

drug or biological product in the application. From a scientific standpoint, the regulatory

process is appropriate since excipients play an integral part to the formulation and cannot

be reviewed separately from the drug product. This is particularly true for lipid excipients

in view of their distinct physicochemical properties and potential complex interactions

with other ingredients or physiological environment that may occur in vivo.

1.9. CURRENTLY MARKETED ORAL LIPID-BASED FORMULATION

PRODUCTS

As determined in a recently published survey by Strickley, oral lipid-based formulations

have been marketed for over 2 decades and currently comprise an estimated 2–4% of the

commercially available drug products surveyed in 3 markets worldwide (Strickley, 2004

& 2007)(Table 1.5-1.7) . These products accounted for approximately 2% (21 products

total) of marketed drug products in the United Kingdom, 3% (27 products total) in the

United States of America, and 4% (8 products total) in Japan. Strickley's survey revealed

that the most frequently chosen excipients for preparing oral lipid-based formulations were

dietary oils composed of medium- (e.g., coconut or palm seed oil) or long-chain

triglycerides (e.g., corn, olive, peanut, rapeseed, sesame, or soybean oils, including

hydrogenated soybean or vegetable oils), lipid soluble solvents (e.g., polyethylene glycol

400, ethanol, propylene glycol, glycerin), and various pharmaceutically- acceptable

surfactants (e.g., Cremophor® EL, RH40, or RH60; polysorbate 20 or 80; D-α-tocopherol

polyethylene glycol 1000 succinate (TPGS®); Span 20; various Labrafils®, Labrasol®, and

Gelucires®). These formulations, which took the form of either bulk oral solutions or

liquid-filled hard or soft gelatin capsules, were applied in instances where conventional

approaches (i.e., solid wet or dry granulation, or water-miscible solution in a capsule) did

not provide sufficient bioavailability, or in instances in which the drug substance itself was


Page 23

an oil (e.g., dronabinol, ethyl icosapentate, indometacin farnesil, teprenone, and tocopherol

nicotinate). The total daily drug dose administered in these formulations, which range in

complexity from simple solutions of the drug in a dietary oil up to multi-excipient, self-

emulsifying drug delivery systems (SEDDS), range from less than 0.25 μg to greater than

2000 mg. The amount of drug contained in a unit-dose capsule product ranges from 0.25

μg to 500 mg and for oral solution products, from 1 μg/mL to 100 mg/mL. The total

amount of lipid excipient administered in a single dose of a capsule formulation ranges

from 0.5 to 5 grams, but can range from as low as 0.1 mL to as high as 20 mL for oral

solution products. Some of these products tolerate room temperature storage for only brief

periods of time and require long-term storage at 2–8 °C due to chemical and/or physical

stability issues.


Page 24

Table 1.5: List of Selected Commercially Available Lipid-based Formulations for Oral Administration in the United States in 2005 Molecule/trade

name/company

Indication Dose Type of

Formulation/Strength

Lipid excipients and surfactants Nonlipid excipients Storage

Amprenavir/

Agenerase®/

GlaxoSmithKline

HIV antiviral 1200 mg (8 capsules) b.i.d Soft gelatin capsule,50, 150

mg

TPGS (280 mg in the 150 mg

capsule)

PEG 400

(247, 740 mg), propylene

glycol(19,57 mg)

RT

Pediatrics

> 4 years old,

< 50 kg at 17 mg/kg (1.1 ml/kg)

t.i.d.;

> 50 kg at 1400 mg

(~93 ml) b.i.d.

Oral Solution, 15 mg/ml TPGS (~12%) PEG 400 (~17%), propylene glycol

(~5%), Sodium Chloride, citric acid,

flavours/sweeteners

RT

Baxarotene/

Targetin®/

Ligand

Antineoplastic 300-750 mg (4-10 capsules) q.d. Soft gelatin capsule, 75 mg Polysorbate 20 PEG 400, povidone, BHA RT, avoid high temp,

humidity and light

Calcitriol/

Rocaltrol®/

Roche

Calcium

regulator

Adults:

0.25-0.5 mcg (1 capsule) q.d.

Soft gelatin capsule, 0.25-0.5

mcg

Fractionated triglyceride of

coconut oil (MCT)

BHA, BHT 15-30°C protect from light

Pediatrics:

10-15 ng/kg (0.01-0.015 ml/kg)

q.d.

Oral Solution, 1 µg/ml Fractionated triglyceride of palm

seed oil

BHA, BHT 15-30°C protect from light

Ciprofloxacin/

Cipro®/

Bayer

Antibiotic 15mg/kg b.i.d. not to exceed the

adult dose of 500 mg per dose

Microcapsules for constitution

to suspension, 5 % or 10 % in

solid, 50 or 100 mg/ml in

suspension

Bottle 1- diluents: MCT, sucrose ,

lecithin, water and strawberry

flavour

Bottle 1- Solid: PVP, methacrylic

acid copolymer, HPMC, magnesium

stearate and Polysorbate 20

Store below 30° C but not

frozen

Cyclosporin A/I.

Neoral®/Novartis

Immunosuppr

essant/Prophyl

axis for organ

transplant

rejection

2-10 mg/kg/day, b.i.d. (1-7

capsules)

Soft gelatin capsule, 10, 25,

50, 100 mg

dI-α-tocopherol, corn oil-mono-

di-triglycerides, cremophore RH

40

Ethanol 11.9%, glycerol, propylene

glycol

RT


Page 25

2-10 mg/kg/day, b.i.d. (1-7 ml) Oral Solution 100 mg/ml dI-α-tocopherol, corn oil-mono-

di-triglycerides, cremophore RH

40

Ethanol 11.9%, glycerol, propylene

glycol

RT, do not store in the

refrigerator

Cyclosporin A/II.

Sandimmune®/Novar

tis

2-10 mg/kg/day, b.i.d. (1-7

capsules)

Soft gelatin capsule, 25, 100

mg

Corn oil, Labrafil M-2125CS Ethanol 12.7%, glycercol RT

2-10 mg/kg/day, b.i.d. (1-7 ml) Oral Solution 100 mg/ml Olive oil, Labrafil M-2125CS Ethanol 12.5% RT

Cyclosporin A/III

Gengraf®/Abbott

2-10 mg/kg/day, b.i.d. (1-7

capsules)

Hard gelatin capsule, 25, 100

mg

Cremophor EL, Polysorbate 80 Ethanol 12.8%, propylene glycol RT

Cyclosporin A/IV

Cyclosporin®/Sidmak

1-9 mg/kg/day 70-700 mg, (1-7

capsules)

Soft gelatin capsule, 100 mg Labrafac, dI-α-tocopherol

glyceryl caprylate, Labrasol,

Cremophor EL

RT

Doxercalciferol/

Hectorol®

Bone care

Management

of secondary

hyperparathyr

oidism

associated

with chronic

renal dialysis

10-20 mcg three times weekly (4-

8 capsules)

Soft gelatin capsule, 0.5, 2.5

µg

Fractionated triglycerides of

coconut (MCT)

BHA, ethanol RT

Dronabinol/Marino®/

Roxane and Unimed

Anorexia or

nausea

2.5-10 mg (1 capsule) b.i.d. Soft gelatin capsule 2.5, 5, 10

mg

Sesame oil None 8-15°C protect form freezing

Dutasteride/Avodart®

/

GlaxoSmithKline

Treatment of

benign

prostrate

hyperplasia

0.5 mg q.d. (1 capsule) Soft gelatin capsule, 0.5 mg Mixture of mono- and

diglycerides of caprylic/capric

acid

BHT RT

Isotretinoin/Accutane®/

Roche

Anti-

comedogenic

0.5-1.0 mg/kg/day subdivided in

two doses (1-2 capsules)

Soft gelatin capsule, 10, 20, 40

mg

Beeswax, hydrogenated soyabean

oil flakes, hydrogenated

vegetable oils, soyabean oil

BHA, EDTA RT, protect from light

Lopinavir and

ritonavir/Kaletra®/

Abbott

HIV antiviral 400/100 mg b.i.d. (2 tablets) or

800/200 mg q.d. (4 tablets)

Tablet 200 mg lopinavir and

50 mg ritonavir

Sorbitan monolaurate Sodium stearyl fumarate,

crosspovidone and silicon dioxide

RT


Page 26

400/100 mg b.i.d. (3 capsules) Soft gelatin capsule. 133.3 mg

lopinavir and 33.3 mg ritonavir

Oleic acid, Cremophor EL Propylene glycol 2-8°C, or at RT for < 2

months

400/100 mg b.i.d. (5 ml) Oral Solution, 80 mg/ml

lopinavir and 20 mg/ml

ritonavir

Cremophor RH 40, peppermint

oil

Alcohol (42.2% v/v), glycerine,

propylene glycol, sodium chloride,

sodium citrate, citric acid, water,

flavours/sweeteners

2-8°C, or at RT for < 2

months

Progesterone/

Prometrium®/Solvay

Hormone

replacement

therapy

200-400 mg q.d. (2-4 capsules) Soft gelatin capsule, 100, 200

mg micronized

Peanut oil None RT, protect from light and

excessive moisture

Ritonavir/Norvir®/

Abbott

HIV antiviral Adults 600 mg (6 capsules) b.i.d. Soft gelatin capsule, 100 mg Oleic acid, Cremophor EL BHT, Ethanol 2-8°C, or at RT for < 1

months

Pediatrics 250-450 mg/m2 upto a

max. Of 600 mg (<7.5 ml) b.i.d.

Oral Solution, 80 mg/ml Cremophore EL, sweetener, dye Ethanol (43%), water, propylene

glycol, citric acid, flavours

RT

Saquinavir/

Fortovase®/

Roche

HIV antiviral 1200 mg capsule (6 capsules)

t.i.d. without ritonavir, 1000 mg

(5 capsules) b.i.d. with ritonavir

Soft gelatin capsule, 200 mg Medium chain mono- and

diglycerides, dI-α-tocopherol

Povidone 2-8°C, or at RT for < 3

months

Sirolimus/

Rapamune®/

Wyeth-Ayerst

Immuno-

suppressant

6 mg (6 ml) loading dose

followed by 2 mg (2ml) q.d.

Oral Solution, 1 mg/ml Phosal 50 PG (phosphatidyl

choline, , mono-and diglycerides,

soy fatty acids, ascorbyl

palmitate), polysorbate 80

Phosal 50 PG, propylene glycol,

ethanol (1.5-2.5%)

2-8°C, or at RT for < 15 days

Tipranavir/Aptivus®/

Boehringer

Ingelheim

HIV antiviral 500 mg (2 capsules) with

ritonavir 200 mg b.i.d.

Soft gelatin capsule, 200 mg Cremophor EL, medium chain

mono- and diglycerides

Ethanol (7% w/w or 0.1 g per

capsule), propylene glycol

2-8°C prior to opening the

bottle, RT for < 60 days

Tolterodine

tartarate/Detrol® LA/

Pharmacia & UpJohn

Overactive

bladder-

muscarinic

receptor

antagonist

2-4 mg q.d. (1 capsule) Extended release hard gelatin

capsule, 2, 4 mg

MCT, oleic acid Sucrose, hypromellose, ethylcellulose RT

Tretinoin/

Vesanoid®/

Roche

Antineoplastic 45 mg/m2 subdivided (8 capsules)

b.i.d.

Soft gelatin capsule, 10 mg Beeswax, hydrogenated soyabean

oil flakes, hydrogenated

vegetable oils, soyabean oil

BHA, EDTA RT


Page 27

Valproic

acid/Depakene®/

Abbott

Antiepileptic 10-60 mg/kg/day (3-15 capsules) Soft gelatin capsule, 250 mg Corn oil None RT

Table 1.6: List of Selected Commercially Available Lipid-based Formulations for Oral Administration in the United Kingdom in 2005 Molecule/trade

name/company

Indication Dose Type of Formulation/Strength Lipid excipients and

surfactants

Nonlipid

excipients

Storage

Alfacalcidol/One-Alpha®

capasule/Leo Laboratories

Calcium regulator 0.5-1 mcg q.d. (1 capsule) Soft gelatin capsule, 0.25, 0.5, 1.0

µg

Sesame oil, dI-α-tocopherol None RT

Clofzimine/Lamprene®

Caosule 100 mg/ Alliance

Pharmaceuticals

Treatment of

leprosy in

combination with

dapsone and

rifampicin

Maximum 300 mg q.d. for

upto 3 months (3

capsules)

Soft gelatin capsule, 100 mg

(micronized suspension in an oil-

wax base)

Rapeseed oil, wax blend

(beeswax hydrogenated

soybean oil, partially

hydrogenated plant oils)

BHT, citric

acid, PG

Below 25°C

Clomethiazole

edisilate/Heminevrin®

Capsules/AstraZeneca

Sedative 1-4 capsules as needed Soft gelatin capsule, 192 mg MCT from fractionated

coconut oil

None RT

Efavirenz/Sustiva® Oral

Solution/Bristol-Meyers

Squibb

HIV antiviral Adults:

600 mg q.d. (up to 20 ml)

Pediatrics:

270-600 mg (9-20 ml)

Oral Solution, 30 mg/ml MCT Benzoic acid,

strawberry/mint

flavour

RT

Fenofibrate/Fenogal®/

Genus

Anti-

hyperlipoproteine

mic

200 mg (1 capsule) q.d. Hard gelatin capsule, 200 mg Gelucire 44/14, hydrogenated

vegetable oil

PEG-20,000,

HPC

RT

Morphine sulphate/

MXL® capsules/Napp

Pharmaceuticals

Analgesic 30-200 mg q.d. (1

capsule)

Hard gelatin capsule containing

multiparticulates, 30, 60, 90, 120,

150 and 300 mg

Hydrogenated vegetable oil PEG-6000, talc,

magnesium

stearate

RT


Page 28

Testosterone

undecanoate/Restandol® 40

mg/Organon Laboratories

Hormone

replacement

therapy

40-160 mg q.d. (1-4

capsules) undecanoate

Soft gelatin capsules, 40 mg HSE

(equivalents of testosterone, 61

mg of testosterone

Oleic acid None 2-8°C until

dispensed, then at

RT after

dispensing.Protect

from light and heat

Valproic acid/Convulex®

100 mg, 200 mg, 500

mg/Pharmacia

Antiepileptic 10-60 mg/kg/day upto

2500 mg per day (1-5

capsules)

Soft gelatin capsule, 100, 200 and

500 mg

MCT HPMC-

phthalate and

dibutyl-

phthalate

RT

Table 1.7: List of Selected Commercially Available Lipid-based Formulations for Oral Administration in the Japan in 2005 Molecule/trade name/company Indication Dose Type of Formulation/Strength Lipid excipients and

surfactants

Nonlipid excipients Storage

Ethyl icosapentate/Epadel® Capsules

300/Mochida Pharmaceuticals

Hyperlipidemia 600 mg (2

capsules) t.i.d.

Soft gelatin capsules, 300 mg α-tocopherol None RT

Ibudilast/Ketas® capsules 10

mg/Kyorin Pharmaceuticals

Asthma and

cerebrovascular

disorders

10 mg (1-2

capsules) b.i.d

or t.i.d.

Extended release, hard gelatin capsules,

10 mg white sustained release granules

and enteric coated sustained release

granules

Cremophor RH 40 Lactose, MCC, povidone,

aminoalkyl-methacrylate-

copolymer RS, PEG 6000,

sodium chloride, silicon

dioxide, magnesium stearate

Indometacin farnesil/Infree®

capsules/Eisai Co.

Anti-

inflammatory and

analgesic

200 mg (1-2

capsules) b.i.d.

Hard gelatin capsule, 100 mg (solid) α-tocopherol Hydrated silicon dioxide,

MCC, tartaric acid, PEG 6000

RT

Soft gelatin capsules, 200 mg (liquid) Cremophor RH 60,

hydrogenated oil,

glyceryl monooleate

Aspartic acid RT

Menatetrenone/Glakay® Osteoporosis 45 mg (3 Soft gelatin capsule, 15 mg (contents of Propylene glycol RT,


Page 29

Capsules 15 mg/Eisai Co. capsules) t.i.d. capsule are a viscous liquid or

semisolid)

esters of fatty acid,

glyceryl monooleate

protect

from light

Teprenone/Selbex® capsules 50 mg and

fine granules 10%/Eisai Co.

Acute gastritis 150 mg (3

capsules) t.i.d.

Hard capsule, 50 mg (contents of

capsule are granules or powder)

α-tocopherol Hydrated silicon dioxide, talc,

mannitol, PEG 6000,lactose

RT

150 mg (1.5 g

granules) t.i.d.

Fine granules, 10% w/w α-tocopherol Hydrated silicon dioxide, talc,

HPMC, mannitol, lactose

RT

Tocopherol nicotinate/

Juvela® N Soft Capsules/

Eisai Co.

Hypertension,

hyperlipidemia

200 mg (1

capsule) t.i.d.

Soft gelatin capsule, 200 mg (contents

of capsule are a viscous suspension or

semisolid)

MCT, glycol esters of

fatty acid

Aspartic acid RT


Page 30

1.10. OUTLINE OF THE STUDY

The present research work is focused on exploiting a few surfactants/ and or solubilizers to

develop self-emulsifying drug delivery system for two investigational lipophilic model

drugs with various ratios of different excipients, commonly used in lipid-based drug

delivery system. The work also includes the pharmacokinetic study of all the developed

formulations in animal model.

The research work is divided in to two Sections, viz. Section I and Section II, dealing

with the two investigational model drugs Nevirapine and Itraconazole, respectively. For

convenience, the formulation development for both the drugs is described into two parts.

First part of both the sections (Chapter 2 and 4) deals with the SEDDS development

using Soluphor® P. Chemically, it is a 2-pyrrolidone (2P) and has been widely used for

topical (Femenia-Font et al., 2006) and parenteral (Shah and Agnihotri, 2011)

pharmaceutical dosage forms. Few literatures are also available on human oral use of 2-

pyrrolidone for improvement of solubility and dissolution of poorly water soluble drugs

(Khachane et al., 2011; Schamp et al., 2006). Physicochemical properties, endogenous

origin and toxicity of Soluphor® P are mentioned in introduction of Chapter 2. Several

drug delivery systems mostly focused on the delivery of oral dosage forms and injectables

(biodegradable implants) using Soluphor® P has been reviewed in the introductory part of

the Chapter 4. The introduction section of Chapter 4 also discussed N-methyl-2-

pyrrolidone, which is widely used as a solubilizer in the development of various

pharmaceutical dosage forms and compared its physicochemical properties and toxicity

issues with that of Soluphor® P (2-pyrrolidone). The present research work has explored

the ability of Soluphor® P to improve the solubility; permeability and bioavailability of

BCS class II drugs.

Second part of both the sections (Chapter 3 and 5) reveal the classical approach for the

development of self emulsifying drug delivery system of poorly water soluble drugs using

traditional excipients. For this, surfactants like Tween 20, Tween 80, Labrasol® and co-

surfactant Transcutol P have been used.

Chapter 3 describes that, patients infected with HIV experience a variety of functional

and anatomical abnormalities in the gastrointestinal tract that result in diarrhoea and


Page 31

nutrient malabsorption of fat, carbohydrates, specific micronutrients and proteins. In such

situations, medium chain triglycerides (MCT) are readily absorbed from the small bowel

under conditions in which the absorption of long chain triglycerides (LCT) is impaired

(Griffin, 1990; Wanke et al., 1996). It has been also investigated that dietary formulations

providing majority of fat in the form of MCT have resulted in the improvement of

diarrhoea, intestinal discomfort, bloating and nitrogen balance both in children and adults

with chronic diarrhoea from chronic pancreatitis, short bowel syndrome, non-specific

enteropathy, cystic fibrosis and biliary atresia (Bach & Babayan, 1982; Wanke et al.,

1996).

Chapter 5 addresses the hydrophobicity of a broad spectrum antifungal agent,

Itraconazole and the need of acidic conditions of GIT for its better absorption. Co-

administration of acidic beverage has been shown to improve the absorption of

Itraconazole especially those who have hypochlorhydria or achlorhydria.


Page 32

REFERENCES

Adkin, D.A., Davis, S.S., Sparrow, R.A., Huckle, P.D., Philips, A.J., Wilding, I.R., 1995.

The effects of pharmaceutical excipients on small intestinal transit. Br. J. clin. Pharmac.

39, 381-387.

Amemiya, T., Mizuno, S., Yuasa, H., Watanabe, J., 1998. Development of emulsion type

new vehicle for soft gelatin capsule. I. Selection of surfactants for development of new

vehicle and its physicochemical properties. Chem. Pharm. Bull. 46, 309-313.

Anderson, B.C., Pandit, N.K., Mallapragada, S.K., 2001. Understanding drug release from

poly (ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) gels, J. Control.

Release. 70, 157–167.

Attwood, D., Currie, L.R.J., Elworthy, P.H., 1974. Studies of solubilized micellar

solutions. I. Phase studies and particle size analysis of solutions with nonionic surfactants.

J. Colloid Interface Sci. 46, 249–256.

Aungst, B.J., 2000. Intestinal permeation enhancers. J. Pharm. Sci. 89(4), 429-442.

Aungst, B.J., Nguyen, N., Rogers, N.J., Rowe, S., Hussain, M., Shum, L., White, S., 1994.

Improved oral bioavailability of an HIV protease inhibitor using Gelucire 44/14 and

Labrasol vehicles. B.T. Gattefosse 87, 49-54.

Aungst, B.J., Rogers, N.J., Shefter, E., 1988. Comparison of nasal, rectal, sublingual and

intramuscular insulin efficiency and the effects of a bile salt absorption promoter. J.

Pharmacol. Exp. Ther. 244, 23-27.

Bach, A.C., Babayan, V.K., 1982. Medium-chain triglycerides: an update. Amer. J. Clin.

Nutr. 36, 950-962.

Basit, A.W., Podczeck, F., Newton, J.M., Waddington, W.A., Ell, P.J., Lacey, L.F., 2002.

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine.

Pharm. Res. 19, 1368–1374.

Bateman, N.E., Uccellini, D.A., 1984. Effect of formulation on the bioavailability of

retinol, d-α-tocopherol and riboflavine. J. Pharm. Pharmacol. 36(7), 461-464.

Bernkop-Schnurch, A., Kast, C.E., 2001. Chemically modified chitosans as enzyme

inhibitors. Adv. Drug Deliv. Rev. 52, 127–137.


Page 33

Burcham, D.L., Maurin, M.B., Hausner, E.A., Huang, S.M., 1997. Improved oral

bioavailability of the hypocholesterolemic DMP 565 in dogs following oral dosing in oil

and glycol solutions. Biopharm. Drug Dispos. 18, 737-742.

Chakrabarti, S., Belpaire, F.M., 1978. Bioavailability of phenytoin in lipid containing

dosage forms in rats. J. Pharm. Pharmacol. 30, 330-331.

Charman, S.A., Charman, W.N., Rogge, M.C., Wilson, T.D., Dutko, F.J., Pouton, C.W.,

1992. Self-emulsifying drug delivery systems: formulation and biopharmaceutical

evaluation of an investigational lipophilic compound. Pharm. Res. 9, 87-93.

Charman, W.N., 1992. Lipid vehicle and formulation effects on intestinal lymphatic drug

transport, In: W.N. Chasmar, V.J. Stella (Eds.), Lymphatic Transport of Drugs, CRC

Press, Boca Raton, FL, pp. 113-179.

Charman, W.N., Noguchi, T., Stella, V.J., 1986. An experimental system designed to

study the in situ intestinal lymphatic transport of lipophilic drugs in anesthetized rats. Int.

J. Pharm. 33, 155-64.

Chen, M.L., Straughn, A.B., Sadrieh, N., Meyer, M., Faustino, P.J., Ciavarella, A.B.,

Meibohm, B., Yates, C.R., Hussain, A.S., 2007. A modern view of excipient effects on

bioequivalence: case study of sorbitol. Pharm. Res. 24, 73-80.

Choc, M.G., 1997. Report: Bioavailability and pharmacokinetics of cyclosporine

formulations: Neoral® vs Sandimmune®. Int. J. Dermatolog. 36(Supp 1), 1-6.

Constantinides, P.P., 1995. Lipid microemulsions for improving drug dissolution and oral

absorption: physical and biopharmaceutical aspects. Pharm. Res. 12, 1561–1572.

Corbo, D.C., Liu, J.C., Chien, Y.W., 1990. Characterization of the barrier properties of

mucosal membranes. J. Pharm. Sci. 79, 202- 206.

Craig, D.Q.M., Barker, S.A., Banning, D., Booth, S.W., 1995. An investigation into the

mechanisms of self-emulsification using particle size analysis and low frequency dielectric

spectroscopy. Int. J. Pharm. 114, 103-110.

Craig, D.Q.M., Lievens, H.S.R., Pitt, K.G., Storey, D.E., 1993. An investigation into the

physico-chemical properties of self-emulsifying systems using low frequency dielectric

spectroscopy, surface tension measurements and particle size analysis. Int. J. Pharm. 96,

147- 155.


Page 34

Dabros, T., Yeung, A., Masliyah, J., Czarnecki, J., 1999. Emulsification through area

contraction. J. Colloids Interface Sci. 210, 222- 224.

Davis, S.S., Illum, L., 1998. Drug Delivery Systems for Challenging Molecules. Int. J.

Pharm.176, 1-8.

Dressman, J.B., Reppas, C., 2000. In vitro–in vivo correlations for lipophilic, poorly

water-soluble drugs. Eur. J. Pharm. Sci. 11 (Suppl. 2), S73–S80.

Embleton, J.K., Pouton, C.W., 1997. Structure and function of gastro-intestinal lipases.

Adv. Drug Deliv. Rev. 25, 15–32

Fagerholm, U., Sjostrom, B., Sroka-Markovic, J., Wijk, A., Svensson, M., Lennernas, H.,

1998. The effect of a drug-delivery system consisting of soybean phosphatidyl choline and

medium-chain monoacylglycerol on the intestinal permeability of hexarelin in the rat. J.

Pharm. Pharmacol. 50, 467-473.

Farah, N., Laforet, J.P., Denis, J., 1994. "Self Micro Emulsifying Drug Delivery Systems

for improving dissolution of drugs: In vitro evaluations". Presented by Gattefosse Patented

Technology at the AAPS Annual Meeting in San Diego, Nov. 1994.

Femenia-Font, A., Padula, C., Marra, F., Balaguer-Fernandez, M.V., Lopez-Castellano,

A., Nicoli, S., Santi, P., 2006. Bioadhesive monolayer film for the in vitro transdermal

delivery of sumatriptan. J. Pharm. Sci. 95, 1561-1569.

Fischl, M.A., Richman, D.D., Flexner, C., Para, M.F., Haubrich, R., Karim, A., Yeramian,

P., Holden-Wiltse, J., Meehan, P.M., 1997. Phase I/II study of the toxicity,

pharmacokinetics, and activity of the HIV protease inhibitor SC-52151. J. AIDS Hum.

Retrovirol. 15, 28-34.

Georgakopoulos, E., Farah, N., Vergnault, G., 1992. Oral anhydrous non-ionic

microemulsions administrated in softgel capsules. B.T. Gattefosse 85, 11-20.

Gershanik, T., Benita, S., 1996. Positively charged self-emulsifying oil formulation for

improving oral bioavailability of progesterone. Pharm. Dev. Technol. 1, 147-157.

Gershanik, T., Benita, S., 2000. Self-dispersing lipid formulations for improving oral

absorption of lipophilic drugs. Eur. J. Pharm. Biopharm. 50, 179– 188.


Page 35

Gershanik, T., Benzeno, S., Benita, S., 1998. Interaction of the selfemulsifying lipid drug

delivery system with mucosa of everted rat intestine as a function of surface charge and

droplet size. Pharm. Res. 15, 863-9.

Gershanik, T., Haltner, E., Lehr, C.M., Benita, S., 2000. Charge-dependent interaction of

self-emulsifying oil formulations with Caco-2 cells monolayers: binding, effects on barrier

function and cytotoxicity. Int. J. Pharm. 211, 29-36.

Gibson, L., 2007. Lipid-based excipients for oral drug delivery, in: D.J. Hauss (Ed.), Oral

Lipid-based Formulations: Enhancing the Bioavailability of Poorly Water-soluble Drugs,

Informa Healthcare, Inc., New York, pp. 43–51.

Greenberger, N.M., Rodgers, J.B., Isselbacher, K.J., 1966. Absorption of medium and

long chain triglycerides: factors influencing their hydrolysis and transport. J. Clin. Invest.

45, 217–227.

Grevel, J., Nuesch, E., Abisch, E., Kutz, K., 1986. Pharmacokinetics of oral cyclosporine

A (Sandimmune) in healthy subjects. Eur. J. Clin. Pharmacol. 31 (2), 211-6.

Griffin, G.E., 1990. Malabsorption, malnutrition, and HIV disease. Bailliere Clin

Gastroenterol. 4, 361-73.

Gursoy, R.N., Benita, S., 2004. Self-emulsifying drug delivery system (SEDDS) for

improved oral delivery of lipophilic drugs. Biomed. Pharmacother. 58, 173-182

Handbook of Pharmaceutical Excipients. Published by American Pharmaceutical

Association, USA, and The Pharmaceutical Society of Great Britain, England, 1986.

Hauss, D.J., 2007. Oral lipid-based formulations. Adv. Drug Deliv. Rev. 59, 667–676.

Hauss, D.J., Fogal, S.E., Ficorilli, J.V., Price, C.A., Roy, T., Jayaraj, A.A., Keirns, J.J.,

1998. Lipid-based delivery systems for improving the bioavailability and lymphatic

transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci. 87, 164-169.

Hauss, D.J., Mehta, S.C., Radebaugh, G.W., 1994. Targeted lymphatic transport and

modified systemic distribution of CI-976, a lipophilic lipid regulator drug, via a

formulation approach. Int. J. Pharm. 108, 85-93.

Hermeling, S., Jiskoot, W., Crommelin, D.J.A., Schellekens, H., 2006. Reaction to the

paper: interaction of polysorbate 80 with erythropoietin: a case study in protein-surfactant

interactions. Pharm. Res. 23, 641–644.


Page 36

Hermeling, S., Schellekens, H., Crommelin, D.J.A., Jiskoot, W., 2003. Micelle associated

protein in epoetin formulations: a risk factor for immunogenicity? Pharm. Res. 20, 1903–

1907.

Humberstone, A.J., Charman, W.N., 1997. Lipid-based vehicles for the oral delivery of

poorly water soluble drugs. Adv. Drug Deliv. Rev. 25, 103–128.

Kennedy, T., 1997. Managing the drug discovery/development interface. Drug Discovery

Today. 2(10), 436-444.

Khachane, P., Date, A.A., Nagarsenker, M.S., 2011. Positively charged polymeric

nanoparticles: application in improving therapeutic efficacy of meloxicam after oral

administration. Pharmazie. 66, 334-338.

Khoo, S.M., Humberstone, A.J., Porter, C.J.H., Edwards, G.A., Charman,W.N., 1998.

Formulation design and bioavailability assessment of lipidic selfemulsifying formulations

of halofantrine. Int. J. Pharm. 167, 155–164.

Khoo, S.M., Porter, C.J.H., 1999. Edwards GA, Charman WN. Intestinal lymphatic

transport is the primary route for halofantrine after oral postprandial administration.

Pharm. Res. 1, S-624.

Klauser, R.M., Irschik, H., Kletzmayr, J., Sturm, I., Brunner, W., Woloszczuk, W.,

Kovarik, J., 1997. Pharmacokinetic cyclosporine A profiles under longterm neoral

treatment in renal transplant recipients: does fat intake still matter? Transplant. Proc. 29,

3137–3140.

Kommuru, T.R., Gurley, B., Khan, M.A., Reddy, I.K., 2001. Self-emulsifying drug

delivery systems (SEDDS) of coenzyme Q10: formulation development and

bioavailability assessment. Int. J. Pharm. 212, 233-46.

Kreilgaard, M., 2002. Influence of microemulsions on cutaneous drug delivery. Adv. Drug

Deliv. Rev. 54 (Suppl. 1), S77–S98.

Lawrence, M.J., Rees, G.D., 2000. Microemulsion-based media as novel drug delivery

systems, Adv. Drug Deliv. Rev. 45, 89–121.

Lim, W.H., Lawrence, M.J., 2004. Influence of surfactant and lipid chain length on the

solubilization of phosphatidylcholine vesicles by micelles comprised of polyoxyethylene

sorbitan monoesters. Colloids Surf. A: Physicochem. Eng. Asp. 250, 449–457.


Page 37

MacGregor, K.J., Embleton, J.K., Perry, E.A., Lacy, J., Seager, H., Solomon, L., Pouton,

C.W., 1997. Influence of lipolysis on drug absorption from the gastrointestinal tract. Adv.

Drug Delivery Rev. 25, 33-46.

Maio, S.D., Carrier, R.L., 2011. Gastrointestinal contents in fasted state and post-lipid

ingestion: In vivo measurements and in vitro models for studying oral drug delivery. J.

Control. Release. (Article in Press).

Malcolmson, C., Lawrence, M.J., 1993. A comparison of the incorporation of model

steroids into non-ionic micellar and microemulsion systems. J. Pharm. Pharmacol. 45,

141-143.

Martin-Facklam, M., Burhenne, J., Ding, R., Fricker, R., Mikus, R.G., Walter-Sack, I.,

Haefeli, W.E., 2002. Dose-dependent increase of saquinavir bioavailability by the

pharmaceutic aid Cremorphor EL. Br. J. clin. Pharmacol. 53, 576–581.

McInnes, G.T., Asbury, M.J., Ramsay, L.E.,Shelton, J.R., Harrison, I.R., 1982. Effect of

micronization on the bioavailability and pharmacologic activity of spironolactone. J. Clin.

Pharmacol. 22, 410-417.

Mueller, E.A., Kovarik, J.M., Van Bree, J.B., Tetzloff, W., Kutz, K., 1994. Improved dose

linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm.

Res. 11, 301-304.

Myers, R.A., Stella, V.J., 1992a. Factors affecting the lymphatic transport of

penclomedine (NSC-338720), a lipophilic cytotoxic drug: Comparison to DDT and

hexachlorobenzene. Int. J. Pharm. 80, 511-62.

Myers, R.A., Stella, V.J., 1992b. Systemic bioavailability of penclomedine (NSC-338720)

from oil--in-water emulsions administered intraduodenally to rats. Int. J. Pharm. 78, 217-

226.

Naylor, L.J., Bakatselou, V., Dressman, J.B., 1993. Comparison of the mechanism of

dissolution of hydrocortisone in simple and mixed micelle systems. Pharm. Res. 10, 865-

870.

Nazzal, S., Guven, N., Reddy, I.K., Khan, M.A., 2002. Preparation and characterization of

Coenzyme Q10 - Eudragit® solid dispersion. Drug Dev. Ind. Pharm. 28(1), 49-57.


Page 38

Nicolaides, E., Galia, E., Efthymiopoulos, C., Dressman, J.B., Reppas, C., 1999.

Forecasting the in vivo performance of four low solubility drugs from their in vitro

dissolution data. Pharm. Res. 16, 1876–1882.

Palin, K.J., Phillips, A.J., Ning, A., 1986. The oral absorption of cefoxitin from oil and

emulsion vehicles in rats. Int. J. Pharm. 33, 99-104.

Patil P, Joshi, J., Paradkar, A., 2004. Effect of formulatiuon variables on preparation and

evaluation of gelled self-emulsifying drug delivery system (SEDDS) of ketoprofen. AAPS

Pharm Sci Tech. 5(3), 34-42

Patil, P., Patil, V., Paradkar, 2007. A. Formulation of a self-emulsifying system for oral

delivery of simvastatin: In vitro and in vivo evaluation. Acta Pharm. 57, 111-122.

Perng, C.H., Kearney, A.S., Patel, K., Palepu, N.R., Zuber, G., 1998. Investigation of

formulation approaches to improve the dissolution of SB-210661, a poorly water soluble

5- lipoxygenase inhibitor. Int. J. Pharm. 176, 31-38.

Porter, C.J., Charman, S.A., Charman, W.N., 1996. Lymphatic transport of halofantrine in

the triple-cannulated anesthetized rat model: effect of lipid vehicle dispersion. J. Pharm.

Sci. 85, 351-356.

Porter, C.J.H., Charman, W.N., 1997. Uptake of drugs into the intestinal lymphatics after

oral administration. Adv. Drug Delivery Rev. 25, 71-90.

Postolache, P., Petrescu, O., Dorneanu, V., 2002.Cyclosporine bioavailability of two

physically different oral formulations. Eur. Rev. Med. Pharmacol. Sci. 6, 127-131.

Pouton, C.W., 2000. Lipid formulations for oral administration of drugs: non-emulsifying,

self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur. J. Pharm. Sci.

11, S93–S98.

Pouton, C.W., Charman, W.N., 1997. The potential of oily formulations for drug delivery

to the gastro-intestinal tract. Adv Drug Deliv Rev. 25, 1-2.

Prentis, R. A., Lis, Y., Walker, S. R., 1988. Pharmaceutical innovation by the 7 UK-

owned pharmaceutical companies (1964-1985). Br. J. clin. Pharmac. 25, 387-396.

Rang, M.J., Miller, C.A., 1999. Spontaneous emulsification of oils containing

hydrocarbon, non-ionic surfactant, and oleyl alcohol, J. Colloids Interface Sci. 209, 179-

192.


Page 39

Rege, B.D., Yu, L.X., Hussain, A.S., Polli, J.E., 2001. Effect of common excipients on

Caco-2 transport of low permeability drugs. J. Pharm. Sci. 90, 1776–1786.

Reiss, H., 1975. Entropy-induced dispersion of bulk liquids. J. Colloids Interface Sci. 53,

61-70.

Rowe, R.C., Sheskey, P.J., 2003a. In:Weller, P.J. (Ed.). Handbook of Pharmaceutical

Excipients, Fourth Edition, Pharmaceutical Press, London, and American Pharmaceutical

Association, Washington, D.C., pp. 454–459.

Rowe, R.C., Sheskey, P.J., 2003b. In:Weller PJ (Ed.). Handbook of Pharmaceutical



Rowe, R.C., Sheskey, P.J., 2003c In:Weller PJ (Ed.). Handbook of Pharmaceutical



Schamp, K., Schreder, S-A, Dressman, J., 2006. Development of an in vitro/in vivo

correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug

substance. Eur. J. Pharm. Biopharm. 62, 227-234.

Schwendener, R.A., Schott, H., 1996. Lipophilic 1-âd - arabino-furanosyl cytosine

derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the

murine L1210 leukemia model. J. Cancer Res. Clin. Oncol. 122, 723-726.

Senior, J.R., 1964. Intestinal absorption of fats. J. Lipid Res. 5, 495-521.

Serajuddin, A.T.M., Sheen, P.C., Mufson, D., Bernstein, D.F., Augustine, M.A., 1988.

Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-

soluble drug from solid dispersion. J. Pharm. Sci. 77, 414-417.

Shabouri M. H., 2002. Positively charged nanoparticles for improving the oral

bioavailability of cyclosporin-A. Int. J. Pharm. 249(1-2), 101-108.

Shah, A.K., Agnihotri, S.A., 2011. Recent advances and novel strategies in pre-clinical

formulation development: An overview. J. Control. Release. (Article in Press).

Shah, N.H., Carvajal, M.T., Patel, C.I., Infeld, M.H., Malick, A.W., 1994. Selfemulsifying

drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro

dissolution and oral absorption of lipophilic drugs. Int. J. Pharm. 106, 15-23


Page 40

Sharma, S., Bader, F., Templeman, T., Lisi, P., Ryan, M., Heavner, G.A., 2004. Technical

investigation into the cause of the increased incidence of antibody-mediated pure red cell

aplasia associated with EprexR. Eur. J. Hosp. Pharm. 5, 86–91.

Stella, V., Haslam, J., Yata, N., Okada, H., Lindenbaum, S., Higuchi, T., 1978.

Enhancement of bioavailability of a hydrophobic amine antimalarial by formulation with

oleic acid in a soft gelatin capsule. J. Pharm. Sci. 67, 1375-1377.

Strickley, R.G., 2004. Solubilizing excipients in oral and injectable formulations. Pharm.

Res. 21, 201–230.

Strickley, R.G., 2007. Currently marketed oral lipid-based dosage forms: drug products

and excipients, in: D.J. Hauss (Ed.), Oral Lipid-based Formulations: Enhancing the

Bioavailability of Poorly Water-soluble Drugs, Informa Healthcare, Inc., New York, p. 2.

Swenson, E.S., Milisen, W.B., Curatolo, W., 1994. Intestinal permeability enhancement:

efficacy, acute local toxicity and reversibility. Pharm. Res. 11, 1132-1142.

Tang, B., Cheng, G., Chun, J., 2008. Development of solid self emulsifying drug delivery

systems, preparation techniques and dosage forms. Drug Discovery Today. 13, 606-611.

Tang, J.L., Sun, J., Guihe, Z., 2007. Self- Emulsifying Drug Delivery Systems: Strategy

for Improving Oral Delivery of Poorly Soluble Drug. Curr. Drug Ther. 2, 85-93.

Tarr, B.D., Yalkowsky, S.H., 1989. Enhanced intestinal absorption of cyclosporine in rats

through the reduction of emulsion droplet size. Pharm. Res. 6, 40-43.

Tayrouz, Y., Ding, R., Burhenne, J., Riedel, K.D., Weiss, J., Hoppe-Tichy, T., Haefeli,

W.E., Mikus, G., 2003. Pharmacokinetic and pharmaceutic interaction between digoxin

and Cremophor RH40. Clin. Pharmacol. Ther. 73, 397–405.

Toguchi, H., Ogawa, Y., Iga, K., Yashiki, T., Shimamoto, T., 1990a. Gastrointestinal

absorption of ethyl 2-chloro-3-(4-(2-methyl-2-phenylpropyloxy) phenyl)propionate from

different dosage forms in rats and dogs. Chem. Pharm. Bull. 38, 2792-2796.

Toguchi, H., Ogawa, Y., Shimamoto, T., 1990b. Effects of the physicochemical properties

of the emulsion formulation on the bioavailability of ethyl 2-chloro-3-(4-(2-methyl-2-

phenylpropyloxy)phenyl)propionate in rats. Chem. Pharm. Bull. 38, 2797-2800.


Page 41

Tokumura, T., Tsushima, Y., Tatsuuishi, K., Kayano, M., Machida, Y., Nagai, T., 1987.

Enhancement of the oral bioavailability of cinnarizine in oleic acid in beagle dogs. J.

Pharm. Sci. 76, 286-288.

Trull, A.K., Tan, K.K.C., Lan, T., Alexander, G.J.M., Jamieson, N.V., 1995. Absorption

of cyclosporine from conventional and new microemulsion oral formulations in liver

transplant recipients with external biliary diversion. Br. J. clin. Pharmac. 39, 627-631.

Tsuji, Y., Kakegawa, H., Miyataka, H., Nishiki, M., Matsumoto, H., Satoh,T., 1996.

Pharmaceutical properties of freeze-dried formulations of egg albumin, several drugs and

olive oil. Biol. Pharm. Bull. 19, 636-640.

U.S. Department of Health and Human Services, Food and Drug Administration, Center

for Drug Evaluation and Research, Center for Biologics Evaluation and Research,

Guidance for Industry: Nonclinical studies for the safety evaluation of pharmaceutical

excipients, Office of Training and Communication, Division of Drug Information, HFD-

240, Center for Drug Evaluation and Research, Food and Drug Administration, or Office

of Communication, Training, and Manufacturers Assistance, HFM-40, Center for

Biologics Evaluation and Research, Food and Drug Administration. May 2005.

http://www.fda.gov/cder/ guidance/5544fnl.pdf.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Inactive

ingredient guide. Division of Drug Information Resources, Office of Management, Center

for Drug Evaluation and Research, Food and Drug Administration. January 1996.

http://www.fda. gov/cder/drug/iig/default.htm.

U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Inactive

ingredient search for approved drug products. Division of Labeling and Program Support,

Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug

Administration. (Database last updated on July 15, 2011). Accessed on August 13, 2011.

http://www.accessdata.fda.gov/scripts/cder/ iig/index.cfm.

U.S. Food and Drug Administration, Title 21, Code of Federal Regulations, Part 182, 184,

186. Office of the Federal Register, National Archives and Records Administration. 2007.

Uchegbu, I.F., Vyas, S.P., 1998. Non-ionic surfactant based vesicles (niosomes) in drug

delivery. Int. J. Pharm. 172, 33-70.


Page 42

Villalobos, A.P., Gunturi, S.R., Heavner, G.A., 2005. Interaction of polysorbate 80 with

erythropoietin: a case study in protein-surfactant interactions. Pharm. Res. 22, 1186–1194.

Vogt, M., Klaus K. and Jennifer B.D., 2008. Dissolution enhancement of fenofibrate by

micronization, cogrinding and spray-drying: Comparison with commercial preparations.

Eur. J. Pharm. Biopharm. 68 (2), 283-288.

Vonderscher, J., Meinzer, A., 1994. Rationale for the development of Sandimmune

Neoral. Transplant. Proc. 26, 2925-2927.

Wakerly, M.G., Pouton, C.W., Meakin, B.J., Morton, F.S., 1986. Self-emulsification of

vegetable oil-non-ionic surfactant mixtures. ACS Symp. Ser. 311, 242-255.

Wanke, C.A., Pleskow, D., Degirolami, P.C., Lambl, B.B., Merkel, K., Akrabawi, S.,

1996. A medium chain triglyceride-based diet in patients with HIV and chronic diarrhea

reduces diarrhea and malabsorption : A prospective, controlled trial. Nutrition. 12, 766-

771.

Wasan, K.M., Constantinides, P.P. (Eds.), 2004. Advances in lipid-based drug

solubilization and targeting. Adv. Drug Deliv. Rev., 56, 1239-1338.

Yu, L., Bridgers, A., Polli, J., Vickers, A., Long, S., Roy, A., Winnike, R., Coffin, M.,

1999. Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by

enhancing its solubility and permeability. Pharm. Res. 16, 1812–1817.

Yuasa, H., Sekiya, M., Ozeki, S., Watanabe, J., 1994. Evaluation of milk fat globule

membrane (MFGM) emulsion for oral administration: absorption of α-linolenic acid in

rats and the effect of emulsion droplet size. Biol. Pharm. Bull. 17, 756-758.

Zhang, P., Liu, Y., Xu, J., 2008. Preparation and Evaluation of Self-emulsifying drug

delivery system of oridonin. Int. J. Pharm. 355, 269-276.

SECTION I Nevirapine

Page no. 43 to 55

Section I Nevirapine

Page 43

I.1. Drug Profile

NEVIRAPINE

(Indian Pharmacopoeia, Addendum 2005; Merck Index, 2006; Moffat et al., 2004; Physician Desk Reference, 2008; Raffanti and Haas, 2001; Sweetman, 2005)

Figure I.1. Structure of Nevirapine

Chemical Formula: C15H14N4O

Molecular weight: 266.30

CAS name: 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido(3,2-b:2,3-

e)(1,4)diazepin-6- one

CAS registry No.: 129618-40-2

Physicochemical properties:

Description: White to off-white crystalline powder

Solubility: Soluble in dimethyl sulfoxide (DMSO), sparingly soluble in dichloromethane

(DCM) and in dimethylformamide (DMF); highly soluble in water at pH < 3 but solubility

decreases to approximately 0.1 g/L at neutral pH.

Dissociation constant (pKa): 2.8

Polarity/partition coefficient (log P): 2.5

Melting point: 242 - 246°C

Mechanism of action:

Nevirapine (NVP) is a non-nucleotide reverse transcriptase inhibitor (NNRTI). It binds

directly to reverse transcriptase (RT) and blocks the RNA dependent and DNA dependent

DNA polymerase activities by causing a disruption of the enzyme’s catalytic site. The

activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2

RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, δ) are not

inhibited by nevirapine.


Page 44

Antiviral activity:

The antiviral activity of nevirapine has been measured in a variety of cell lines including

peripheral blood mononuclear cells, monocyte derived macrophages, and lymphoblastoid

cell lines. EC50 values (50% inhibitory concentration) ranged from 14-302 nM against

laboratory and clinical isolates of HIV-1, using human cord blood lymohocytes and human

embryonic kidney 293 cells. Nevirapine in combination with efavirenz eshibited strong

antagonistic anti-HIV-1 activity in cell culture and was additive to the antagonistic with

protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited

additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors

amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the

NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and

zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by anti-HBV drug

adefovir, and by the anti-HCV drug ribavirin in cell culture.

HIV-1 isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in cell

culture. Genotypic analysis showed mutations in the HIV-1 RT gene Y181C and/or

V106A depending upon the virus strain and cell line employed. Time to emergence of

resistance in cell culture was not altered when selection included nevirapine in

combination with several other NNRTIs.

Pharmacokinetics

Absorption: Nevirapine is readily absorbed (> 90%) after oral administration in healthy

volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy

adults following single-dose administration was 93 ± 9% for a 50 mg tablet and 91 ± 8%

for an oral solution. Peak plasma Nevirapine concentrations of 2 ± 0.4 µg/mL were

attained by 4 hours following a single 200 mg dose.

Distribution: Nevirapine is highly lipophilic and essentially non-ionized at physiological

pH. Following intravenous administration to healthy adults, the apparent volume of

distribution (Vd) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely

distributed in humans. It readily crosses the placenta and is also found in breast milk.

Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-

10 µg/mL. Nevirapine concentration in human cerebrospinal fluid (n=6) were 45% (± 5%)

of the concentrations in plasma. This ratio is approximately equal to the fraction not bound

to plasma protein.


Page 45

Metabolism/Elimination: In vivo studies in human and in vitro studies with human liver

microsomes have shown that nevirapine is extensively biotransformed via cytochrome

P450 (oxidation) metabolism to several hydroxylated metabolites. In vitro studies with

human liver microsomes suggest that oxidative metabolism of nevirapine is mediated

primarily by cytochrome P450 (CYP) isozymes from the CYP3A4 and CYP2B6 families,

although other isozymes may have a secondary role. In a mass/balance excretion study in

8 healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily

followed by single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5 % of the

radio-labelled dose was recovered, with urine (81.3 ± 11.1 %) representing the primary

route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity

in urine was made up of glucouronide conjugates of hydroxylated metabolites. Thus

cytochrome P450 metabolism, glucouronide conjugation and urinary excretion of

glucourinated metabolites represent the primary route of nevirapine biotransformation and

elimination in humans. Nevirapine is an inducer of hepatic cytochrome P450 metabolic

enzymes 3A4 and 2B6. It induces CYP3A4 and CYP2B6 by approximately 20-25%, as

indicated by erythromycin breath test results and urine metabolites. Autoinduction of

CYP3A4 and CYP2B6 mediated metabolism leads to an approximately 1.5 to 2 fold

increase in the apparent oral clearance of nevirapine as treatment continues form a single

dose to two-to-four weeks dosing with 200-400 mg/day. Autoinduction also results in a

corresponding decrease in the terminal phase half-life of nevirapine in plasma, from

approximately 45 hours (single dose) to approximately 25-30 hours following multiple

dosing with 200-400 mg/day.

Interaction: Nevirapine being itself mild to moderate enzyme inducer may thus reduce

plasma concentrations of other drugs.

Antibacterials: Plasma concentrations of nevirapine may be decreased by rifabutin and

rifampicin, probably as a result of enzyme induction.

Antifungal: Use of nevirapine and ketoconazole may result in reduction in the plasma

concentration of ketoconazole and increase in that of nevirapine. Use of nevirapine with

fluconazole may increase the bioavailability of nevirapine and caution required when the

drugs are used together.

Hormonal contraceptives: Nevirapine may decrease the plasma concentrations of

hormonal contraceptives.


Page 46

Adverse effects: The most frequently adverse events are rash, nausea, fatigue, somnolence,

headache and abnormal liver function test. Rashes are usually mild to moderate,

maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the

trunk, face and extremities. Allergic reactions (anaphylaxis, angioedema and urticaria)

have been reported. Severe and life-threatening skin reactions have occurred in patients

treated with nevirapine, including Steven-Johnson syndrome (SJS) and toxic epidermal

necrolysis (TEN). Rashes occur alone or in the context of hypersensitivity reactions

characterized by rash with constitutional symptoms such as fever, arthralgia, myalgia and

lymphadenopathy plus visceral involvement, such as hepatitis, eosinophilia,

granulocytopenia and renal dysfunction.

I.2. Background of the study

Introduction

Nevirapine, chemically 11-cyclopropyl-5,11- dihydro-4-methly-6H-dipyrido[3,2-b: 2´,3´-

e] diazepin- 6-one, a dipyridodiazepinone (Murphy and Montaner, 1996; Malaty and

Kupper, 1999) is a non-nucleoside reverse transcriptase inhibitor of human

immunodeficiency virus type 1 (HIV-1). Nevirapine was discovered by Hargrave et al.

(1994) at Boehringer Ingelheim Pharmaceuticals, Inc. It is covered by US patent and

corresponding foreign patents. Nevirapine was the first Non-Nucleoside Reverse

Transcriptase Inhibitor (NNRTI) approved by the FDA of the United States and currently

used in the treatment of HIV-1 infections (Waters et al., 2007; Devi and Pai, 2006). It was

approved on June 21, 1996 for adults and September 11, 1998 for children. It was also

approved in Europe and Canada in 1997 and 1998, respectively.

It is a hydrophobic drug with a log octanol–water partition coefficient (log P) = 2.5, Tm =

244.5°C, and pKa = 2.8 (Wishart et al., 2006; Pereira et al., 2007) and is practically

insoluble in water (0.1 mg/mL) at physiological pH conditions and soluble only under

extremely acidic media (Merck Index, 2006). Anhydrous form of nevirapine is used in

tablet formulations, while nevirapine hemihydrae is used in suspension formulation

(AHFS Drug Info, 2004). Although, the drug appears to be readily absorbed orally,

nevirapine particularly at higher doses (> 50 mg) exhibit characteristics of solubility rate-

limited absorption with a resultant decrease in bioavailability (Hawi and Bell, 1994;

Lamson et al., 1995). Nevirapine is also used in fixed dose combinations (FDCs) along

with lamivudine and stavudine. In comparison to other drugs, nevirapine (NVP) is poorly


Page 47

soluble hydrophobic molecule which poses processing problems in the manufacture of

FDCs (Sarkar et al., 2008).

Nevirapine belongs to Biopharmaceutical Classification System (BCS) class II (low

solubility/high permeability), poses a challenge in achievement of optimal dissolution

kinetics from the dosage form (Kasim et al., 2004). NVP is a weak base (pKa= 2.8) with

low intrinsic water solubility (0.06 mg/ml) which gives rise to difficulties in the

formulation of dosage forms and leads to variable dissolution rates with a resultant

decrease in bioavailability (Hawi and Bell, 1994; Macha et al., 2009a and 2009b; Lamson

et al., 1995).

HIV Infection:

At the present time, more than 33 million people are infected with the human

immunodeficiency virus (HIV), with 2.5 million new infections diagnosed in 2008. Sub-

Saharan Africa remains most heavily affected by the pandemic, accounting for 67% of all

people living with HIV and >70% of deaths from the acquired immune deficiency

syndrome (AIDS) in recent years. Globally, the percentage of women among people living

with HIV has remained stable at 50% for several years, but women’s share of infection is

increasing in several countries. The overall number of people living with HIV has

increased as a result of new infections and the beneficial effects of more widely available

antiretroviral therapy (HIV/AIDS, 2008). The introduction of combination antiretroviral

therapy, compounded with the routine use of HIV RNA viral load and CD4+ T-cell counts

as surrogate markers of drug efficacy and disease progression (Mellors et al., 1996), has

brought about a dramatic increase in life expectancy among HIV-infected patients (The-

Antiretroviral-Therapy-Cohort-Collaboration, 2008).

There have been significant accomplishments in the past 25 years in terms of greater

emphasis on disease prevention, technologies for diagnosis, and development of

innovative therapeutic strategies (Gallo, 2006). At present, there are over 20 different anti-

retroviral drugs approved in the United States under the general classes of nucleoside

reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors

(NNRTI), protease inhibitors (PI), and fusion inhibitors (FI) (Chearskul et al., 2006).

Current treatment options have not yet reached the vast majority of people living with

HIV. Although the eradication of HIV infection is unlikely to be a short-term prospect, the

voices of experts have begun to herald a change in the future paradigm of HIV treatment


Page 48

by shifting the new long-term goal towards achieving virus control that would allow for

durable drug-free remissions (Richman et al., 2009). HIV infection cannot be cured with

current treatments and patients are destined to undergo treatment for life. Simplification of

therapy, improvement of patient adherence and minimization of drug resistance are

foreseeable near-term goals that will likely also be important stepping stones towards

achieving long-term drug-free virus control and ultimately finding a cure.

One of the major problems in the chronic treatment is the fact that the viral particles are

able to reside in cellular and anatomical sites in the body following replication and remain

viable even when there are adequate drug concentrations in the blood (Schrager and

D´Souza, 1998; Chun et al., 2000). Examples of cellular reservoirs include T-

lymphocytes, monocytes, and macrophages, while the major anatomical reservoirs include

central nervous system (CNS), lymph nodes, liver, spleen, lungs, and the genitals (Vyas et

al., 2006). Poor drug availability in the cellular and anatomical reservoirs is affected by

expression of efflux transporters (e.g., P-glycoprotein), presence of drug metabolizing

enzymes (e.g., cytochrome P-450), poor permeability properties, non-targeted distribution,

and rapid clearance. The reduced bioavailability and short residence of anti-retroviral

agents at these viral reservoir sites have profound impact on the clinical management of

the disease. The overall consequence is that upon discontinuation of therapy or when drug

resistance develops, HIV is able to re-seed the systemic circulation and continue to

propagate the infection (Clarke et al., 2000, Kulkovsky and Bray, 2006).

The immunopathogenesis of HIV/AIDS has been previously amply documented; from the

time of infection to the end stage of the disease (Chinen and Shearer, 2008). The end stage

of the disease may be characterised by a spectrum of diseases (Stoddart and Reyes, 2006)

including opportunistic infections (such as Pnuemocystis carinii and Mycobacteruim

tuberculosis), dementia and cancer (Stoddart and Reyes, 2006). In addition to

macrophages, lymph nodes, bone marrow, spleen and lungs, the CNS represents one of the

most important anatomical sites of the virus after infection. This causes significant

neuronal damage and loss that often leads to HIV associated dementia. Without treatment,

HIV 1 infection is nearly uniformly fatal within 5-10 years (Stoddart and Reyes, 2006).

The majority of orally administered drugs gain acess to the systemic circulation by

absorption into the portal blood. However, for some extremely lipophilic compounds,

transport via the intestinal lymphatics provides an additional route of access to the

systemic circulation. Exogenous compounds absorbed via the intestinal lymph are


Page 49

generally transported in association with the lipid core of intestinal lipoprotein thereby

requiring co-administered lipid to stimulate lipoprotein formation.

B- and T- lymphocytes, which play a major role in maintaining the immune system, also

circulate through the lymphatics in relatively high concentrations compared with systemic

blood. Consequently, there is considerable interest in the specific delivery of anti-infective

or anti-viral agents to the lymph to combat lymphocyte destruction by, for example, HIV

(Porter and Charman, 1997).

I.3. Scope and objectives of the present work

Reducing the dosing frequency would significantly improve patient compliance and their

quality of life. To study new forms of administration, it is necessary to do pre-clinical

studies and know the absorption characteristics of nevirapine in laboratory animals.

However, there are no reports about its bioavailability in rats and about its

pharmacokinetic. One of the objectives of this study was to describe the pharmacokinetics

of nevirapine in rats after oral administration of the developed SEDDS and marketed

suspension.

Although the metabolism of NVP in different animal species has been studied (Riska et

al., 1999), pharmacokinetic studies in experimental animals are few, and there is meagre

information available about the bioavailability of this drug in laboratory animals, e.g. in

rats (Usach and Peris, 2011). Knowledge on the absorption characteristics of NVP in

laboratory animals is crucial for undertaking pre-clinical studies on new dosage forms to

reduce the dose or dosing frequency. Since HIV-infected patients require long-term

therapy with antiretroviral drugs, such as NVP, an improvement in the treatment regimen

will improve their quality of life. This objective could be reached through various dosage

delivery approaches and the self-emulsifying drug delivery system is one of them. A rash

which is the major adverse reaction and few others can be minimized if the dose can be

reduced.

A range of novel strategies are currently being developed for efficient delivery of anti-

retroviral (ARV) drugs including nevirapine. Efficient delivery could be achieved by

encapsulating the drug or by attaching it with a carrier system (Ferrari, 2005; Duncan,

2003; Gonzalez de Requena et al., 2002). Several delivery systems have been reported for

the delivery of ARV drugs including bioadhesive coated matrix tablets (Betagiri et al.,

2001; Govender et al., 2005), ceramic implants (Benghuzzi 2000), liposomes


Page 50

(Desormeaux and Bergeron, 1998; Jain et al., 2006; Jin et al., 2005; Makabi Panzu et al.,

1998; Ramana et al., 2010), solid colloidal nanoparticles (Mainardes et al., 2009; Kuo and

Su, 2007; Chattopadhyay et al., 2008; Kaur et al., 2008), microparticles by supercritical

antisolvent method (Sanganwar et al., 2010), dendrimers (Dutta et al., 2007), micelles &

microemulsion (Griffin and Driscoll, 2006), nanopowders (Erdenburgh et al., 2007) and

suspensions/nanosuspension (Kinman et al., 2003; Shegokar and Singh, 2011; Shegokar et

al., 2011; Yang et al., 2011). Table I.1 shows the commercially available nevirapine

formulations in India.

Table I.1: Commercially available nevirapine formulations in India

Brand Name Dosage form Company Neve Tablet Cadila Nevimune Tablet, Suspension Cipla Nevipan Tablet Ranbaxy Neviretro 200 Tablet Alkem Nevivir Tablet Hetro HC

The main objective of the study was to contribute to the understanding of the

physicochemical principles, key factors in predicting the performance and applicability of

self-emulsifying drug delivery system for the improvement of dissolution and in vivo

performance of poorly water soluble/lipophilic drugs.

The specific objectives of this investigation include:

1. To explore SEDDS as a novel formulation for a lipophilic drug- nevirapine

2. This novel SEDDS formulation for nevirapine will be suitably modified so as to

a. Enhance the solubility

b. Increase diffusion and permeation of the drug

3. To compare the new formulations thus developed with marketed formulation for

their in vivo absorption using a suitable animal model

4. In addition, to see the effect of ratios of oil and surfactant on droplet size

5. To study the effect of droplet size on uptake of the drug by gastrointestinal tissue

of rat


Page 51

REFERENCES

AHFS Drug Info. 2004. Nevirapine. p. 1-8.

Benghuzzi, H., 2000. Long term sustained delivery of 3'-azido-2',3'-dideoxy thymidine in

vivo by means of HA and TCP delivery devices. Biomed. Sci. Instrum. 36, 343-348.

Betagiri, G.V., Deshmukh, D.V., Gupta, R.B., 2001. Oral sustained- release bioadhesive

tablet formulation of didanosine. Drug Dev. Ind. Pharm. 27, 129-136.

Chattopadhyay, N., Zastre, J., Wong, H.L., Wu, X.Y., Bendayan, R., 2008. Solid lipid

nanoparticle enhance the delivery of the HIV protease inhibitor, atazanavir, by a human

brain endothelial cell line. Pharm. Res. 25, 2262-2271.

Chearskul, P., Rongkavilit, C., Al-Tatari, H., Asmar, B., 2006. New antiretroviral drugs in

clinical use. Indian J. Pediatr. 73, 335–341.

Chinen, J., Shearer, W.T., 2008. 6. Secondary immunodeficiencies, including HIV

infection. J. Allergy Clin. Immunol.121, S388-92; quiz S417.

Chun, T.W., Davey, R., Ostrowski, M., Engel, D., Mullins, J., Lane, C., Fauci, A., 2000.

Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia

after discontinuation of highly active antiretroviral therapy. Nat. Med. 6, 757–761.

Clarke, J.R., White, N.C.,Weber, J.N., 2000. HIV compartmentalization: pathogenesis and

clinical implications. AIDS Rev. 2, 15–22.

Desormeaux, A., Bergeron, M.G., 1998. Liposome as drug delivery system: a strategic

approach for the treatment of HIV infection. J. Drug target. 6, 1-15.

Devi, K.V., Pai, R.S., 2006. Antiretrovirals: Need for an Effective Drug Delivery. Indian

J. Pharm. Sci. 68, 1‐6.

Duncan, R., 2003. The drawing era of polymer therapeutics. Nat. Rev. Drug Discov. 3,

347-360.

Dutta, T., Agashe, H.B., Garg, M., Balasubramanium, P., Kabra, M., Jain, N.K., 2007.

Poly(propyleneimine) dendrimer based nanocontainers for targeting of efavirenz to human

monocyte/macrophage, in vitro. J. Drug Target. 15, 89-98.

Eerdenburgh, B.V., Froyen, L., Martens, J.A., Blaton, N., Augustijins, P., Brewster, M.,

Mooter, G.V.D., 2007. Characterization of physiochemical properties and pharmaceuticals


Page 52

performance of sucrose co-freeze dried solid nanoparticulate powder of the anti-HIV agent

loviride prepared by media milling. Int. J. Pharm. 338, 298-206.

Ferari, M., 2005. Nanovector therapeutics. Curr. Opin. Chem.Biol.9, 343-346.

Gallo, R.C., 2006. A reflection on HIV/AIDS research after 25 years. Retrovirology 3, 72.

Gonzalez de Requena, D., 2002. Nunez M, Jimenez Nacher I, Soriano V: Liver toxicity

caused by nevirapine. AIDS: Research Letters. 16, 290-291.

Govender, S., Pillay, V., Chetty, D.J., Essack, S.Y., Dangor, C.M., Govender, T., 2005.

Optimisation and characterization of bioadhesive controlled release tetracycline

microspheres. Int. J. Pharm. 306, 24-40.

Griffin, B.T., Driscoll, C.M.O., 2006. A comparison of intestinal lymphatic transport and

systemic bioavailability of saquinavir from three lipid based formulation in the

anaesthetized rat model. J. Pharm. Pharmacol. 58, 917-925.

Hargrave, K.D., Proudfoot, J.R., Adams, J., Grozinger, K.G., Schmidt, G., Engle, W.,

Trummlitz, G., Eberlein, W., 1994. 5,11-dihydro-6H-dipyrido (3,2-B: 2’,3’-E)(1,4)

diazepines and their use in the prevention or treatment of HIV infection. U.S. Patent

5366972.

Hawi, A., Bell, G., 1994. Preformulation studies of nevirapine, a reverse transcriptase

inhibitor. Pharm. Res.11 (Suppl), S 236

HIV/AIDS, J.U.N.P.o., 2008. Report on the Global AIDS Epidemic. UNAIDS; Geneva:

2008. (http://www.unaids.org/en/)

Jain, S., Tiwary, A.K., Jain, N.K., 2006. Sustained and targeted delivery of anti HIV agent

using elastic liposomal formulation: Mechanism of action. Curr. Drug Deliv. 3, 157-166.

Jin, S.X., Wang, D.Z.J., Wang, Y.Z., Hu, H.G., Deng, Y.G., 2005. Pharmacokinetic and

tissue distribution of zidovudine in rats following intravenous administration of

zidovudine myristate loaded liposomes. Pharmazie. 60, 840-843.

Kasim, N.A., Whitehouse, M., Ramachandran, C., Bermejo, M., Lennernas, H., Hussain,

A.S., Junginger, H.E., Stavchansky, S.A., Midha, K.K., Shah, V.P., Amidon, G.L., 2004.

Molecular properties of WHO Essential drugs and Provisional. Mol. Pharm. 1(1), 85-96.

Kaur, A., Jain, S., Tiwary, A.K., 2008. Mannan-coated gelatine nanoparticles for sustained

and targeted delivery of didanosine for site specific delivery. Acta Pharma. 58, 61-74.


Page 53

Kinman, L., Brodie, S.J., Tsai, C.C., Bui, T., Larsen, K., Schmidt, A., Anderson, D.,

Morton, W.R., Hu, S.L., Ho, R.J.Y., 2003. Lipid drug association enhanced HIV-1

protease inhibitor indinavir localization in lymphoid tissue and viral load reduction: a

proof of concept study in HIV-22870-infected macaques. J. Acquir. Immune Deficiency

Syndrome. 34, 387-397

Kulkovsky, J., Bray, S., 2006. HAART-persistent HIV-1 latent reservoirs: their origin,

mechanisms of stability, and potential strategies for eradication. Curr. HIV Res. 4, 199–

208.

Kuo, Y.C., Su, S.L., 2007. Transport of stavudine on polybutylcyanoacrylate and

methyacrylate-sulfopropylmethacrylate and solid lipid nanoparticle. Int. J. Pharm. 340,

143-152.

Lamson, M.J., Sabo, J.P., MacGregor, T.R., Pav, T.W., Rowland, L., Hawi, A, Cappola,

M., Robinson, P., 1995. Single dose pharmacokinetics and bioavailability of nevirapine in

healthy volunteers. Biopharm. Drug Dispos. 20, 285-91

Macha, S., Yong, C-L., Darrington, T., Davis, M.S., MacGregor, T.R., Castles, M., Krill,

S.L., 2009a. In vitro-in vivo correlation of nevirapine extended release tablets. Biopharm.

Drug Dispos. 30, 542-550.

Macha, S., Yong, C-L., MacGregor, T.R., Castles, M., Quinson, A-M., Rouyrre, N.,

Wilding, I., 2009b. Assessment of nevirapine bioavailability from targeted sites in the

human gastrointestinal tract. J. Clin. Pharmacol. 49, 1417-1425.

Mainardes, R.M., Gremiao, G.P., Brunetti, I.L., Fonseca, L.M.D., Khalil, N.M., 2009.

Zidovudine loaded PLA and PLA-PEG blend nanoparticle: influence of polymer type on

phagocytic uptake by polymorphonuclear cells. J. Pharm. Sci. 98, 257-67.

Makabi-Panzu, B., Gourde, P., Desormeaux, A., Bergeron, M.G., 1998. Intracellular and

serum stability of liposomal 2, 3'-deoxycytidine, Effect of lipid composition. Cell. Mol.

Bio. 44, 277-284.

Malaty, L.I., Kupper, J.J., 1999. Drug interactions of HIV protease inhibitors. Drug Saf.

20, 147-169.

Mellors, J.W., Rinaldo Jr., C.R., Gupta, P., White, R.M., Todd, J.A., Kingsley, L.A., 1996.

Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 272,

1167–1170.


Page 54

Merck Index/ O’Neil, M.J., 2006. In: Merck Index: An encyclopedia of chemicals, drugs

and biological. 14th ed. Merck & Co. Inc. USA, pp. 1123.

Moffat, A.C., Osselton, M.D., Widdop, B., 2004. In: Clarke’s Analysis of Drugs and

Poisons (3rd ed): Monographs Nevirapine. Pharmaceutical Press, vol 2, 1329-1330.

Murphy, R.L., Montaner, J., 1996. Nevirapine: A review of its development,

pharmacological profile and potential for clinical use. Expert Opin. Investig. Drugs 5(9),

1183–1199.

Pereira, B.G., Fonte-Boa, F.D., Resende, J.A.L.C., Pinheiro, C.B., Fernandes, N.G.,

Yoshida, M.I., Vianna-Soares, C.N., 2007. Pseudopolymorphs and intrinsic dissolution of

nevirapine.Cryst. Growth Des. 7, 2016–2023.

Physician’s Desk Reference (62nd edition), Medical Economics Staff, Thomson

Healthcare, Montvale, NJ, 2008, pp. 866-872.

Porter, C.J.H., Charman, W.N., 1997. Uptake of drugs into the intestinal lymphatics after

oral administration. Adv. Drug Deliv. Rev. 25, 71-90.

Raffanti S., Haas, D.W., 2001. In:Goodman & Gilman’s: The Pharmacological basis of

therapeutics, (Hardamn, J.G., Limbird, L.E., eds. 10th edition). Antimicrobial agents,

McGraw Hills, pp. 1360-1362.

Ramana, L.N., Sethuraman, S., Ranga, U., Krishnan, U.M., 2010. Development of a

liposomal nanodelivery system for nevirapine. J. Biomed. Sci. 17, 57.

Richman, D.D., Margolis, D.M., Delaney, M., Greene, W.C., Hazuda, D., Pomerantz, R.J.,

2009. The challenge of finding a cure for HIV infection. Science. 323, 1304–1307.

Riska, P.S., Joseph, D.P., Dinallo, R.M., Davidson, W.C., Keirns, J.J., Hattox, S.E., 1999.

Biotransformation of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor,

in mice, rats, rabbits, dogs, monkeys, and chimpanzees. Drug Metab. Dispos. 27, 1434–

1447.

Sanganwar, G.P., Sathigari, S., Babu, R.J., Gupta, R.B., 2010. Simulataneous production

and co-mixing of microparticles of nevirapine with excipients by supercritical antisolvent

method for dissolution enhancement. Eur. J. Pharm. Sci. 39, 164-174.

Sarkar, M., Perumal, O.P., Panchagnula, R., 2008. Solid-state characterization of

nevirapine. Indian J. Pharm. Sci. 70, 619-630.


Page 55

Schrager, L.K., D’Souza, M.P., 1998. Cellular and anatomical reservoirs of HIV- 1 in

patients receiving potent antiretroviral combination therapy. J. Am. Med. Assoc. 280, 67–

71.

Shegokar, R., Jansch, M., Singh, K.K., Muller, R.H., 2011. In vitro protein adsorption

studies on nevirapine nanosuspensions for HIV/AIDS chemotherapy. Nanomedicine. 7,

333-40.

Shegokar, R., Singh, K.K., 2011. Nevirapine nanosuspensions for HIV reservoir targeting.

Pharmazie. 66, 408-15.

Stoddart, C., Reyes, R., 2006. Models of HIV-1 disease: A review of current status. Drug

Discov. Today Dis. Models. 3, 113-119.

Sweetman, S.C., 2005. In: Martindale: The complete drug reference. 34th ed.,

Pharmaceutical Press, Great Britain, pp. 650

The Indian Pharmacopoeia 1996, Addendum 2005. Monographs: Nevirapine. Govt. Of

India Ministry of Health and Family Welfare, The Indian Pharmacopoeia Commission,

Ghaziabad. pp. 977.

The-Antiretroviral-Therapy-Cohort-Collaboration, 2008. Life expectancy of individuals

on combination antiretroviral therapy in high-income countries: a collaborative analysis of

14 cohort studies. Lancet. 372, 293–299.

Usach, I., Peris, J-E., 2011. Bioavailaability of nevirapine in rats after oral and

subcutaneous administration, in vivo absorption from gastrointestinal segments and effect

of bile on its absorption from duodenum. Int. J. Pharm. (Article in Press)

Vyas, T.K., Shah, L., Amiji, M.M., 2006. Nanoparticulate drug carriers for delivery of

HIV/AIDS therapy to viral reservoir sites. Expert Opin. Drug Deliv. 3, 613–628.

Waters, L., John, L., Nelson, M., 2007. Non‐nucleoside reverse transcriptase inhibitors: a

review. Int. J. Clin. Pract. 61, 105‐118.

Wishart, D.S., Konx, C., Guo, A.C., Shrivastava, S., Hassanali, M., Stothard, P., Chang,

Z., Woolsey, J., 2006. Drugbank: a comprehensive resource for in silico drug discovery

and exploration. Nucleic Acids Res. 34, D668–D672.

Yang, J-T., Kuo, Y-C., Chung, J-F., 2011. Human serum albumin-grafted cationic solid lipid nanoparticles for delivery of nevirapine in vivo. Int. Conf. Biosci. Biochem, Bioinfo. 66-70.

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