Chapter 1

Introduction

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Taste masking of Gabapentin Page 1

INRODUCTION

Epilepsy is a common and complex pathology characterized by anomalous neuronal

discharges (Chang et al., 2003). Chronic treatment with antiepileptic drugs aims to

minimize the recurrence of convulsions by reducing the neuronal activity and excitability.

At the same time, their inherent mechanism of action can eventually affect different

neurobiological systems related to the cognitive process. From this perspective, both the

disease and its treatment trigger cognitive impairment (Browne and Holmes, 2000;

Vermeulen et al., 1995) that could be especially critical in the earlier stages of the

learning process. Scientists proclaimed that Gabapentin (GBP), a well-known add-on

antiepileptic drug used under chronic management, had minimal effects on cognitive

functions and improved memory and attention in different tests (Kalviainen et al., 1997).

GBP was approved for use in the US in the early nineties (Dichter et al., 1996; Taylor et

al., 1998).

GBP [1-(aminomethyl) cyclohexane acetic acid] is a structural analog of γ-aminobutyric

acid (GABA), with an incorporated cyclohexyl ring. It is freely soluble in water and

across a wide range of pH and is characterized by a marked bitter taste (Kiel J S,

Thomas H. G.et al., EP1628656 B1, 2008).

Due to a relatively fast renal clearance it is administered several times a day (Gidal et al.,

1998) in epilepsy, neuropathic pain and also in off-label treatments (Magnus, 1999;

Mack, 2003), being all these chronic regimes.

GBP is currently marketed as an adjunctive therapy for partial seizures in adults with

epilepsy and for the management of postherpetic neuralgia (Bryans and Wustrow,

1999). In clinically recommended doses, it is rapidly absorbed following oral, single-dose

administration to healthy volunteers (Vollmer et al., 1989; Hooper et al., 1991). The site

of action of GBP is, the alpha2—delta (α2—δ) protein, an auxiliary subunit of voltage-

gated calcium channels. It subtly reduces the synaptic release of several

neurotransmitters, apparently by binding to α2—δ subunits, and possibly accounting for

its actions in vivo to reduce neuronal excitability and seizures.

From the point of view of pharmacokinetics, it is essential for the concentration of GBP

in the plasma to reach its peak in 2 to 3 hours. Currently in market tablets, capsules and

oral Neurontin solution is available. Although all these dosage forms allow the

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satisfactory concentration of GBP in the plasma, they are, however, unsuitable for

paediatric patients because of bitter taste. Therefore, there is need for development of oral

taste masked formulations of gabapentin to target both paediatric as well as geriatric

patients and to improve patient palatability and acceptability. In addition to bitter taste,

this drug has another issue of stability. It is moisture sensitive and is known to undergo

intramolecular cyclization to form lactam impurity (Zong Z, Desai S et al., 2011) which

should be below 0.4%.(USP, 2007) GBP degrades via intramolecular cyclization to form

a γ -lactam: 3, 3-pentamethylene-4-butyrolactam (2- azaspiro [4,5]decan-3-one).

Therefore, an attempt was made to develop taste masked and stable formulations of GBP

for conventional oral delivery.

1.1 TASTE MASKING

Taste has an important role in development of oral pharmaceuticals with respect to

patient acceptability and compliance and is one of the prime factors determining the

market penetration and commercial success of oral formulations, especially in paediatric

medicine. Hence, pharmaceutical industries invest time, money and resources into

developing palatable and pleasant tasting products and adopt various taste-masking

techniques to develop an appropriate formulation.

Taste, smell, texture and after taste are important factors in the development of dosage

forms. Enhanced taste, flavour and texture are found to significantly affect the sales of

the product and its preference. Current taste masking technologies offer a great scope for

invention and patents. There are numerous pharmaceutical and OTC preparations that

contain actives, which are bitter in taste. With respect to OTC preparations, such as

cough and cold syrups, the bitterness of the preparation leads to lack of patient

compliance.

Currently, companies are developing dissolvable films as alternative dosing mechanisms

for drug actives for patients who are unable to use the traditional dosing method: tablets.

In order to ensure patient compliance and to allow dissolvable films to become a viable

delivery system, bitterness masking becomes an essential component.

1.1.1 The Physiology & Psychology of Taste

To obtain an understanding of the reasoning behind this research, a basic understanding

of the physiological and psychological events that occur simultaneously in the experience

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of taste is necessary. The earlier teaching of a taste map of the tongue showing distinct

areas responding to certain stimuli have been replaced with a new theory. The currently

accepted theory is that all taste buds respond to all stimuli (Smith DV et al., 2001).

These stimuli include sweet, sour, bitter, salt, and umami. Taste buds are composed of

50–150 taste receptor cells (Smith et al., 2001) distributed across different papillae.

Circumvallate papillae are found at the very back of the tongue and contain hundreds

(mice) to thousands (human) of taste buds. Foliate papillae are present at the posterior

lateral edge of the tongue and contain a dozen to hundreds of taste buds. Fungiform

papillae contain one or a few taste buds and are found in the anterior two-thirds of the

tongue. TRCs project microvillae to the apical surface of the taste bud, where they form

the 'taste pore'; this is the site of interaction with tastants. Chemicals from food or oral

ingested medicaments are dissolved by the saliva and enter via the taste pore. There they

either interact with surface proteins, i.e. taste receptors or with pore-like proteins called

ion channels. These interactions cause electrical changes within the taste cells that trigger

them to send chemical signals that translate into neurotransmission to the brain. Salt and

sour responses are of the ion channel type of responses, while sweet and bitter are surface

protein responses. The electrical responses that send the signal to the brain are a result of

a varying concentrations of charged atoms or ions within the taste cell. These cells

normally have a net negative charge. Tastants alter this state by using varying means to

increase the concentration of positive ions within the taste cell. This depolarization

causes the taste cells to release neurotransmitters, prompting neurons connected to the

taste cells to relay electrical messages to the brain (Smith et al., 2001).

Fig 1.1: Taste receptor cells, buds and papillae on the human tongue

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Fig 1.2: Taste receptor cells, buds Fig 1. 3: Transduction mechanisms in

and papillae a taste cell

In the case of bitter taste, such as quinine, stimuli act by binding to G-protein coupled

receptors on the surface of the taste cell. This then prompts the protein subunits of alpha,

beta, and gamma to split and activate a nearby enzyme. This enzyme then converts a

precursor within the cell into a ―second messenger.‖ The second messenger causes the

release of calcium ions (Ca++

) from the endoplasmic reticulum of the taste cell. The

resulting build-up of calcium ions within the cell leads to depolarization and

neurotransmitter release. The signal now sent to the brain is interpreted as a bitter taste

(Schiffman, 2000). Based upon the recent theory that taste cells can interpret and process

all the different stimuli, a method of diminishing the overall response to one stimulus

would be to introduce a second stimulus. This is based upon the assumption that

differences among responses to stimuli are not so much a distinction between firing and

non-firing of the neurons, but instead the difference in the amount of firing (Schiffman,

2000). This theory is the basis for the current research in taste perception; the ability to

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transform the responses of certain stimuli by introducing other stimuli. Effective blocking

of the taste receptors can be accomplished by either coating the surface pore or

competing within the channel themselves to reduce the net effect of the bitter stimuli

firings. While the introduction of competing stimuli is part of the masking system,

specific flavors and sweetness profiles are essential to complete the experience and

produce a pleasant taste for the consumer (Lindemann, 1996).

1.1.2 Taste Masking Technologies

Numerous pharmaceuticals contain actives that are bitter in taste. With respect to OTC

preparations, such as cough and cold syrups, the bitterness of the preparation leads to lack

of patient compliance. The problem of bitter and obnoxious taste of drug in pediatric and

geriatric formulations is a challenge to the pharmacist in the present scenario. In order to

ensure patient compliance bitterness masking becomes essential. Molecule interacts with

taste receptors on the tongue to give bitter, sweet, or other taste sensation, when they

dissolve in saliva. This sensation is the result of signal transduction from the receptor

organs for taste, the taste buds. These taste buds contain very sensitive nerve endings,

which produce and transmit electrical impulses via the seventh, ninth and tenth cranial

nerves to those areas of the brain, which are devoted to the perception of taste

(Remington et al., 2002).

Two approaches are commonly utilized to overcome bitter taste of drugs (Brahmankar

et al., 1995). The first includes reduction of drug solubility in saliva, where a balance

between reduced solubility and bioavailability must be achieved. Another approach is to

alter the ability of the drug to interact with taste receptor. An ideal taste masking process

and formulation should have properties viz., involve least number of equipments and

processing steps, require minimum number of excipients for an optimum formulation, no

adverse effect on drug bioavailability, require excipients that are economical and easily

available, least manufacturing cost, can be carried out at room temperature, require

excipients that have high margin of safety, rapid and easy to prepare ( Kuchekar et al.,

2003). Various methods are available to mask undesirable taste of the drugs. Some of

these are as given in Fig 1.4.

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Fig 1.4: Taste Masking: Modus Operandi

Use of Flavor Enhancers

Flavoring and perfuming agents are obtained from either natural or synthetic

sources. Natural products include fruit juices, aromatic oils such as peppermint and

lemon oils, herbs, spices and distilled fractions of these. They are available as

concentrated extracts, alcoholic or aqueous solutions, syrups or spirit. Use of flavor

enhancers is limited only to unpleasant tasting substances, and is not applicable to oral

administration of extremely bitter tasting drugs like some antibiotics. The materials for

taste masking purpose have often been classified depending upon the basic taste that is

masked (Lindemann, 2000). Apart from these conventional materials many compositions

have been found to show effective taste masking abilities with improved flavor such as

alkaline earth oxide, alkaline earth hydroxide or an alkaline hydroxide (Catania et al.,

US5633006, 1997). Another composition includes phosphorylated amino acid such as

phosphotyrosine, phosphoserine, and phosphothreonine and mixtures thereof (Nelson et

al., US5766622, 1998). Anethole effectively masked bitter taste as well as the after taste

of zinc, which is used in treating the common cold (Georage et al., US5002970, 1991).

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Clove oil and calcium carbonate, which have been found to be particularly useful to mask

the unpalatable active in formulations which are intended to be chewed or dissolve in

mouth prior to ingestion in solution (Pandya et al.,US5837286, 1998).

Rheological Modifications

Increase in viscosity with rheology modifiers for example gums or carbohydrates can

lower the diffusion of bitter substances from the saliva to the taste buds. Acetaminophen

suspension has been formulated with xanthan gum (0.1–0.2%) and microcrystalline

cellulose (0.6–1%) to reduce bitter taste (Blasé et al., EP0556057, 1993). The bitter taste

of a syrup composition comprising of phenobarbital or acetaminophen was masked by

using a polyhydric alcohol such as polyethylene glycol or polypropylene glycol with

polyvinyl pyrollidone, gum arabic, or gelatin (Suzuki et al., EP0441307, 1991).

Addition of anaesthetics agent

Addition of anesthetising agents to formulations numbs the taste buds long enough to

administer the unpleasant drugs without the perception of taste. For example, sodium

phenolate addition to aspirin-medicated floss serves to numb the taste buds sufficiently

for 4–5 seconds, rendering the bitter taste of aspirin imperceptible (Fuisz et al.,

US5028632, 1991).

Salt preparation

Adding alkaline metal bicarbonate such as sodium bicarbonate masks the unpleasant taste

of water-soluble ibuprofen salts in aqueous solution (Gregory et al., EP0418043, 1990).

The bitter taste of caffeine may be masked by formulating it as a carbonated oral solid

preparation using sodium bicarbonate, ascorbic acid, citric acid, and tartaric acid

(Nishikawa et al., 1990). Magnesium aspirin tablets are rendered tasteless by preparing

magnesium salts of aspirin (Nanda et al., 2002). Penicillin prepared as N, N’-

dibenzylethylene-diamine diacetate salts or N, N’-bis (deyhdroabiety) ethylenediamine

salts is tasteless (Nanda et al., 2002).

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Coating of drug particles with inert agents:

Coating of drugs using a suitable polymer offers an excellent method of concealing the

drug from the taste buds. The coated composition may be incorporated into number of

pharmaceutical formulations, including chewable tablets, effervescent tablets, powders,

and liquid dispersions ( Corbo et al., US6.663893, 2003) (Friend et al., US 6139865,

2000) (Augello et al., US6099865, 2000).

By coordinating the right type of coating material, it is possible to completely mask the

taste of a bitter drug, while at the same time, not adversely affecting the intended drug

release profile (Mauger et al., US5728403, 1998). Any nontoxic polymer that is

insoluble at pH 7.4 and soluble at acidic pH, would be an acceptable alternative for taste

masking. Various inert coating agents like starch; povidone, gelatin, methylcellulose,

ethyl cellulose etc. are used for coating drug particles.

Taste masking of ibuprofen has been successfully achieved by using the air suspension

coating technique to form microcapsules comprised of a pharmaceutical core of a

crystalline ibuprofen and methacrylic acid copolymer coating that provides chewable

taste masked characteristics (Shen et al., US5552152, 1996).

Kato et al. studied the low melting point substances for masking bitter taste of the drug.

Beef tallow (a low melting point substance) was mixed with micropulverized active

ingredients (e.g. antiulcer methyl benactyzuim bromide) and the mixture was nozzle

sprayed to form coated spheres having homogenous particle size (Kato, JP 8259466).

Maccari et al. conducted a special study to assess the bioavailability of a Flucoxacillin

preparation microencapsulated for taste abatement with 17 % ethyl cellulose made up as

a granular’ product for extemporaneous resuspension when compared to commercially

available Flucoxacillin preparations. Both dosage forms were bioequivalent proving that

Flucoxacillin microencapsulated for taste abatement is as available from the dosage form

as the raw unprocessed antibiotic (Maccari et al., 1980).

Yajima et al. developed a method of taste masking using a spray-congealing technique to

mask the bitter taste of clarithromycin. Glyceryl monostearate and aminoalkyl

methacrylate copolymer E (AMCE) were selected as ingredients, the objective being

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prevention of drug release in the mouth while ensuring rapid release in GIT. The

palatability and taste of optimized formulation was significantly improved, compared

with conventionally coated granules (Yajima et al., 1996).

Sugao et al. prepared Microparticles of Imdeloxazine HCl (a bitter tasting drug) and

coated them with a mixture comprising of hydrogenated oil and surfactants in a fluidized

bed using side spray method. Drug release from the coated particles was significantly

delayed which was overcome by heat treatment. This method sufficiently suppressed the

bitter taste of Imdeloxazine HCl powder without loss of bioavailability

(Sugao et al., 1998).

Udea et al. described a novel microencapsulation process combined with the wet

spherical agglomeration technique by using modified phase separation method in order to

mask the bitter taste of enoxacin (Ueda et al., 1993).

Ozer et al. microencapsulated Beclamide in order to mask the bitter taste by a simple co-

acervation method-using gelatine. The unpleasant taste of an antiepileptic drug,

beclamide, can be masked by microencapsulation followed by tableting. Anhydrated

sodium sulfate was used as the coaceravating agent (Ozer et al., 1980).

Multiple encapsulated flavor delivery systems have been developed which is useful in

chewing gums, pharmaceutical preparations as well as other food products for effective

taste masking (Cherukuri et al., US5004595, 1991).

Taste masking by formation of inclusion complexes

Cyclodextrin is the most widely used complexing agent for inclusion complex formation

which is capable of masking the bitter taste of the drugs either by decreasing the

solubility on digestion or decreasing the amount of drug particles exposed to taste buds

thereby reducing taste perception of bitter taste. Bitter taste of ibuprofen and gymnima

sylvestre has been effectively masked by cyclodextrin complexes (Motola et

al., US5024997, 1991) ( Ueno et al., JP0411865, 1992).

In inclusion complex formation, the drug molecule fits into the cavity of a complexing

agent i.e., the host molecule forming a stable complex. The complexing agent is capable

of masking the bitter taste of the drug by either decreasing its oral solubility on ingestion

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or decreasing the amount of drug particles exposed to taste buds thereby reducing the

perception of bitter taste. Vander Waals forces are mainly involved in inclusion complex

formation (Mendes et al., 1976).

Beta-cyclodextrin is most widely used complexing agent for inclusion type complexes. It

is sweet, nontoxic, cyclic oligosacchride obtained from starch. Strong bitter taste of

carbapentane citrate syrup (Kurusumi et al., 03236616) was reduced to approximately

50% by preparing a 1:1 complex with cyclodextrin. The suppression of bitter taste by

cyclodextrin was in increasing order of alpha, gamma and beta cyclodextrins.

Molecular complexes of drug with other chemicals

The solubility and adsorption of drug can be modified by formation of molecular

complexes. Consequently lowering drug solubility through molecular complex formation

can decrease the intensity of bitterness of drug. Higuchi and Pitman, (Lachman et al.,

1986) reported that caffeine forms complexes with organic acids that are less soluble than

xanthane and as such can be used to decrease the bitter taste of caffeine (Kurusumi et

al., 03236616).

Solid dispersion systems

Solid dispersions are dispersions of one or more active ingredients in an inert carrier or

matrix at solid state prepared by melting solvent method (Liberman et al., 1989). Solid

dispersions are also called as coprecipitates for those preparation obtained by solvent

method such as coprecipitates of sulphathiazale and povidone. Solid dispersions using

insoluble matrices or bland matrices may be used to mask the bitter taste of drugs. Also

using them as absorbates on various carriers may increase the stability of certain drugs.

Microencapsulation

Microencapsulation as a process has been described by Bakan as a means of applying

relatively thin coating to small particles of solids, droplets of liquids and dispersions.

This process is used for masking taste of bitter drugs by microencapsulating drug

particles with various coating agents. Coating agents employed includes gelatin,

povidone, HPMC, ethyl cellulose, Bees wax, carnauba wax, acrylics and shellac. Bitter

tasting drugs are first encapsulated to produce free flowing microcapsules, which are then

blended with other excipients and compressed into tablets. Microencapsulation can be

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accomplished by variety of methods including air suspension, coacervation, phase

separation, spray drying and congealing, pan coating, solvent evaporation and

multiorifice centrifugation techniques (Bakan et al., 1986) (Venkata et al., 2010).

Multiple Emulsions

A novel technique for taste masking of drugs employing multiple emulsions has been

attempted by dissolving drug in the inner aqueous phase of w/o/w emulsion. The

formulation is designed to release the drug through the oil phase in the presence of

gastrointestinal fluid ( Rao et al., 1993; Manek et al., 1981)( Khan et al., 2006).

Microemulsions

Microemulsions and self-emulsifying drug delivery systems (SEEDS) containing

phenobarbital have been recently developed to improve its chemical stability, solubilizing

capacity and taste-masking in oral liquid dosage forms (Ezequiel et al., 2013).

Liposomes

Another means of masking the unpleasant taste of therapeutic agents is to entrap them

into liposomes. For example, incorporating into a liposomal formulation prepared with

egg phosphatidyl choline masked the bitter taste of chloroquine phosphate in HEPES (N-

2-hydroxyetylpiperzine-N’- 2- ethane sulfonic acid) buffer at pH 7.2 (Kasturagi et al.,

1995) (Agarwal et al.,2010).

Prodrugs

A prodrug is a chemically modified inert drug precursor, which upon biotransformation

liberates the pharmacologically active parent drug. Taste of Chloramphenicol and

clindamycin have been improved by formation of its palmitate ester (Brahmankar et al.,

1995). Karaman recently studied computational approach for prodrug synthesis for

masking bitter taste of antibacterial drugs viz., cefuroxime (Karaman, 2013).

Melt extrusion method (Dispersion coating)

This technology involves softening the active blend using the solvent mixture of water-

soluble polyethylene glycol, using methanol, and expulsion of softened mass through the

extruder or syringe to get a cylinder of the product into even segments using heated blade

to form tablets. The dried cylinder can also be used to coat granules of bitter tasting drugs

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and thereby masking their bitter taste (Kasturagi et al., 1995). It has been recently

reported that hot melt extrusion achieves taste masking of bitter APIs via various

mechanisms such as the formation of solid dispersions and inter-molecular interactions

and this has led to its wide-spread use in pharmaceutical formulation research

(Maniruzzaman et al., 2013).

Ion Exchange Resins

Another popular approach in the development of taste masking is based on use of ion

exchange resins. Ion exchange resins are solid insoluble high molecular weight

polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding

medium. The resulting ion exchange is reversible and stoichiometric with the

displacement of one ionic species by another (Swarbik, 2003). Synthetic ion exchange

resins have been used in pharmacy and medicine for taste masking or controlled release

(Dorfner, 1972). Being high molecular weight water insoluble polymers, the resins are

not absorbed by the body and are therefore inert. The long-term safety of ion exchange

resins, even while ingesting large doses cholestyramine to reduce cholesterol is

established unique advantage of ion exchange resins. This is due to the fixed positively or

negatively charged functional groups attached to water insoluble polymer backbone

(Jain, 2001). The adsorption of bitter drugs onto synthetic ion exchange resins to achieve

taste coverage has been well documented. Ion exchange resin Amberlite CG 50 was used

for taste masking of pseudoephedrine in the chewable Rondec decongestant tablet

(Suhagiya et al., 2010). Ciprofloxacin was loaded on cation exchanger and administered

to animals. The taste was improved as animal accepted the material more readily

(Borodkin et al., 1970). Binding to a cation exchange resin like Amberlite IRP-69

masked the taste of peripheral vasodilator buflomid. Manek et al. evaluated resins like

Indion CRP 244 and CRP 254 as taste masking agents (Manek et al., 1981).

Ion exchange resins (IER) have received considerable attention from pharmaceutical

scientists because of their versatile properties as drug delivery vehicles. Several ion

exchange resin products for oral administration have been developed for immediate

release and sustained release purposes. Research over last few years has revealed that

IER are equally suitable for drug delivery technologies, including controlled release,

transdermal, nasal, topical, and taste masking (Venkatesh et al., 2013).

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Techniques employed for Taste Masking of different Dosage Forms

The drug i.e. the active pharmaceutical ingredient is finally formulated for oral

administration in a suitable dosage form such as tablets, powders, syrups, etc and they

may need taste masking.

I) Tablets

Most of the tablets can be effectively masked for their taste by applying inert polymer

coatings that prevent the interaction of the drug substance with the taste buds.

Nevertheless, attempts have been made time and again by several workers to investigate

and explore the use of newer materials in bad taste abatement and good taste

enhancement (Table 1.1).

Table 1.1: Taste masking of tablets

Materials Method used for preparing Tablet

Gelatin, Sugar, Citric acid, Concentrated

Juice, Colorants, Flavors.

A solid preparation of Acetaminophen was

prepared using gumi base (Namiki et al.,

JP09052850, 1997).

A series of Eudragit polymers with

difference in the frequency of the ester

substituents in the chemical structure.

Polymer coating was applied on the solid

dosage form and evaluated for water

permeability, pH solubility, and taste

masking (Lulei et al.,1997).

Effervescent admixture of sodium

bicarbonate and citric acid encapsulated

with ethyl cellulose

Microcapsules were used in formulating taste

masked effervescent chewable tablets of

NSAID (Bettman et al., US5639475).

Sodium alginate, calcium gluconate A core tablet of Ampirilose was prepared

which was under coated with calcium

gluconate and over coated with sodium

alginate which led to the formation of a gel

on the surface of the tablet that exhibited

good taste masking effect (Kaneko et al.,

1997).

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II) Granules / Powders

Granules for reconstituting as liquids (e.g. sachets, sprinkle capsules & powders) hold a

high share of pediatric and geriatric market. A large number of patents on the topic

highlight the significance of the same. Thus, taste masking of granules becomes an

important priority in product development and varied technologies and methodologies

exist for the same. Hayward et al. have reported a granular composition for taste

masking, comprising of drug core of a NSAID and methacrylate ester copolymers as

coating agents for taste masking. The method comprises of coating the drug cores with

separate layers of aqueous dispersions of the copolymers. Granules of the invention could

be used in the preparation of chewable tablets, which had good palatability and

bioavailability ( Hayward et al ., US37277, 1998).

Kishimoto et al. used mannitol and lactose in different weight ratios (1: 1.5 - 1:5) as

coating materials for masking bitter taste of solid drug preparations (Kishimoto et al.,

JP09143100, 1997).

Yajina et al., in their patent have described a composition comprising of a drug with

unpleasant taste of polymer solution and D-crystals of monoglycerides. Eudragit E (100

g) was dissolved in melted stearic acid monoglyceride (600g) and then Erythromycin

(300g) was added to the mixture to obtain a powder. This powder was again mixed with

sorbitol, magnesium oxide and starch to give taste masked granules of Erythromycin

(Yajina et al., WO 96342819).

Danielson et al. invented a dosage form comprising granules containing the histamine

receptor antagonist which are provided with taste masking coating comprising a water

insoluble, water permeable methacylate ester copolymer in which the coating is applied

to the granules in an amount which provides a taste masking effect for a relatively short

period during which the composition is being chewed by a patient but which allows

substantially immediate release of the histamine receptor antagonist after the composition

has been chewed and ingested (Danielson et al., US6270807, 2001).

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Kumar provided a means and method for manufacturing palatable drug granules using a

polymer having at least one free carboxyl group and poly vinyl pyrolidone (Kumar,

US6372259, 2002).

III) Liquids

They present a major challenge in taste masking because the majority of pediatric

preparations are syrups and suspensions. The aforementioned methodologies have also

been used for improving liquid taste and few patents in this area described here. Nakona

et al. masked the bitter taste of vitamin B1 derivatives such as dicethimine by

formulating with menthol and polyoxyethylene or polyoxypropylene for formulating oral

liquids (Nakano, JP 11139992). Osugi et al. in their invention subjected oral liquids

containing Diclofenc and its salts to heat treatment in the presence of glycine,

glycerrhizinic acid or salt thereof to mask the bitter taste and to prevent the irritation of

the throat upon oral administration (Osugi et al JP 11139970, 1999).

Meyer et al. used prolamine, applied as single coating in weight ratio 5% to 100%

relative to active substance being coated. This resulted in the production of a liquid

suspension, which effectively masked the taste of orally administered drugs that are

extremely bitter. Prolamine coating does not restrict the immediate bioavailbility of the

active substance Prolamine coating is effective in masking the taste of antibiotics,

vitamins, dietary fibers, analgesic, enzymes, and hormones (Meyer et al., US5599556,

1997).

Pharmaceutical composition comprising polyhydric alcohol based carrier to mask the

bitter taste of a drug were reported by Swaminathan et al. who prepared the liquid

containing cimetidine, peppermint oil and glycerol (Swaminathan et al., WO9733621,

1997).

Morella et al. invented a liquid suspension of microcapsules taste masked as a function of

a polymer coating and the pH of suspended medium at which pharmaceutically active

ingredients remain substantially insoluble (Morella et al., US 6197348, 2001).

Yu et al. developed a liquid composition comprising a pharmaceutically active

medicament coated with a taste masking effective amount of polymer blend of

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dimethylaminoethyl methacrelate and neutral methacrelic acid ester and a cellulose ester

in an aqueous vehicle. The liquid composition utilizes a reverse enteric coating, which is

soluble in acid pH of the stomach generally about 1-4 but relatively insoluble at the non-

acidic pH of the mouth. The coating provides the rapid release and absorption of the

drug, which is generally desirable in case of liquid dosage forms (Yu et al., U.S. Patent,

6586012, 2003).

1.1.3 Trends In Taste Masking Technologies With Their Patent Overview

Different taste masking technologies have been used to address the problem of patient

compliance. Quantitative analysis was performed by Zelalem et al. to compare the

multitude of existing taste masking technologies based on the patents filed. It discusses

the possible reasons for the current trend in inventions (Zelalem et al., 2009). The

worldwide database of European patent office was used to search the taste masking

patents and the patent applications published in the period of 1997-2007.

Patents and patent applications filed in different countries such as Republic of Korea,

Japan, USA, Canada, China, France, Russia, Mexico, South Africa, United Kingdom,

Australia and Ukraine were included in the analysis. As indicated in Fig. 1.5 from the

collected 76 patents and 108 patent applications, about 49.34% of taste masking patents

and patent applications are contributed from Asia. North America accounts for about

41.45% of which 62.67% were filed in USA and about 9.30% from Europe.

Fig 1.5: Geographical distribution of taste

masking patents and patent applications filed in

the period of year 1997 to 2007.

Fig 1.6: Taste masking technology filed in

the period of year 1997 to 2007.

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Based on the collated data, different taste masking technologies were enlisted and

percentage contribution of each was calculated as shown in Fig1.6. Taste masking

technologies are increasingly focussed on aggressively bitter tasting drugs like the

macrolide antibiotics, non-steroidal anti-inflammatory drugs and penicillins. Taste

masking of water soluble bitter drugs, especially those with a high dose, is difficult to

achieve by using sweeteners alone.

Consequently, more efficient techniques such as coating, microencapsulation and

granulation have been used in combination with the sweeteners. Coating, which accounts

for 27% of patents and patent applications, was the most commonly used technique in the

decade. An almost equivalent percentage of patents were filed on the flavors and

sweeteners for taste masking.

Microencapsulation, granulation technologies, suppressants and potentiators also hold a

prominent share of patents in this field. Less commonly used taste masking technologies

such as use of viscosity modifiers, solid dispersions, complexing agents, ion exchange

resins, pH modifiers hold ≤5% share of the total taste masking patents and patent

applications.

Trend analysis was drawn for individual technology to delineate its relative usage in

periods of four years (1997- 2000 and 2001-2004) and the subsequent three years (2005-

2007) over a decade as indicated in Fig.1.7. Usage of sweeteners was the most prominent

taste masking technology in the period of year 1997 to 2000 and 2001 to 2004 with an

overall increment of about 41.6% but did not show any further increment. For the coating

technology the number of patents filed in period of 2001 to 2004 increased by 133% as

compared to year 1997 to 2000. The increment in the period of years 2005 to 2007 for

coating technique was about 78.6%. Year 2005 to 2007 accounts for about 55.5% of

coating patents and patent applications published in the decade.

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Fig 1.7: Trend of taste masking technology filed in the period of year 1997 to 2007

Contribution of suppressant and potentiators was comparable to granulation in the period

1997 to 2000. However, the use of granulation has shown a steady increase during the

decade. Other strategies such as solid dispersions and microencapsulation also show an

increment in their application for taste masking of active pharmaceuticals.

1.1.4 Factors Affecting Selection of Taste Masking Technology

A. Extent of Bitter Taste

With aggressively bad tasting medicaments even a little exposure is sufficient to perceive

the bad taste. For example, sweeteners could not achieve taste masking of oral

formulation of ibuprofen due to its dominating taste (Krise et al., US20046740341,

2004). Coating is more efficient technology for aggressively bitter drugs even though

coating imperfections, if present, reduce the efficiency of the technique (Kolter et al.,

US20010007680 A1, 2001).

Similarly, microencapsulation of potent bitter active agents such as azithromycin is

insufficient to provide taste masking of liquid oral suspensions (Catania et al.,

US5633006, 1997). Viscosity enhancers can complement the taste masking efficiency.

Oral suspension containing viscosity enhancers can masquerade the objectionable taste,

which arises from the leakage of drug from the coated medicaments or microcapsules.

This approach was also used for the microencapsulated oxazolidinone particles to limit

the transport of drug from the polymer coated drug particles to the vehicle (Fredrickson

et al.,WO2004087108, 2004). Conventional taste masking techniques such as the use of

sweeteners, amino acids and flavoring agents alone are often inadequate in masking the

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taste of highly bitter drugs such as quinine, celecoxib, etoricoxib, antibiotics like

levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and

clarithromycin (Kulkarni et al, WO2005056619., 2005).

B. Dose of Active Pharmaceuticals

Dose of a drug may dictate whether a particular formulation strategy would be suitable to

achieve taste masking. In pediatric formulations, the dose is small enough so as to allow

the usage of flavoring agents to mask the taste of the medicine. For example, low dose

palatable pediatric aspirin oral formulation was developed by adding sweeteners, but the

same approach failed to address the problem of drugs like acetaminophen because of its

high dose. In such cases, coating is preferred to achieve taste masking along with

sweeteners to attain an acceptable final dosage form size (Roche et al., EP0473431,

1995).

C. Drug Particle Shape and Size Distribution

Particle characteristics of the drug would affect the taste masking process efficiency.

Core materials with irregular shapes and small particle size lead to poor taste masking

efficiency and varying dissolution of coated particles (Julian et al., US4851226, 1989).

Fines, abrasion and variable coating thickness can lead to situations wherein the taste

mask coating is compromised. Multilayer coating using inner spacing layer to sequester

the drug from taste masking layer helps to reduce or eliminate such coating

imperfections. Taste masked granules of gatifloxacin and dextromethorphan were

formulated by multilayer coating consisting of inner spacing layer followed by outer taste

masking layer (Krise et al., US20046740341, 2004).

D. Dosage Forms

It is estimated that 50% of the population have problem of swallowing tablets, especially

the pediatric and geriatric population. Chewable tablets and liquid oral dosage forms have

been used to address these problems. However, it is difficult to formulate some drugs in

these dosage forms due to their poor palatability (Venkatesh et al., US20060078614,

2006).

For formulations which are swallowed unchewed: capsules, coated tablets and slowly

disintegrating hard tablets have been used as preferred taste masking technologies.

Chewable tablets and liquid oral formulations are preferable in case of large dose drugs

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for an ease of intake. Taste masking technologies such as sweeteners, particulate coating,

microencapsulation and granulation can be employed for chewable tablets and supported

with technologies such as viscosity enhancers and pH modifiers to achieve taste masking

in liquid oral formulations (Kolter et al, US20060204587, 2006).

Microencapsulation of the unpleasant tasting active agent with ethyl cellulose or a

mixture of ethyl cellulose and hydroxypropyl cellulose or other cellulose derivatives has

been used to provide chewable taste-masked dosage forms. However, this approach

suffers from the disadvantage that the polymer coating releases the active agent in an

inconsistent fashion and may not provide an immediate release. Moreover, coating is

more suitable when the formulation is stored in a dry form. Viscosity enhancers or pH

modifiers can be used in the suspending medium to achieve taste masking of suspended

coated particles, especially for extremely bitter drugs like erythromycin and its

derivatives during the shelf life of a reconstituted suspension (Mehta et al.,

WO2004096175, 2004).

E. Drug Solubility

Physicochemical properties of the drug play an important role in the selection of taste

masking technology. For example, ondansetron has a relatively lower water solubility at

higher pH, based on which a rapidly disintegrating taste masked composition of

ondansetron was formulated by adding an alkalizing agent(sodium bicarbonate) to reduce

the water solubility and the consequent taste perception (Park et al., WO2004096214,

2004). Douglas and Evans(1994) described different approaches to achieve the taste

masking of ranitidine base and its salts having different solubility profiles. The bitter taste

associated with a poorly soluble form of ranitidine may be satisfactorily masked by lipid

coating of the drug substance. However, for water soluble forms of ranitidine (e.g.

ranitidine hydrochloride), the degree of taste masking achieved by simple lipid coating of

the drug substance may not be entirely satisfactory, particularly if the product is to be

formulated in an aqueous medium. Thus ranitidine hydrochloride was first incorporated

into the inner core of a polymeric binder, or a lipid or wax having a melting point higher

than that of the outer lipid coating to achieve an efficient taste masking (Douglas et al.,

CA2146999, 1994).

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F. Ionic Characteristics of the Drug

Ionic characteristics of drugs govern the selection of ion exchange resin polymers and the

suitability of the drug candidate for this technology. For example, anionic polymers (e.g.

alginic acid) are good candidates for cationic drugs like donepezil hydrochloride, and the

cationic polymers are choice of excipients for anionic drugs like sildenafil (Koji et al.,

JP161679, 2004).

1.1.5 Taste Assessment of Pharmaceuticalsls

Taste assessment is one important quality-control parameter for evaluating taste-masked

formulations. Any new molecular entity, drug or formulation can be assessed using in

vitro or in vivo methods for taste assessment (Table 1.2). In vivo approaches include

human taste panel studies, electrophysiological methods and animal preference studies.

Several innovative in vitro drug release studies utilizing taste sensors, specially designed

apparatus and drug release by modified pharmacopoeial methods have been reported in

the literature for assessing the taste of drugs or drug products. The multichannel taste

sensor, also known as the electronic tongue or e-tongue, is claimed to determine taste in a

similar manner to biological taste perception in humans (Jain et al., 2010). Furthermore,

such taste sensors have a global selectivity that has the potential to classify an enormous

range of chemicals into several groups on the basis of properties such as taste intensities

and qualities (Kiyoshi Toko, 2013).

In vivo approaches for taste assessment

During in vivo studies, stimuli are applied on to the tongues of either humans or animals.

The stimulus interacts with receptors embedded in the membrane of the taste buds and

the information is ultimately transduced as an electrical signal, which is further

transmitted along the nerve fiber to the brain, where taste is perceived. Such studies

include human taste panel studies, electrophysiological methods and animal preference

tests.

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Table 1.2: The current in vitro and in vivo taste assessment approaches

Human taste panel studies

Human taste panel studies evaluate tastants (food, chemicals, drugs and so on) by

estimating the gustatory sensation responses in healthy human volunteers within well-

controlled procedures. Such studies are therefore also known as physiological evaluation,

psychophysical evaluation, gustatory sensation tests, sensory tests or taste trials. They are

sensitive measures of taste and are statistically designed to minimize bias and variable

responses within and between human volunteers. Well-established methodologies for

performing sensory analysis can be broadly divided into five types, namely

discrimination tests, scaling tests, expert tasters, affective tests and descriptive methods

(Meilgaard et al., 2006). Volunteers assess the taste quality and intensity of standard and

test stimuli on different adjective scales.

Human taste panels are preferred for assessing the taste of drugs or formulations, but

their use is limited because of the subjectivity of panel members, potential toxicity and

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liability issues. Further problems are found in recruiting, motivating and maintaining

taste panel lists, which becomes a particularly difficult task when working with

unpleasant molecules, drugs or drug products. NMEs cannot be ethically tasted by human

beings because of the lack of appropriate toxicological data. Even in the case of new

nontoxic drugs, finding human volunteers for taste assessment is an arduous mission.

Animal preference tests

Bottle preference and conditioned taste aversion tests are used for determining taste

preference and concentration-response properties of tastants by animals (Tordoff et al.,

2003; Cotterill et al., 2005). Rats, mice, cats and dogs are used for conducting such

preference determination tests. Attempts have been made to develop methodologies that

can produce robust behavioral tests, capable of providing data comparable with those

obtained from physiological investigations. A brief contact procedure has been studied to

evaluate the ability of rats to detect the presence of a weak bitter compound dissolved in a

strong sucrose solution. These results demonstrate the acute ability of rats to discriminate,

by taste, not only the presence but also the concentration of a dilute bitter compound

dissolved in a strong sucrose solution (Contreras et al., 1995). Moreover, animal

preference tests might be of little use in assessing the taste of NMEs. The results from

such tests are extrapolated, which might or might not be accurate because it is assumed

that a molecule disliked by the animal might be bitter.

Electrophysiological methods

Electrophysiological recordings from animals (Zotterman et al, 1935), primate (Scott et

al., 1999) and human taste nerves (Oakley et al., 1985) have provided insights into the

physiology of taste sensation. Responses of tastants from single glossopharangeal or

chorda tympani nerve fibers or nerve bundles can be utilized for taste assessment

(Formaker et al., 2004). Mice (Ming et al., 1999), bull frogs (Rana ctesbeiana)

(Katsuragi et al., 1996; Katsuragi et al., 1997) or gerbils (Meriones unguiculatus)

(Schiffman et al., 2000) have all been described in the literature in this respect. In these

tests, the animal is anaesthetized; following which electrodes are implanted in the chorda

tympani nerve bundle and/or glossopharyngeal nerve. Tastant solutions are then passed

over the tongue for a controlled period. Electrophysiological recordings from the chorda

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tympani and/or glossopharyngeal nerve provide a means of directly measuring the

temporal profiles or dose response curves of taste stimuli (Ming et al., 1999).

Electrophysiological methods involving animals are difficult and costly because of the

requirement for surgery and they are not amenable to the screening of a large number of

samples.

In vitro approaches for taste assessment

Drug release studies are also used in taste assessment to measure the effectiveness of

coating and complexation within a formulation. They are indirect methods for assessing

taste because these methods do not contribute to the evaluation of taste and sweetness of

the drug product. Novel drug release apparatus and pharmacopoeial apparatus have both

been adapted to simulate buccal dissolution of dosage forms so as to compare taste in

different pharmaceutical formulations. Such novel apparatus and methods for drug

dissolution or release studies tend to simulate the release of bitter or undesirable tasting

drug in the mouth (Yajima et al., 2002). The in vitro biochemical assay of gustducin

and/or transducin can also be used for the high-throughput taste assessment of new

molecular entities (NMEs). The in vitro biochemical assay of gustducin and/or transducin

can be used to identify and determine the concentration response function of many bitter

compounds. It can also be used for the rapid throughput screening of high-potency

bitterness inhibitors.

In vitro drug release studies

Pharmacopoeial release tests have been modified by altering the chemical composition of

the dissolution media (e.g. artificial saliva) and reducing the size of the basket screen size

(screen size <0.381 mm square opening) to prevent particles from escaping. Taste

masking is achieved when, in the early time points from 0 to 5 min, the drug substance in

the dissolution medium is either not detected or the detected amount is below the

threshold for identifying its taste. Drugs can be analyzed either spectrophotometrically or

using HPLC. HPLC is preferred, especially when testing is performed in the presence of

UV-absorbing components, such as flavourings and sweeteners. Furthermore, the drug

signal is frequently indistinguishable from background in the UV estimation when there

is a high excipient: drug ratio in the taste-masked formulations.

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A novel in vitro buccal dissolution testing apparatus and method for the assessment of

taste masking in oral dosage forms has recently been invented (Hughes et al, 2003). The

apparatus consists of a single, stirred, flow-through filtration cell including a dip tube

designed to remove fine solid particles. Simulated saliva is used as the dissolution

medium. The filtered solution is removed from the apparatus continuously and used to

analyze the dissolved drug. The method enables the relative prediction of taste intensity

of dosage forms. The method is rapid and repeatable. (Fig 1.8)

In vitro assay methods

Gustducin and transducin are guanine nucleotide-binding regulatory proteins (G proteins)

expressed in taste receptor cells (TRCs). Gustducin is selectively expressed in 20–30% of

TRCs in the palate and all taste papillae, and in apparent chemosensory cells in the gut

and the vomeronasal organ (Glibertson et al, 2000). Most bitter stimuli can activate both

transducin and gustducin, and this activation depends upon receptors in the taste-bud

membrane (Ming et al., 1998). The activation of gustducin and/or transducin in the

presence of the taste-bud membrane can be measured to identify certain bitter tastants,

determine molecular mode of action, quantitatively determine potency profiles and screen

chemical libraries for potential bitterness inhibitors (Ruiz-Avila et al., 2000).

Fig 1.8: A novel mini-column apparatus for evaluating the bitterness of dry syrups

(Yajima et al., 2002)

Not all the bitter compounds demonstrate in vitro activity (gustducin independent taste

modifiers, e.g. caffeine and aristolochic acid), which could be due to the presence of

multiple transduction pathways. Furthermore, gustducin and/or transducin are not

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activated in the presence of sucrose, glycine, monosodium glutamate, citric acid or

potassium chloride.

Biomimetic taste sensing systems (BMTSSs)

The use of multivariate data analysis (MVDA), combined with sensors that have partially

overlapping selectivities, has become an incredibly powerful tool in taste measurement

technology. Such systems, often referred to as artificial senses, emulate biological taste

reception at the receptor level, the circuit level and the perceptual level (Fig 1.9).

BMTSSs have been marketed as taste sensors, or electronic tongues or e-tongues (Toko

et al., 2005). These instruments employ electrochemical sensors coupled with

chemometric methodologies to perform qualitative and quantitative analyses of

organoleptic and chemical properties of substances and products. The data can be

processed using MVDA, either to search for correlation within the data or to develop

predictive models. BMTSS shave been shown to be globally selective for detecting and

quantifying specific classes of chemical compounds (Toko et al., 2000). They do not

discriminate minute differences in the structure of compounds but can transform

molecular information from interactions with biological membranes into several types of

group, that is, taste intensities and qualities (Toko et al., 1998). Taste sensors therefore

act as intelligent sensors to reproduce the complex and comprehensive taste sense of

humans. Global selectivity signifies the quantification of a combination or mixture of

various types of substances that result in a compound effect, such as a synergistic effect

or suppression effect amongst the substances.

New regulatory guidelines, for testing and evaluation of age-adapted dosage forms meant

for geriatric and paediatrics will emphasize the need to conducting taste studies in special

populations. The overall impact will limit the use of humans in taste assessment. There

has been an increase in the number of in vitro studies using either taste sensor or

innovative apparatus for drug release studies. Taste sensor output is similar to that of the

biological gustatory system, which further advocates its application to the taste

assessment of not only drugs and formulations, but also new molecular entities. In vitro

approaches should therefore be useful both in the development of more desirable and

palatable dosage forms and in high-throughput taste assessment.

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Fig 1.9: Development of taste sensors on the basis of mechanisms found in biological

systems.

Taste is an important factor in the development of dosage form. Nevertheless, it is

that arena of product development that has been overlooked and undermined for its

importance. Taste masking technologies offer a great scope for invention and

patents.

The literature review discussed here was modest effort to give a brief account of

different technologies of taste masking with respect to dosage form and novel

methods of evaluation of taste masking effect. With thorough knowledge of these

technologies, massive efforts have been put forth for masking the bitter taste of GBP

molecule.

Another objective was to develop oral controlled release delivery systems of GBP.

Hence, a brief discussion of modalities and current status of art in field of oral

controlled release formulations is presented in next section.

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1.2 CONTROLLED DRUG DELIVERY SYSTEMS OF GBP

GBP has a relatively short half-life (i.e., 5-7 hours), requiring three doses per day in most

patients which leads to substantial fluctuations in the plasma concentration of the drug.

This absorption pathway is apparently saturated at doses normally used to treat

neuropathic pain. As a result, the plasma exposure to GBP in patients receiving GBP is

not dose proportional, and therefore may not reach therapeutically useful levels in some

patients (Gidal et al., 2000).

Frequent dosing is necessary to maintain reasonably stable plasma concentrations. The

effective dose of GBP is 900 to 1800 mg/day, which is given in divided doses. Dosing

regimens requiring three or four doses per day lead to significant noncompliance in

epilepsy patients (Richter et al., 2003).

It has been determined that GBP is typically absorbed from the upper intestine, i.e., it has

a narrow absorption window and is absorbed by active transport through a large neutral

amino acid (LNAA) transporter (Stewart et al.,1993; Uchino et al., 2002). This

transporter is located in the upper small intestine, has limited transport capacity, and

becomes saturated at high drug concentrations. Consequently, the plasma levels of GBP

are not dose proportional and, therefore, higher doses do not give proportionately higher

plasma levels. Since the LNAA transporter responsible for GBP absorption is present

only in the upper region of the intestine, the dosage form used to provide GBP should be

designed to release GBP in the stomach at a rate such that the maximum amount of the

drug is available in the intestinal segment.

Prolonged, stable exposure to GBP may provide other clinical benefits, including greater

efficacy, prolonged duration of action, and a reduced incidence of adverse effects related

to peak drug levels. However, it has been difficult to achieve these benefits with a

sustained-release formulation of GBP, primarily due to the lack of significant absorption

in the large intestine (Stevenson et al., 1997; Kriel et al., 1997; Cundy et al., 2004a,

2004b). These pharmacokinetic complexities may directly affect the efficacy of a

sustained-release formulation. In addition, the rate and site of drug release may also

influence the magnitude and duration of the pharmacological response (Castaneda-

Hernandez et al., 1994; Hoffman and Stepensky, 1999). Therefore, an essential step in

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Taste masking of Gabapentin Page 29

developing controlled-release formulations is to establish a rationale that accommodates

both the in vitro and in vivo properties of the drug.

Therefore, attempts have been put forth for designing Controlled release gastroretentive

bioadhesive drug delivery systems of gabapentin that will release drug over an extended

period of time, and majorly in upper gastrointestinal tract to provide therapeutically

effective plasma levels.

1.2.1 Gastroretentive Drug Delivery Systems

Oral administration is the most convenient and preferred means of any drug delivery to

the systematic circulation. Oral controlled release drug delivery systems have recently

gained increasing interest in pharmaceutical field to achieve improved therapeutic

advantages, such as ease of dosing administration, patient compliance and flexibility in

formulation. Drugs that are easily absorbed from gastrointestinal tract (GIT) and have

short half-lives are eliminated quickly from the systemic circulation. Frequent dosing of

these drugs is required to achieve suitable therapeutic activity. To avoid this limitation,

the development of oral sustained-controlled release formulations is an attempt to release

the drug slowly into the gastrointestinal tract (GIT) and maintain an effective drug

concentration in the systemic circulation for a long time. After oral administration, such a

drug delivery would be retained in the stomach and release the drug in a controlled

manner, so that the drug could be supplied continuously to its absorption sites in the

gastrointestinal tract (GIT) (Streubel et al., 2006).

These drug delivery systems suffer from mainly two adversities: the short gastric

retention time (GRT) and unpredictable short gastric emptying time (GET), which can

result in incomplete drug release from the dosage form in the absorption zone (stomach

or upper part of small intestine) leading to diminished efficacy of administered dose

(Iannucelli et al., 1998).

To formulate a site-specific orally administered controlled release dosage form, it is

desirable to achieve a prolonged gastric residence time by the drug delivery. Prolonged

gastric retention improves bioavailability, increases the duration of drug release, reduces

drug waste, and improves the drug solubility that are less soluble in a high pH

environment (Garg et al., 2008).

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Also prolonged gastric retention time (GRT) in the stomach could be advantageous for

local action in the upper part of the small intestine e.g. treatment of peptic ulcer, etc.

Gastroretentive drug delivery is an approach to prolong gastric residence time, thereby

targeting site-specific drug release in the upper gastrointestinal tract (GIT) for local or

systemic effects. Gastroretentive dosage forms can remain in the gastric region for long

periods and hence significantly prolong the gastric retention time (GRT) of drugs. They

enable oral therapy by drugs with a narrow absorption window in the upper part of the

gastrointestinal tract or are useful for drugs with a poor stability in the colon. Over the

last few decades, several gastroretentive drug delivery approaches being designed and

developed, including: high density (sinking) systems that is retained in the bottom of the

stomach (Rouge et al., 1998) low density (floating) systems that causes buoyancy in

gastric fluid (Streubel et al., 2003; Goole et al., 2007; Shrma et al., 2006)

mucoadhesive systems that causes bioadhesion to stomach mucosa (Santosh et al.,

2010), unfoldable, extendible, or swellable systems which limits emptying of the dosage

forms through the pyloric sphincter of stomach (Klausner et al., 2003; Deshpande et al.,

1997), superporous hydrogel systems (Park et al., 1988), magnetic systems (Fujimori et

al.,1994) etc.

1.2.1.1 General considerations

The anatomy and physiology of stomach constrain the parameters to be considered in

development of gastrioretentive dosage forms. Probably, the two most important features

are their size and density. Size is especially important in designing indigestible solid

dosage forms (single unit systems). The human pyloric diameter is 12±7mm

(Timmermans et al., 1993). It is open while the stomach is in a fasting state. The first

mouthful thus passes directly into the duodenum, triggering closure of the pyloric

sphincter. The pylorus then sorts the gastric contents, large particles being carried away

by retrograde flow to the center of the stomach. Solids are evacuated by the pylorus

slowly and regularly. Finally, indigestible materials, including solid pharmaceutical

dosage forms, are evacuated by a Interdigestive Migration Myoelectric Complex (IMMC)

peristaltic wave (Bernier et al., 1988). Particles with diameter <7 mm are efficiently

evacuated, and it is generally accepted that a diameter >15 mm is necessary for useful

prolongation of retention especially during the fasting state. Chance determines whether a

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Taste masking of Gabapentin Page 31

single unit system is lost during a particular gastric emptying, so that high variability in

gastrointestinal transit time is a major drawback of these systems. Multiple unit systems,

such as those based on microparticles, avoid this phenomenon by their statistical

repartition throughout the gastrointestinal tract. When single unit systems are evacuated

through the pylorus at the end of the digestion or during the phase III of the IMMC,

multiple unit systems are evacuated either with a linear profile or in bolus at the end of

the digestion (Dubernet, 2004; Dressman et al., 2000). Density determines the location

of the system in the stomach. Systems with density lower than gastric contents can float

to the surface, while high-density systems sink to bottom of the stomach. Both positions

may isolate the dosage system from the pylorus. Finally, the molecular weight and the

lipophilicity of the active agent, depending on its ionization state are also important

parameters. Gastric secretion is an aqueous isotonic solution containing H+, Na+, K+,

Cl_, HCO3

_, mucus, intrinsic factor, pepsinogen and gastric lipase. The gastro-duodenal

lumen pH approaches 2, while the layer immediately adjacent to the epithelium is almost

neutral (pH 7) (Gue´nard, 1996; G. Frieri et al, 1995). This pH gradient, which helps

protect the mucous membrane from digestion by the acid-dependent pepsin, is maintained

by the secretion of HCO3 _ and mucus (Frieri et al, 1995; G. Flemstrom et al, 1994).

Gastric mucus is an approximately 5% aqueous solution of glycoproteins with molecular

weight >106 Da (Bernier et al., 1988). Mucus and HCO3 are produced by the epithelial

cells, the mucous neck cells of gastric glands and the Brunner’s duodenal glands. The

layer of mucus varies in thickness between 100 Am (Jordan et al., 1998; Newton et al.,

1998; J.L. Newton et al., 2000) and 200 Am (Gu et al., 1988) according to the gastric

location. Mucus ensures lubrication of solid particles, and its gelatinous consistency

enables retention of water and HCO3 close to the epithelium. The gastric mucus layer acts

as a sacrificial physical barrier against luminal pepsin, which digests the surface of the

mucus gel to soluble mucin. The continuity and almost constant thickness of the mucus

gel layer observed in vivo is evidence that mucus secretion balances the losses by peptic

digestion and mechanical erosion. Diffusion of drugs through the mucus to the epithelium

is dependent on their size. Shah et al. showed that gastric mucus was more permeable to

metronidazole (171 Da) than amoxicillin (365.4 Da) (Shah et al., 1999). Larhed et al.

demonstrated that charge decreased diffusion of a drug but lipophilicity was the most

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important physicochemical parameter: a high lipophilicity reducing diffusion across the

very hydrophilic mucus layer.

Out of several Gastroretentive approaches, mucodhesive drug delivery systems have been

attempted in the present research work hence are discussed in detail.

1.2.1.2 Gastrointestinal Mucoadhesive Drug Delivery Systems

Oral route is undoubtedly most favored route of administration, but hepatic first-pass

metabolism, degradation of drug during absorption, mucus covering GI epithilia, and

high turnover of mucus are serious concerns of oral route. In recent years, the

gastrointestinal tract (GIT) delivery emerged as a most important route of

administration. Mucoadhesive retentive system involves the use of bioadhesive polymers,

which can adhere to the epithelial surface in the GIT. With the use of bioadhesive system

it is possible to achieve increased GI transit time and increase in bioavailability.

Ahmed studied gastric retention formulations (GRFs) made of naturally occurring

carbohydrate polymers and containing riboflavin in vitro for swelling and dissolution

characteristics as well as in fasting dogs for gastric retention (Ahmed et al., 2007). The

bioavailability of riboflavin, from the GRFs was studied in fasted healthy humans and

compared to an immediate release formulation. It was found that when the GRFs were

dried and immersed in gastric juice, they swelled rapidly and released their drug payload

in a zero-order fashion for a period of 24 h. In vivo studies in dogs showed that a

rectangular shaped GRF stayed in the stomach of fasted dogs for more than 9 h, then

disintegrated and reached the colon in 24 h. Considering pharmacokinetic parameters of

human subjects under fasting conditions, bioavailability of riboflavin from a large size

GRF was more than triple of that measured after administration of an immediate release

formulation.

Salman (Salman et al., 2007) aimed to develop polymeric nanoparticulate carriers with

bioadhesive properties and to evaluate their adjuvant potential for oral vaccination.

Thiamine was used as a specific ligand–nanoparticle conjugate (TNP) to target specific

sites within the gastrointestinal tract, namely enterocytes and Peyer’s patches. The

affinity of nanoparticles to the gut mucosa was studied in orally inoculated rats. The

authors concluded that thiamine-coated nanoparticles showed promise as particulate

vectors for oral vaccination and immunotherapy.

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Mucoadhesive Systems

The term bioadhesion can be defined as the state in which two materials, at least one

biological in nature, are held together for an extended period of time by interfacial forces

(Good WR, 1983). For drug delivery purposes, the term bioadhesion implies attachment

of a drug carrier system to a specified biological location. The biological surface can be

epithelial tissue or the mucus coat on the surface of a tissue. If adhesive attachment is to a

mucus coat, the phenomenon is referred to as mucoadhesion. Leung and Robinson

described mucoadhesion as the interaction between a mucin surface and a synthetic or

natural polymer (Leung et al., 1988).

The study of mucoadhesive polymers was initiated by Park and Robinson in 1988.

Shortly afterwards, Smart et al. reported in vitro tests of adhesiveness of various

materials to mucus. Interactions between glycoproteins or phospholipid bilayers with a

polymeric surface govern mucoadhesion. The exact adhesion mechanism is not clearly

understood. Adhesion could be the result of a combination of mechanisms operating

simultaneously. Several mechanisms have been proposed to explain observed

bioadhesion; however, no individual theory has been universally accepted. Firstly, the

electronic theory proposes attractive electrostatic forces between the glycoprotein mucin

network and the bioadhesive material (Deraguin et al., 1969) Adhesion: Fundamentals and

Practice. Secondly, the adsorption theory suggests that bioadhesion is due to secondary

forces such as Van der Waals forces and hydrogen bonding (Wake et al., 1982). The

wetting theory is based on the ability of bioadhesive polymers to spread and develop

intimate contact with the mucus layers, (McBain et al., 1925) and finally, the diffusion

theory proposes physical entanglement of mucin strands and the flexible polymer chains,

or an interpenetration of mucin strands into the porous structure of the polymer substrate.

(Jimenez et al, 1993).

Chapter 1

Taste masking of Gabapentin Page 34

1.2.1.3 Mucoadhesive Materials

Mucoadhesive polymers have numerous hydrophilic groups, such as hydroxyl, carboxyl,

amide, and sulfate. These groups attach to mucus or the cell membrane by various

interactions such as hydrogen bonding and hydrophobic or electrostatic interactions.

These hydrophilic groups also cause polymers to swell in water and, thus, expose the

maximum number of adhesive sites (Yang et al., 1998).

An ideal polymer for a bioadhesive drug delivery system should have the following

characteristics: (Ahuja et al., 1997)

1. The polymer and its degradation products should be nontoxic and nonabsorbable.

2. It should be nonirritant.

3. It should preferably form a strong noncovalent bond with the mucus or epithelial

cell surface.

4. It should adhere quickly to moist tissue and possess some site specificity.

5. It should allow easy incorporation of the drug and offer no hindrance to its

release.

6. The polymer must not decompose on storage or during the shelf life of the dosage

form.

7. The cost of the polymer should not be high so that the prepared dosage form

remains competitive.

Mucoadhesion may be affected by a number of factors, including hydrophilicity,

molecular weight, cross-linking, swelling, pH, and the concentration of the active

polymer (Peppas et al., 2000).

1.2.1.4 Factors Affecting Mucoadhesion

i) Hydrophilicity

Bioadhesive polymers possess numerous hydrophilic functional groups, such as hydroxyl

and carboxyl. These groups allow hydrogen bonding with the substrate, swelling in

aqueous media, thereby allowing maximal exposure of potential anchor sites. In addition,

Chapter 1

Taste masking of Gabapentin Page 35

swollen polymers have the maximum distance between their chains leading to increased

chain flexibility and efficient penetration of the substrate.

ii) Molecular Weight

The interpenetration of polymer molecules is favored by low-molecular-weight polymers,

whereas entanglements are favored at higher molecular weights. The optimum molecular

weight for the maximum mucoadhesion depends on the type of polymer, with

bioadhesive forces increasing with the molecular weight of the polymer up to 100,000.

Beyond this level, there is no further gain (Gurny et al., 1984).

iii) Cross-linking and Swelling

Cross-link density is inversely proportional to the degree of swelling (Gudeman et

al., 1995). The lower the cross-link density, the higher the flexibility and hydration rate;

the larger the surface area of the polymer, the better the mucoadhesion. To achieve a high

degree of swelling, a lightly cross-linked polymer is favored. However, if too much

moisture is present and the degree of swelling is too great, a slippery mucilage results and

this can be easily removed from the substrate (McCarron et al., 2004). The mucoadhesion

of cross-linked polymers can be enhanced by the inclusion in the formulation of adhesion

promoters, such as free polymer chains and polymers grafted onto the preformed

network.

iv) Spatial Conformation

Besides molecular weight or chain length, spatial conformation of a polymer is also

important. Despite a high molecular weight of 19,500,000 for dextrans, they have

adhesive strength similar to that of polyethylene glycol (PEG), with a molecular weight

of 200,000. The helical conformation of dextran may shield many adhesively active

groups, primarily responsible for adhesion, unlike PEG polymers, which have a linear

conformation.

Chapter 1

Taste masking of Gabapentin Page 36

v) pH

The pH at the bioadhesive to substrate interface can influence the adhesion of

bioadhesives possessing ionizable groups. Many bioadhesives used in drug delivery are

polyanions possessing carboxylic acid functionalities. If the local pH is above the pK of

the polymer, it will be largely ionized; if the pH is below the pK of the polymer, it will be

largely unionized. The approximate pKa for the poly(acrylic acid) family of polymers is

between 4 and 5. The maximum adhesive strength of these polymers is observed around

pH 4–5 and decreases gradually above a pH of 6. A systematic investigation of the

mechanisms of mucoadhesion clearly showed that the protonated carboxyl groups, rather

than the ionized carboxyl groups, react with mucin molecules, presumably by the

simultaneous formation of numerous hydrogen bonds (Park et al., 1985).

vi) Concentration of Active Polymer

Ahuja stated that there is an optimum concentration of polymer corresponding to the best

mucoadhesion (Ahuja, 1997). In highly concentrated systems, beyond the optimum

concentration the adhesive strength drops significantly. In concentrated solutions, the

coiled molecules become solvent-poor and the chains available for interpenetration are

not numerous. This result seems to be of interest only for more or less liquid

mucoadhesive formulations. It was shown by Duchene that, for solid dosage forms such

as tablets, the higher the polymer concentration, the stronger the mucoadhesion

(Duchene et al., 1988).

vii) Drug/Excipient Concentration

Drug/excipient concentration may influence the mucoadhesion. BlancoFuente studied the

effect of propranolol hydrochloride to Carbopol® (a lightly cross-linked poly(acrylic

acid) polymer) hydrogels adhesion (Blanco Fuente et al., 1996). Author demonstrated

increased adhesion when water was limited in the system due to an increase in the

elasticity, caused by the complex formation between drug and the polymer. While in the

presence of large quantities of water, the complex precipitated out, leading to a slight

decrease in the adhesive character. Increasing toluidine blue O (TBO) concentration in

Chapter 1

Taste masking of Gabapentin Page 37

mucoadhesive patches based on Gantrez® (poly(methylvinylether/maleic acid)

significantly increased mucoadhesion to porcine cheek tissue (Donnelly et al., 2007).

This was attributed to increased internal cohesion within the patches due to electrostatic

interactions between the cationic drug and anionic copolymer.

viii) Other Factors Affecting Mucoadhesion

Mucoadhesion may be affected by the initial force of application (Smart et al., 1991).

Higher forces lead to enhanced interpenetration and high bioadhesive strength. In

addition,the greater the initial contact time between bioadhesive and substrate, the greater

the swelling and interpenetration of polymer chains (Kamath et al., 1992). Physiological

variables can also affect mucoadhesion. The rate of mucus turnover can be affected by

disease states and also by the presence of a bioadhesive device (Lehr et al., 1991). In

addition, the nature of the surface presented to the bioadhesive formulation can vary

significantly depending on the body site and the presence of local or systemic disease.

Materials commonly used for bioadhesion are poly(acrylic acid) (Carbopol\,

polycarbophil), chitosan, Gantrez\ (Polymethyl vinyl ether/maleic anhydride

copolymers), cholestyramine, tragacanth, sodium alginate, HPMC, sephadex, sucralfate,

polyethylene glycol, dextran, poly(alkyl cyanoacrylate) and polylactic acid. Even though

some of these polymers are effective at producing bioadhesion, it is very difficult to

maintain it effectively because of the rapid turnover of mucus in the gastrointestinal tract.

Furthermore, the stomach content is highly hydrated, decreasing the bioadhesiveness of

polymers. Indeed, Kockisch et al. compared different polymeric microspheres (poly

(acrylic acid), Gantrez\ and chitosan) in different conditions (tensile tests on porcine

oesophageal mucosa and in elution experiments involving a challenge with artificial

saliva). In tensile tests, poly (acrylic acid) particles exhibited a greater mucoadhesive

strength and better swelling properties than those made from chitosan or Gantrez.

To produce targeted mucoadhesion, some research groups have produced particles coated

with lectins, characterized by their ability to bind carbohydrates with considerable

specificity.

Chapter 1

Taste masking of Gabapentin Page 38

1.2.1.5 Methods to assess the Mucoadhesive Strength of Mucoadhesive Agents

The mucoadhesive characterization of synthetic, semi synthetic or natural gum involves

two various evaluation techniques with different methods. To, conform the mucoadhesive

character of mucoadhesive agent following methods are applicable (Asana, 2007;

Pranshu et al., 2011; Latheeshjlal et al., 2011). Some of them are Shear stress

measurement, Wihelmy’s method, Detachment force measurement, Recording of

adherence, Falling sphere method, Rotating cylinder method, Falling liquid film

technique, In vitro Mucoadhesive Strength, Ex vivo residence time, In vivo bioadhesive

study, etc.

1.3.1 PATENT SEARCH FOR TASTE MASKING OF GBP

Sr.

no

Patent

Number

Date Author Title

1 6488964 December 3,

2002

Bruna , et al. Process for manufacturing coated

GBP or pregabalin particles

2

EP19910810380

11/27/1991

Cherukuri, Subraman

Rao ; et al.

Delivery system for cyclic amino

acids with improved taste, texture

and compressibility

3

EP20000942044

10/08/2003

Villa, Roberto ; et al.

Controlled release and taste

masking oral pharmaceutical

compositions

4

10/965968

03/03/2005

Santi, Patricia Delli

A. ; et al.

Taste masking of phenolics using

citrus flavors

5

PCT/EPO08/00292

11/11/2010

Adnan Badwan, et al.

Aqueous compositions comprising

of chitosan and an acidic drug

6

US 7,256,216 B2

14/8/2007

Neema Kulkarni M ;

et al.

Liquid Pharmaceutical

Compositions

7

US2010/0316724A1

16/12/2010

Nicola Kim

Whiefield ; et al.

Composition

8

US2003/0211136A1

13/11/2003

Neema Kulkarni ; et

al.

Fast dissolving orally consumable

films containing sweetner

9

US 2010/0062988

A1

11/3/2009

Andrew Xian Chen ;

et al.

Chewable sustained release

formulations

10 US

2006/0247291A1

2/11/2006 Shelly Rene Graham

; et al.

Amino Acid Derivatives

Chapter 1

Taste masking of Gabapentin Page 39

1.3.2 PATENTS RELATED TO SUSTAINED RELEASE FORMULATIONS OF

GBP

Sr.

no

Patent

number

Date Author Title

1 20050158380 July 21, 2005 Chawla,

Manish ; et al.

Sustained release oral dosage forms

of GBP.

2 6,465,012 October 15, 2002 Vilkov Pharmaceutical tablet formulation

containing GBP with improved

physical and chemical characteristics

and method of making the same.

3 20060039968 February 23, 2006 Manikandan;

Ramalingam ; et al.

GBP tablets and method for their

preparation.

4 20050163848 July 28, 2005 Wong, Patrick S.L.

; et al.

Compositions and dosage forms for

enhanced absorption of GBP and

pregabalin

5 6,488,964 December 3, 2002

Bruna , et al. Process for manufacturing coated

GBP or pregabalin particles.

6 WO/2007/107835 September 29, 2007 Yande Vikas,

Kulkarni Shailesh ;

et al.

Formulations liquides stables

d'agents anti-epileptiques

7 6090411 July 18, 2000 Fassihi ; et al. Monolithic tablet for controlled drug

release

8 6337091

January 8, 2002

Kim Hyunjo ; et al. Matrix for controlled delivery of

highly soluble pharmaceutical agents

Chapter 1

Taste masking of Gabapentin Page 40

1.3.3 PATENTS RELATED TO GASTRORETENTIVE DOSAGE FORMS OF

GBP

Sr.

no

Patent

Number

Date Author Title

1 6723340 April 20, 2004 Bret Berner,

Gloria Gusler ; et al. Optimal polymer mixtures for gastric

retentive tablets

2 WO/2007/079195 December 29, 2006 Berner, Bret ; et al Gastric retentive GBP dosage forms

and methods for using same

3 5232704 March 8, 1993

Franz, Michel R.; et

al.

Sustained release, bilayer buoyant

dosage form

4 6960356

November 1, 2005

Talwar Naresh,

Sen Himadri ; et al

Orally administered drug delivery

system providing temporal and

spatial control

5 20050064027 March 24, 2005

Jules S. Jacob. ; et al

Mathiowitz, Edith

Bioadhesive drug delivery system

with enhanced gastric retention

6 20060045865 May 30, 2007

Jules S. Jacob ; et al Controlled Regional Oral Delivery

7 20050249798

November 11, 2005

Mohammad Hassan ;

et al

Gastroretentive drug delivery system

comprising an extruded hydratable

polymer

8 20060013876 January 19,2006

Lohray, Braj

Bhushan ; et al.

Tiwari, Sandip B.

Novel floating dosage form

Chapter 1

Taste masking of Gabapentin Page 41

1.4 Review of some patents based on Gastroretentive bioadhesive principle:

Gastroretentive dosage forms were developed by using various approaches in the past.

One such approach was based on the mucoadhesive polymers. Ilium et al. disclosed in

US 6,207,197 Bl a bioadhesive formulation for the treatment of gastric ulcer caused by

Helicobacter pylori. It comprised a drug core coated with rate controlling water insoluble

polymer layer of ethylcellulose followed by bioadhesive outer layer of chitosan which

was crosslinked with glutaraldehyde. The formulation was capable of adhering onto the

gastric mucosa and releases the drug for an extended period of time within the stomach.

Yeon et al. disclosed in WO2008/010690 Al a bioadhesive composition which comprised

multiple numbers of pellets coated with metformin hydrochloride followed by a

bioadhesive polymer such as sodium alginate, sodium carboxymethyl cellulose,

hydroxylpropylmethyl cellulose and chitosan. The pellets could be filled in the capsule or

compressed into tablet along with the immediate release pellets which comprised

glimepiride.

The patent, WO2008/074108 A2 discloses a bioadhesive composition for the treatment of

diabetes mellitus. It was prepared by wet granulating the mixture of metformin

hydrochloride, bioadhesive polymer crosslinked polyacrylic acid and other ingredients

and compressing the granules to form a tablet. The tablet was coated with a film forming

hydrophilic polymer and glimepiride. The gelling behaviour of crosslinked polyacrylic

acid led to adhesion of the dosage form to the gastric mucosa.

Mucoadhesive microspheres were developed by Liu et al. (Zhepeng Liu, Weiyue Lu,

Lisheng Qian, Xuhui Zhang, Pengyun Zeng and Jun Pan, Journal of Controlled

Release, 102, 135, 2005) for the treatment of gastric and duodenal ulcers associated with

Helicobacter pylori. The microspheres were prepared by emulsification and evaporation

method. Ethylcellulose was dissolved in acetone and the powder of crosslinked

polyacrylic acid and the antibiotic amoxicillin were added and blended. The blend was

dispersed in the light paraffin oil to form microspheres. Similar microspheres were

prepared without using bioadhesive polymer as a control.

Chapter 1

Taste masking of Gabapentin Page 42

1.5 PROJECT HYPOTHESIS

I. Development of taste masked formulations of GBP

GBP [1-(aminomethyl) cyclohexane acetic acid] is a structural analog of γ-aminobutyric

acid (GABA), with an incorporated cyclohexyl ring. GBP is currently marketed as an

adjunctive therapy for partial seizures in adults with epilepsy and for the management of

postherpetic neuralgia (Bryans and Wustrow, 1999). In clinically recommended doses,

it is rapidly absorbed following oral, single-dose administration to healthy volunteers

(Vollmer et al., 1989; Hooper et al., 1991). The site of action of GBP is, the alpha2—

delta (α2—δ) protein, an auxiliary subunit of voltage-gated calcium channels. It subtly

reduces the synaptic release of several neurotransmitters, apparently by binding to α2—δ

subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability

and seizures. From the point of view of pharmacokinetics, it is essential for the

concentration of GBP in the plasma to reach its peak in 2 to 3 hours.

GBP is a white to off-white crystalline solid and is a polymorphic substance. In addition

to bitter taste, this drug has another issue of stability. It is freely soluble in water and

across a wide range of pH and is characterized by a marked bitter taste (Kiel J S,

Thomas H. G.et al., EP1628656 B1, 2008). It is moisture sensitive and tends to form

lactam impurity which should be below 0.4%. GBP degrades via intramolecular

cyclization to form a γ -lactam: 3, 3-pentamethylene-4-butyrolactam (2- azaspiro

[4,5]decan-3-one).

In market currently conventional tablets, capsules and Neurontin oral solution are

available. Gabapentin sold under the brand name, Neurontin is indicated as adjunctive

therapy in the treatment of partial seizures with and without secondary generalization in

patients over 12 years of age with epilepsy. Neurontin is also indicated as adjunctive

therapy in the treatment of partial seizures in pediatric patients with age of 3 – 12 years.

Neurontin solution is stable for only 7 days at room temperature. The recommended

storage condition of Neurontin is 2º to 8ºC (Pharmacists letter 2008).

Formulations that are available in market are unsuitable for paediatric patients. Therefore,

there is need for development of oral taste masked formulations of gabapentin to target

both paediatric as well as geriatric patients and to improve patient palatability and

acceptability. Therefore, in present research work an attempt was made to develop taste

Chapter 1

Taste masking of Gabapentin Page 43

masked stable formulations of GBP for conventional delivery. Many taste masked oral

solid dosage forms like tablets, powders and multiparticulate preparations were

investigated, as they are more stable in comparison to liquid dosage forms.

II. Development of controlled release mucoadhesive tablets of GBP

GBP has a relatively short half-life (i.e., 5-7 hours), requiring three doses per day in most

patients which leads to substantial fluctuations in the plasma concentration of the drug. It

has been determined that GBP is typically absorbed from the upper intestine, i.e., it has a

narrow absorption window and is absorbed by active transport through a large neutral

amino acid (LNAA) transporter (Stewart et al.,1993; Uchino et al., 2002). This

transporter is located in the upper small intestine, has limited transport capacity, and

becomes saturated at high drug concentrations. This absorption pathway is apparently

saturated at doses normally used to treat neuropathic pain. As a result, the plasma

exposure to GBP in patients receiving GBP is not dose proportional, and therefore may

not reach therapeutically useful levels in some patients (Gidal et al., 2000).

Consequently, the plasma levels of GBP are not dose proportional and, therefore, higher

doses do not give proportionately higher plasma levels. Since the LNAA transporter

responsible for GBP absorption is present only in the upper region of the intestine, the

dosage form used to provide GBP should be designed to release GBP in the stomach at a

rate such that the maximum amount of the drug is available in the intestinal segment.

Frequent dosing is necessary to maintain reasonably stable plasma concentrations. The

effective dose of GBP is 900 to 1800 mg/day, which is given in divided doses. Dosing

regimens requiring three or four doses per day lead to significant noncompliance in

epilepsy patients (Richter et al., 2003).

Prolonged, stable exposure to GBP may provide other clinical benefits, including greater

efficacy, prolonged duration of action, and a reduced incidence of adverse effects related

to peak drug levels. However, it has been difficult to achieve these benefits with a

sustained-release formulation of GBP, primarily due to the lack of significant absorption

in the large intestine (Stevenson et al., 1997; Kriel et al., 1997; Cundy et al., 2004a,

2004b). These pharmacokinetic complexities may directly affect the efficacy of a

sustained-release formulation. In addition, the rate and site of drug release may also

Chapter 1

Taste masking of Gabapentin Page 44

influence the magnitude and duration of the pharmacological response (Castaneda-

Hernandez et al., 1994; Hoffman and Stepensky, 1999). Therefore, an essential step in

developing sustained-release formulations is to establish a rationale that accommodates

both the in vitro and in vivo properties of the drug.

Because gabapentin is administered t.i.d., patient compliance with the conventional

immediate release dosage forms of the drug is an issue. In this respect, controlled release

dosage forms that would lower the number of daily dosings of gabapentin to once-daily

or twice-daily dosings would provide a significant advantage over the conventional

immediate release dosage form; however, in order for the controlled release dosage form

to be effective, the dosage form must overcome the poor absorption of the drug in the

lower gastrointestinal tract.

Therefore, attempts have been put forth for designing Controlled release gastroretentive

bioadhesive drug delivery systems of gabapentin that will release drug over an extended

period of time, and majorly in upper gastrointestinal tract to provide therapeutically

effective plasma levels.

It is also an objective of the present research work to provide a pharmaceutical

composition constituting an oral controlled drug delivery system that maintains its

physical integrity i.e., remains intact or substantially gains a monolithic form when

contacted with an aqueous medium, even when the quantity of medicaments is large, and

wherein the proportion of polymers is small compared to other components of the system.

Another objective of the present research work was to provide a drug delivery system that

incorporates a high dose medicament without the loss of any of its desirable attributes

such that the system is of an acceptable size for oral administration.

1.6 Objectives of the study

I. To design and develop and evaluate conventional stable taste masked

formulations of gabapentin

II. To design and develop controlled release Mucoadhesive tablets of gabapentin.

• To study in vitro release profile of developed formulations

• To perform pharmacodynamic and pharmacokinetic study on the

developed formulations

Chapter 1

Taste masking of Gabapentin Page 45

Plan of work

The experimental work was planned as follows:

Standardization of drug and polymers

i. Drug –excipients incompatibility studies

ii. Analytical method development for the estimation of gabapentin formulations in

dissolution media and plasma.

iii. Analytical method development for estimation of GABA in rat brain.

iv. Development of taste masked formulations of gabapentin by various approaches.

Evaluation of the developed formulation for taste masking potential.

Monitoring this formation for lactam impurity formation by HPLC

Evaluation of the developed formulations by performing Human Panel Studies

and by monitoring in- vitro release profiles.

v. Development of the controlled release mucoadhesive tablets

Evaluation of the developed formulations for in- vitro release profiles, DSC,

mucoadhesion testing and physicochemical properties.

Scale up and reproducibility studies.

Stability studies as per ICH guidelines.

vii. In- vivo studies

Development of Epilepsy induced animal models

To confirm induction of the disease and efficacy of the developed formulations

following criteria were chosen.

To determine changes in onset of seizure, seizure duration, percentage

mortality of the epilepsy induced animals

Estimation of GABA after oral administration of mucoadhesive tablet.

Pharmacokinetic studies on the developed formulations.

Toxicity studies

The work carried out as per the above plan is described in the forthcoming

chapters.