Pharmaceutical Excipients Pure Drugs Biology Essay


In this modern era, the researchers in pharmaceutical technology concentrates on new novel dosage forms which are targeted to the exact site at the right time, with utmost efficiency and with lowest unwanted effects. All these pharmaceutical dosage forms can easily be found in the Pharmacopoeias such as United States Pharmacopoeia, European Pharmacopeia and Japanees Pharmacopeia etc. Different names are given to these systems such as delayed release, sustained release or pulsatile release. In all these systems the drug release rate of the Active Pharmaceutical Ingrediants (APIs) are precisely controlled by special composition and/or by special manufacturing procedures.

The properties of excipients or additives and APIs used in pharmaceutical formulations sometimes make it difficult to be compressed by direct compression method, hence one should use some intermediate steps such as dry granulation or wet granulation, in order to increase the compressibility of the granules in the development of complete dosage forms.

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The research into and use of excipients from natural sources had been reviewed and discussed by many researchers. Natural polymeric excipients and their modifications have continued to dominate the research efforts of scientists in finding cheap, less expensive, biodegradable, ecofriendly excipients. Some of these excipients have obvious advantages over their synthetic counterparts in some specific delivery systems due to their inherent characteristics. If the current vigorous investigations on the use of natural polymeric materials are sustained and maintained, it is probable that there would be a breakthrough that will overcome some of the disadvantages of this class of potential pharmaceutical excipients that would change the landscape of the preferred pharmaceutical excipients for drug delivery in the future.

Pharmaceutical Excipients

Pure drugs can hardly be administered as such but are almost always formulated into an appropriate dosage form with the help of excipients, which play different functions e.g. binding, lubricating, gelling, suspending, flavoring, sweetening and bulking agent among others [1]. The International Pharmaceutical Excipients Council defines excipients as substances, other than the active drug substances of finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing of the drug delivery system during its manufacture; protect, support or enhance stability, bioavailability, or patient acceptability; assist in product identification; or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use [2]. Excipients play a critical role in the creation of medicines, helping to preserve the efficacy, safety, and stability of active pharmaceutical ingredients (APIs) and ensuring that they deliver their promised benefits to the patients. Optimal use of excipients can provide pharmaceutical manufacturers with cost-savings in drug development, enhanced functionality and help in drug formulations innovation.

Pharmaceutical excipients are substances that are included in a pharmaceutical dosage form not for their direct therapeutic action. They may also assist in product identification and enhance the overall safety or function of the product during storage or use2.

There is a long list of uses and purposes for which excipients are used as defined in international pharmacopoeias. Many excipients have more than one use, which can be an advantage since it reduces the number of excipients needed and minimizes the risk of interactions between them.

Ideally, an excipient is pharmacologically inactive, non-toxic, and does not interact with the active ingredients or other excipients. However, in practice few excipients meet these criteria. Toxicity may relate to compounds used as excipients in the final dosage form or to residues of compounds (such as solvents) used during the manufacturing process.2 Martindale: The complete drug reference. 37th ed. London: Pharmaceutical Press; 2011. (electronic and hard copy available)

Pharmaceutical excipients are ingrediants or substances other than the active pharmaceutical ingrediants (API), which have been appropriately evaluated for safety and are intentionally included in a drug delivery system. In different dosage forms excipients plays different roles, for example excipients can:

• aid in the processing of the drug delivery system during its manufacture,

• protect, support or enhance stability, bioavailability or patient acceptability,

• assist in product identification,

• enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use.

The quality and efficacy of a medicine does not depend only on the properties of the API or the production method but also, to a large extent, on the quality of the excipients. In general, the latter adds markedly to the quality of the drug, contrary to what were believed in the past, and this is important to assure the safety, quality and efficacy of the final pharmaceutical dosage form [3].

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Hence, the excipients have to accomplish the functions of diluent, filler and solvent in order to give, "to the dose of API", suitable weight, consistency and volume from the galenic point of view, and make it suitable and easy to administer [7]. In this case, the excipient assumes the function of vehicle suitable for the desired administration route, so as to transport the active principle to the desired place of absorption in the organism.

Besides the traditional functions of support and vehicle therefore, the excipient is also expected to function as an adjuvant, from the Latin verb 'adjuvare', that is to help the active principle to carry out its activity by conditioning its release from the pharmaceutical dosage form. In the National Formulary Admission Policy of 1994 [8] there is the following definition: ''Excipients are any component other than the active substance(s) intentionally added to the formulation of a dosage form.'' To interpret the adverb 'intentionally' in this definition, we must remember the main administration routes of a medicinal product and the complexity of the roles the excipient must play in their respective formulations [9]. For each of the administration routes the excipient must guarantee the stability of the pharmaceutical dosage form, the precision and accuracy of the dosage, as well as modify, when necessary, its organoleptic characteristics (smell, taste, swallowability and local tolerability) so as to improve the patient's 'compliance'.

The evolution of excipients

From the standpoint of what we have said so far, the excipient is no longer to be considered an inert product but an essential and functional component of a modern

pharmaceutical dosage form [10].

Moreover, the interest in and wide-spread use of new therapeutic systems and modified-release forms is another factor that intensifies the demand for more sophisticated excipients that can fulfill specific functions within the formulation. The increased interest in modified release forms and in new therapeutic systems, as well as new production technologies has contributed to research into new materials gifted with specific technological properties and their development as functional excipients. All these factors have changed the traditional concept of an excipient into the more up-to-date one of functional agent, that is, one that can fulfil several functions within the pharmaceutical formulation.

On the basis of the preceding considerations, it is clear that excipients are no longer to be considered as inert materials but essential components of ever more sophisticated and modern pharmaceutical dosage forms.

Excipients can be generally divided into 3 major categories: 1) Established "approved", 2) New "novel" and 3) essentially new excipients.

Established excipients are renowned materials with extensive use in pharmaceutical preparations. A novel excipient is a chemical or a compound which has not been formerly used or allowed for use in a pharmaceutical dosage form. Essentially new excipients make an intermediate class and include materials resulting from a physical or chemical modification of an "approved" excipient, already accepted food additive, a structurally altered food additive or a cosmetic ingredient. Such research oriented discussions and data published by researchers and academics would supplement the current developments in pharmacopoeial standardization of excipient quality and as a result it may be possible to have excipients reviewed by a committee of an international pharmacopoeia with the safety data assessed by designated experts and these data would then be acceptable to international regulatory bodies.

Natural Gums As Pharmaceutical Excipients

Excipients are the largest components of any pharmaceutical formulation. They can be of natural or synthetic origin and synthetic excipients have become common place in today's pharmaceutical dosage forms [3]. It is common knowledge that both synthetic and semi-synthetic products have enjoyed a long history of use, frequently offering unique properties and advantages over naturally derived compounds. The terms 'synthetic' and 'semi-synthetics are both broadly used to distinguish this family of excipients from those extracted from natural sources. Semi-synthetic typically refers to a substance that is naturally derived but has been chemically modified. Most excipients in use today fall into this category and there must be the 'natural' to obtain the 'semi-synthetic' excipients. In contrast, 'synthetic' 'is usually defined as a pure synthetic organic chemical that is derived from oil or rock [3].

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Natural gums are polysaccharides of natural origin, capable of causing a large viscosity increase in solution, even at small concentrations. These natural polysaccharides do hold advantages over the synthetic polymers, generally because they are non toxic, less expensive and freely available. In the food and pharma industry they are used as thickening agents, gelling agents, emulsifiers and stabilizers. The recent developments in the area of natural gums and their derivatives as carriers in the sustained release of drugs are explored by Tilak and associates (Tilak et al., 2000)

In the past most of the research has been aimed towards using the synthetic polymers to prepare the matrix drug delivery system. However, few of the researchers have used the natural gums also (Tilak et al., 2000). Nonetheless, there are very few researchers who worked on the combination of different natural gums (Baichwal & wappinger, 1998). Combination of the gums may alter the release pattern from the matrix and therefore might affect the release kinetics. So, the present study is aimed at preparing the matrix systems using single natural gum or a combination of two or three gums and to compare the release pattern and the release kinetics. The prepared systems will be compared for their release pattern and release kinetics with their respective marketed preparations. If a particular combination of gums has a synergistic increase in the viscosity of the matrix when in the dissolution media, lower amount of the polymer can be used to sustain the release. This may be an advantage over the existing systems and may be an alternative for the present marketed systems.

Pharmaceutical applications of Natural Gums and their modified forms

Natural polysaccharides, as well as their derivatives, represent a group of polymers that are widely used in pharmaceutical formulations and in several cases their presence plays a fundamental role in determining the mechanism and rate of drug release from the dosage form. These naturally occurring polymers have been employed as excipients in the pharmaceutical industry in the formulation of solid, liquid and semisolid dosage forms in which they play different roles as disintegrates, binders, film formers, matrix formers or release modifiers, thickeners or viscosity enhancers, stabilizers, emulsifiers, suspending agents and muco adhesives [4,5]. Specifically, they have been used in the formulation and manufacture of solid monolithic matrix systems, implants, films, beads, micro particles, nanoparticles, inhalable and injectable systems as well as viscous liquid formulations [5-7].

Their growing role and application in the pharmaceutical industry may be attributable not only to the fact that they are biodegradable and toxicologically harmless raw materials of low cost and relative abundance compared to their synthetic counter parts [8,9], but also because natural resources are renewable and if cultivated or harvested in a sustainable manner, they can provide a constant supply of raw material [10]. Furthermore, their extensive applications in drug delivery have been realized because as polymers, they offer unique properties which so far have not been attained by any other materials [11]. They can be tailored for many applications based on the very large chains and functional groups which can be blended with other low- and high-molecular-weight materials to achieve new materials with various physicochemical properties. Consequently, many of the widely used excipients today are chemical modifications of the natural excipients to overcome some of their disadvantages.

Only few review articles on natural gums are available in literatures [12,13]. Some of the reviews covered the chemical structure, occurrence and production of exudate gums, their size and relative importance of the various players on the world market and focused on their application in food and other areas [13]. Due to the growing interest in the use of natural polymeric materials as pharmaceutical excipients, as demonstrated by the number of published scientific papers, it is difficult to cover all that might be available in a single article. It is intended in this review to discuss the uses of natural polymers as excipients in pharmaceutical formulations. Specific mention is made of some of the natural products already in use as pharmaceutical excipients and those being researched for this purpose.

Gums have found pharmaceutical application since the early 1800 having gums like tragacanth, acacia, and sterculia appearing in the United States Pharmacopoeia of 1820 and sodium alginate and agar in the 1947 National Formulary. The gums have been used as suspending agents for insoluble solids in mixtures, as emulsifying agents for oils and resins and as adhesive in pill and troche masses. Some gums are used as demulcent and emollient in hand lotion while others are used as protective colloid and as binding and disintegrating agents in tablet formulations [36].

Gums are naturally occurring components in plants, which are essentially cheap and plentiful. They have diverse applications as thickeners, emulsifiers, viscosifiers, sweeteners etc. in confectionary, and as binders and drug release modifiers in pharmaceutical dosage forms. However, most of the gums in their putative form are required in very high concentrations to successfully function as drug release modifiers in dosage forms due to their high swellability/ solubility at acidic pH. Hence, gums need to be modified to alter their physicochemical properties. For example, the modification of gums through derivatisation of functional groups, grafting with polymers, cross-linking with ions and other approaches as well as the factors influencing these processes in the pursuit of making them suitable for modifying the drug release properties of pharmaceutical dosage forms and for other purposes have been discussed with respect to optimization of their performance [37].

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1.1.3 Types of Natural Gums

Natural polymers are obtained from different sources and we will attempt to briefly introduce them according to their sources. Mention is made of those that are relevant to the current project.

Polysaccharides of the plant cell wall

Natural polymers which have their origin from the plant cell wall mainly include cellulose, hemicelluloses and pectin.

Cellulose is insoluble in water and indigestible by the human body. Cellulose obtained from fibrous materials such as wood and cotton can be mechanically disintegrated to produce powdered cellulose which has been used in the pharmaceutical industry as filler in tablets. High quality powdered cellulose when treated with hydrochloric acid produces microcrystalline cellulose which is preferred over powdered cellulose because it is more free-flowing containing non-fibrous particles. It is consequently employed as diluents or filler/binder in tablets for both granulation and direct compression processes [15]. Some other examples of derivatives of cellulose, which are in common use as pharmaceutical excipients are hydroxyl-propyl-methylcellulose, carboxyl-methyl-cellulose, cellulose nitrate, cellulose acetate and cellulose acetate phthalate.

Gums and mucilages

Gums are natural plant hydrocolloids that may be classified as anionic or nonionic polysaccharides or salts of polysaccharides [36]. According to Claus and Tyler [36] it is difficult to distinguish between gums and mucilage. In their opinion, one attempt is to refer to gums as water soluble and mucilage as water insoluble and the other approach is to refer to mucilage as pathological product and gums as physiological products.

Seaweed polysaccharides

Seaweed gums are typified by the carrageenans, agar and the alginates. Alginates offer various applications in drug delivery, such as in matrix type alginate gel beads, in liposomes, in modulating gastrointestinal transit time, for local applications and to deliver the bio molecules in tissue engineering applications [41].

Carageenans: The carrageenans are sulphated marine hydrocolloids obtained by extraction from seaweeds of the class Rhodophyceae. Carrageenan is not assimilated by the human body. It provides only bulk but no nutrition. Studies have shown that the carrageenans are suitable in the formulation of controlled release tablets [49-51].

Microbial polysaccharides

Natural polysaccharide gums have also been obtained as carbohydrate fermentation products including Xanthan gum, produced in pure culture fermentation by the bacteria Xanthomonascampestris. It was originally obtained from the rutabaga plant [53]. Gellan gum is a microbial polysaccharide obtained by fermentation by Pseudomonas elodea [53,54]. Pullulan is an extracellular homo-polysaccharide of glucose produced by many species of the fungus Aureobasidium, specifically A. pullulans.

Animal polysaccharides

Natural gums have also been obtained from animal sources. Examples include chitin and chitosan. Chitin is a structural polysaccharide which takes the place of cellulose in any species of lower plants and animals. It therefore occurs in fungi, yeast, green, brown and red algae and forms the main component of the exoskeleton of insects and shells of crustaceans [46]. Chitin is insoluble in water but when treated with strong alkali, it forms the water-soluble polysaccharide chitosan which is the only polysaccharide carrying a positive charge [46].

1.1.3(a) Konjac Gum (Glucomannan)

KGM is extracted from the tuber of the A. konjac plant C. Koch.38 There are many species of konjac plants in the Far East and Southeast Asia, for example, A. konjac K. Koch (Japan, China, and Indonesia), A. bulbifer B1. (Indonesia), A. oncophyllus Prain ex Hook. F. (Indonesia), A. variabilis Blume (Philippines, Indonesia, and Malaysia), etc.39,40 KGM which constitutes 60-80% of the tuber is obtained by pulverizing thin slices of the dried tubers into a powder and is separated usually by wind sifting.

KGMis a neutral polysaccharide that consists of (b1!4)-linked D-mannose and D-glucose with about one in 19 units being acetylated. KGM forms a thermally stable gel upon addition of alkaline coagulant and the gelation of KGM is promoted by heating, in contrast to many other thermoreversible gels. The gelation occurs through the formation of a network structure of junction zones, which are considered to be stabilized by hydrogen bonding.41 KGM is derived from the tuber of Amorphophallus konjac C. Koch, and its gels have been important food materials in Asia especially in Japan and China. The glucomannan backbone possesses 5-10% acetyl-substituted residues, and it is widely accepted that the presence of substituted group confers solubility to the glucomannan in aqueous solution. If the molecules of KGM lose their acetyl groups with the aid of alkalis, the aqueous solution of KGM is transformed into a thermally stable gel. This gelation process is promoted by heating. The addition of alkali toKGMdispersion not only enhances their solubilization but also facilitates the deacetylation of the chain. The physicochemical properties, however, have not been fully elucidated mainly because of the difficulty in obtaining easily soluble and wellfractionated KGM samples. Recent studies on the effect of molar mass and the acetyl group content in KGM molecule on the gelation mechanism of KGM dispersions are described.

1.1.3(b) Tara Gum (Galactomannan)

Tara gum is derived from the tara bush, Caesalpinia spinosa, which is a wild perennial grown for commercial purposes exclusively in Ecuador, Peru, and also in tropical East Africa. The shrub is grown up to 5m in height. The fruits, the tara pods, are collected and threshed on the spot. The tara pods contain seeds that are about 10mm long and weigh about 0.25 g each. The threshing process separates the seeds from the husk.

Galactomannans are widely distributed in nature and have attracted considerable academic attention as well as industrial interest due to their thickening and gelling properties in aqueous media. They are generally heterogeneous, linearly branched polysaccharides based on a backbone of (b1!4)-linked D-mannopyranose (Man) residues to which are attached (1!6)-linked D-galactopyranose (Gal) residues. The rheological properties of dispersions of galactomannans depend on the molar mass and the degree of substitution: locust bean gum, Gal/Man¼1/4; in taragum, Gal/Man¼1/3; in guar gum, Gal/Man¼1/2; and in fenugreek gum, Gal/Man¼1/1. Mixtures of galactomannans with

xanthan and carrageenan have been studied extensively. Recent advances in the understanding of conformation, rheological behavior of dispersions of galactomannans, and gelation of galactomannans with other polysaccharides and with borax are described.

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1.1.3(c) Xanthan Gum (Changes to be made and also add some more info)

The Xanthan gum is a high molecular weight, water soluble, anionic-bacterial heteropolysaccharide, produced by fermentation with the gram-negative bacterium Xanthamonas campestris. (N¨urnberg and Retting, 1974)

Xanthan gum (XG) is a commercial hydrophilic polymer generally used as a thickening agent in food and beverages industries whereas in pharmaceutical sector its use has been introduced since last two decades and the pharmaceutical scientists like (Toko, 1991; Talukdar and Kinget, 1995; (Morris, 1995); Ntawaukulilyayo et al., 1996; Talukdar et al., 1996; Tobyn et al., 1996; Talukdar and Kinget, 1997; Talukdar et al., 1998; Santos et al., 2004; 2005; Veiga-Santos et al., 2005 had been extensively studied xanthan gum as an excipient in different pharmaceutical dosage forms. Xanthan gum shows superb swelling properties and in sustained release dosage form the swelling of the xanthan gum polymer matrix indicates a square root of time dependence while drug release is essentially linear (Talukdar and Kinget, 1995).

[Xanthan gum exhibited highest degree of swelling after water absorbtion and lesser degree of erosion as a result of polymer relaxation. In previous studies, the use of xanthan gum as a potential polymer matrix for oral controlled release tablet dosage forms was systematically assessed and characterized by in vitro tests (Munday and Cox, 2000; Talukdar et al., 1998; Cox et al., 1999; Sujja-areevath et al., 1998; Talukdar and Kinget, 1997) found that Fickian diffusion was prevailing during the first half of the dissolution study of Diclofenac Sodium mini-matrices with xanthan gum at different ratios, whereas erosion predominates in the second half, showing an approach near to zero-order release.

Xanthan gum, a complex microbial exopolysaccharide produced from glucose fermentation by Xanthomonas campestrispv. Campestris, a plant bacterium. It has a molecular weight of about 2 million [55]. The gum consists of D-glucosyl, D-mannosyl, and D-glucuronyl acid residues in a molar ratio of 2:2:1. It also contains O-acetyl and pyruvyl residues in variable proportions [56]. Xanthan gum is an acidic polysaccharide gum of penta-saccharide subunits. The penta-saccharide subunits form a cellulose backbone with trisaccharide side-chains.

The applications of xanthan gum have been widely researched. It is non-toxic and has been approved by the Food and Drug Administration (FDA) for use as food additive without quantity limitations [57]. Xanthan gum has been used in a wide range of industries including food, oil recovery, cosmetics and pharmaceutical industries. This wide application is due to its superior rheological properties. It is used as stabilizer for emulsions and suspensions. The gum forms highly viscous solutions which exhibit pseudoplasmic flow behavior [58]. The literatures are littered with uses of xanthan as a pharmaceutical material [59-61].

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1.2 Administration Routes

The selection of a route for drug delivery is driven by patient acceptability, the physico-chemical properties of the drug, such as its solubility, access to a site of action, or its effecacy in dealing with the specific disease [13]. The drug action can be influenced with different dosage forms, such as microemulsions{16} gels{14}, Transdermal Therapeutic systems (TTSs){15}, [14-16] at a particular site of action. Today, oral administration is still the most preferable, convenient and common means of drug delivery to the systematic circulation [17], as this route offers advantages of convenience and cheapness of administration, and potential manufacturing cost savings that's why it is still the most intensively investigated route. In case of oral administration, the exact site of action can be accurately determined, for example in case of APIs acting in the colon, gastroretentive drug delivery systems, buccal dosage forms etc. Besides this, there are many other frequently applied delivery sites, such as the lungs in pulmonary delivery systems, or the skin in case of transdermal drug delivery, vaginal administration route and numerous parenteral routes [13]. Bio/Mucoadhesive administration route also need to be emphasized as this dosage form has been developed and used clinically for many years in local therapy and systemic delivery of systemically effective drugs.

1.2.1 Orall Solid Drug Delivery System

For many years, increased attention has been given to drug administration characteristics, which has led to the development of new pharmaceutical dosage forms allowing the control of drug release. Among the many oral dosage form that can be used for controlled drug-release, tablets are of major interest in the pharmaceutical industry because of their highly efficient manufacturing technology. The most accepted, suitable and habitually preferred mode of drug administration is the oral route of drug administration because of its simplicity and convenience to the patients as well as the healthcare professional. According to (Juliano 1980, from jia bhai thesis) delivering the drug at a precise rate, for a specific period of time and at a designated location - is an ideal oral dosage form.

Large number of currently available controlled release dosage forms drop into one of the following three technologies:

1. Matrix Systems: hydrophilic, hydrophobic or inert matrices. Matrix systems are also called monoliths, since in these systems, the drug is homogeneously dispersed or dissolved in a soluble or insoluble matrix system [4] and it is released either by diffusion or erosion or by the combination of the two, from the dosage form. One of the most popular approaches in the design and development of oral controlled preparations is based on the matrix system because of its low cost and ease of fabrication (Lee, 1985). 2. Reservoir systems, where the drug is entrapped as an inner core within the polymer coatings [5]. In membrane-controlled reservoir systems, the drug is released by diffusion through this rate-controlling membrane.

3. Osmotic pump systems: Dosage form in which osmosis pumping is a release mechanism was defined by Theeuwas in 1975. In this system the drug or dispersion thereof is coated or encircled by a rigid rate-controlling membrane which is semipermeable. Penetration of water through the membrane at a controlled rate will enable the device to deliver, via an orifice in the membrane, a saturated drug solution equal to the volume of water absorbed. As the mechanism of this system is based on osmotic pressure therefore the rate of drug delivery is ultimately independent of stirring rate and the environmental pH. Based on this principle Alza Corporation USA, has marketed their product under the name 'OROS', and its applications has been examined with nifedipine (Chung et al., 1987) and oxprenolol (Bradbrook et al., 1985). In case of indomethacin some clinical problems were faced, resulting in the withdrawal of the product and this has been reviewed by Bem et al. (1988).

Solid matrix systems have proven dominant among controlled drug delivery systems because of their simplicity, ease of manufacturing, good reproducibility, stability of the materials as well as dosage form, and ease of commercial scale-up and process validation and their release controlling properties on the dissolution of APIs [6]. This is revealed by the huge number of patents filed each year and by the presence of a large number of novel drug delivery systems, based on matrix technologies, in the global market [7].

In my work, two hydrophilic matrix systems were chosen for the evaluation of natural gums. One of them is a swelling controlled delivery system, which is a special approach to developing an orally applicable system, the controlled release of the API in the other system is mainly by adhering the dosage form to the biological membrane; this is intended to be applied internally as well as externally.

1.2.2 Bio/Mucoadhesive Drug Delivery System

Bioadhesive drug delivery, a vital route of drug administration, has been extensively reviewed by many researchers.[1-3] Since biooadhesion can prolong the residence time of dosage form at the absorption sites as a result better drug absorption will be attained. V.V. Khutoryanskiy has elaborated the history of bio adhesive drug delivery system in his review article[2]. Sticking of any drug dosage form to the biological membranes, in the gastrointestinal tract or any other body cavity, can be described as bioadhesion and/or mucoadhesion. The occurrence of interaction between polymer and epithelial surface is generally referred as bioadhesion. The same interaction when occurs with mucus layer of the biological membrane is referred as mucoadhesion. In general bioadhesion is deeper than mucoadhesion. Though, these two terms appear to be used interchangeably[4]. Different bioadhesive mucosal dosage forms have been developed, such as adhesive tablets [5-7], microspheres[8-10], mucoadhesive nano-particles[11], gels [12, 13], ointments[13], mucoadhesive liposomes[14], patches[15] and films [16, 17].

Mucoadhesion is defined as attractive interaction at the interface between a pharmaceutical dosage form and a mucosal membrane. One of the first applications of mucoadhesive formulations dates back to 1947, when Scrivener and Schantz [2] reported the use of gumtragacanth mixed with dental adhesive to administer penicillin to the oral mucosa. Eventually this therapeutic application of mucoadhesives laid grounds for formulating Orabase. [3] The potential of mucoadhesion in drug delivery has been fully recognized in the early eighties, when Nagai and coworkers demonstrated the applicability of viscous gel ointments and mucoadhesive tablets for drug administration in the oral cavity [4, 5] and polymer-mediated enhancement in the bioavailability of nasally administered peptide.[6]

Various administration routes, such as ocular, nasal, buccal and gingival, gastrointestinal (oral), vaginal and rectal, make mucoadhesive drug delivery systems attractive and flexible in dosage form development. Recent reports have suggested that the market for mucoadhesive drug delivery systems is expanding rapidly.[3,7,8] The advantages associated with the use of mucoadhesives in drug delivery include increased dosage form residence time, improved drug bioavailability, reduced administration frequency, simplified administration of a dosage form and termination of a therapy as well as the possibility of targeting particular body sites and tissues.[8] Moreover, the drugs administered via transmucosal non-oral routes often avoid the metabolism associated with its passage through the gastrointestinal tract and also benefit from better mucosal penetration compared to relatively low permeability of transdermal route.[9]

Mucoadhesive drug delivery systems maybe formulated as tablets, lozenges, solid inserts, wafers, pessaries, films, gels, viscous solutions, micro- and nano-particulate

suspensions, in situ gelling systems and sprays. The majority of these dosage forms incorporate polymeric excipients, which play a major role in their mucoadhesivity.

Some mucoadhesive polymers can not only increase the dosage form residence time at the site of administration but also may enhance drug permeability through the epithelium

by modifying the tight junctions between the cells.[10]

Despite several decades of research, mucoadhesion is still not fully understood. The complexity of interactions between various polymer-based mucoadhesive dosage

Forms and biopolymer-based viscoelastic mucus gel present on the surface of mucosal membranes continues to attract attention of researchers. Numerous studies on developing novel mucoadhesive polymers, mechanisms of their interactions with mucins and mucosal membranes, formulating and administering novel active ingredients via

trans mucosal routes increasingly appear in the literature.

1.3 Controlled release dosage forms

As the conventional dosage forms are designed for immediate release and for quick absorption of the drug so that optimal therapeutic results can be achieved. These products are intended to use with multiple dose administration, as a result, wide fluctuations in peak and trough steady-state drug levels are frequently obtained, mainly for drugs having short biological half-lifes (Roda et al., 2002). Such undesirable fluctuations particularly with drugs of narrow therapeutic indices can be controlled by increasing the frequency of dosing. Though, it will be bother some for the patient and will result in poor compliance. To prevail over this problem, a variety of sustained release formulations have been developed to improve the desired pharmacological effects with reduced unwanted effects and to maximize the therapeutic performance of drugs (Pather, Russell et al. 1998; Sanchez-Lafuente, Teresa Faucci et al. 2002) (Kramar, Turk et al. 2003)

In recent years, controlled release drug delivery system has made enormous progress in terms of patient compliance as well as improving therapeutic efficacy (Reza, Quadir et al. 2003). An ultimate controlled release drug delivery system should release its active content at a constant rate by maintaining plasma drug levels constant and with reduced fluctuation, for a prolong time period and the duration of its therapeutic effect is sustained.

In 1959 (British Patent No. 808014) was introduced called Duretter® which was a matrix tablets produced by compressing granules to form plastic matrices (FRYKLOF, SANDELL et al. 1959). Since then, different sustained release products have been introduced into the market with their mechanism of release being described by such names as sustained action, prolonged action, extended release, long acting and extended action preparations (GUPTA 1999).

The early sustained release products in the 1950s were associated with problems. At that time, the science of pharmaceutics and pharmacokinetics was still in its early stages. Also the shortage of appropriately sensitive analytical techniques at that time probably made the evaluation of blood-drug levels, impossible. Thus the efficacy of these products could only be measured by pharmacological methods which were often unreliable or even inapplicable to the drug under test.

To the end of 1960's, a new phase, controlled drug delivery was introduced with improved bioavailability, efficacy and safety (Banker and Anderson, 1986; 1987; 1991).

In the past two decades significant progress has been made in this area and today controlled drug delivery system have become an important product line of most major drug companies. Different techniques have been adopted in the formulation of these products but mostly they all work on the same principle of slowing the rate of drug dissolution.

1.3.1 Matrix controlled release systems

Matrix system due to its low cost and ease of fabrication is one of the most acceptable approaches in the design and development of oral controlled preparations. (Lee, 1985). Most of the oral matrix controlled release formulations employ either hydrophilic or hydrophobic matrices where the drug is homogenously dissolved or dispersed throughout the polymer (Khan and Reddy, 1997; Viega et al., 1997; 1998; Reza et al., 2003). The release mechanism of drug occurs mainly through diffusion and erosion.

1.3.2 Types of matrix systems

The matrix systems can be divided into two categories depending on whether the polymers used to make the matrices are hydrophilic or hydrophobic in nature.

1.3.2 (a) Hydrophilic matrix systems

Of all drug forms, solid oral dosage is enormously preferred by patients, and hydrophilic matrix systems are the most widely used means of providing controlled release in solid oral dosage forms.

Hydrophilic matrix systems are created using water soluble polymeric materials. Drugs dispersed in a soluble matrix depend on a slow dissolution of the matrix to provide sustained release. When the matrix is immersed in aqueous media, the water penetrates into the free spaces between macromolecular chains of the polymers. As a result of the pressure, exerted by the penetrated water, the polymers may undergo a relaxation process and the polymer chains become more flexible causing the matrix to swells and thus permit the drug to dissolve and diffuse out of the matrix. (Rajabi-Siahboomi et al., 1994a; 1994b; Rajabi-Siahboomi and Jordan, 2000). Since the diffusion path is lengthened by matrix swelling and drug release from the matrix is slowed down. Nevertheless, according to Sujja-Areevath et al., 1998 polymer swelling and diffusion are not the only components that regulate the rate of drug release. For soluble polymer matrix, polymer dissolution is another important factor that can control the drug release rate. Although either swelling or dissolution may be the predominant cause for a specific type of polymer, in maximum cases drug release kinetic is a result of a combination of these two mechanisms (Tahara et al., 1995).

Some examples of Hydrophillic Polymers:

Hydrophilic polymers were considerably investigated on the basis of release mechanism and drug release from hydrophilic matrix systems like tablets as well as pellets (Alderman, 1984; Khan et al., 1996; Khan and Jiabi, 1998; Khan and Zhu, 1998; Sen et al., 2001; Huang et al., 2004).

Hydroxypropyl methylcellulose (HPMC) is a classical example of water soluble matrix former. Of the available range of cellulosic controlled-release agents this is the most extensively used semisynthetic derivative of cellulose, it has its popularity for the formulation of controlled release dosage forms as a swellable and hydrophilic polymer [9-11]. HPMC and HPC polymers attain considerable consideration, due to their distinctive properties along with their good compression properties. They are well-known excipients with an excellent safety record. Its nontoxic properties, ease of compression, ease of handling, negligible influence of the processing variables on drug release rates, ability to accommodate a large amount of drug and relatively simple tablet manufacturing technology make it an excellent carrier material [12]. HPMC is nonionic, so it reduces incompatiblity problems when used in acidic, basic, or other electrolytic systems. It works well with soluble and insoluble APIs at high and low dosage levels [8]. (Swarbrick, 1996; Carstensen, 2000; Rani and Mishra, 2001; Mishra et al., 2003; 2005)

Lotfipour et al. (2004) investigated the effect of various polymers, fillers and their concentration on the release rate of atenolol form polymeric matrix. They concluded that the release rate and mechanism of atenolol release from hydrophobic and hydrophilic matrices are mainly controlled by the drug to polymer ratio. The results also showed that an increase in the concentration of fillers resulted in an increase in the release rate of the drug from matrices and hydrophilicity or hydrophobicity of the fillers had no significant effect on the release profile. Regarding the mechanism of release, the results showed that in most cases the drug release was controlled by both diffusion and erosion depending on the polymer type and concentration. On the other hand, incorporation of water soluble fillers like polyethylene glycol, lactose and surfactant into gel forming matrices can improve the drug release in case of matrices where complete drug is not released or is very slowly released, because these excipients can enhance the penetration of the solvent or water into the inner part of matrices (Genc et al., 1999; Nokhodchi et al., 2002).


Hydroxypropyl methylcellulose (HPMC) is a water soluble hydrophilic polymer, with the ability to swell in water to form a swollen gel phase (Harland et al., 1988; Bonferoni et al., 1994). It is prepared by reacting alkali treated cellulose first with methyl chloride to introduce methoxy groups and then with propylene oxide to introduce propylene glycol ether groups. The resulting products are commercially available in different viscosity grades. The erosion of the gel layer is dependent on the polymer viscosity. Increasing viscosity yields slower drug release as a stronger, more viscous gel layer is formed, providing a greater barrier to diffusion and slower attrition of the tablets (Cheong et al., 1992). HPMC matrices undergo the following during dissolution test: absorption of dissolution media, swelling, gelling, erosion and complete dissolution at the end of test. The mechanism of release from hydrogel matrix systems is complex and has not been completely understood. In general, on contact with aqueous medium, initially HPMC undergoes a relaxational process that is observed macroscopically as gelation and swelling (Vueba et al., 2004). As a result of these processes, a transparent gel layer appears. Outside this layer, there is an eroding front (gel/dissolution medium interface) at which HPMC chain disentanglement and concomitant dissolution of gel occurs. Inside this layer, there is a swelling front (glassy polymer/gel interface), at which HPMC hydrates, and swells.

Huang et al. (2004) developed once daily propranolol extended release tablets using HPMC polymer as a retarding agent. The mechanism of the drug release from the HPMC matrix tablets followed non-Fickian diffusion, while the in vivo absorption and in vitro dissolution showed a linear relationship.

Other polymers used in hydrophilic matrix preparations include poly ethylene oxide (Sriwongjanya and Bodmeier, 1998; Maggi et al., 2003), hydroxypropylcellulose (Ferrero et al., 1997) and hydroxyethylcellulose.

Hydroxypropylcellulose (HPC) is non-ionic water-soluble cellulose ether, formed by reacting cellulose with propylene oxide. It provides a remarkable set of physical properties for tablet binding, sustained release and film coating (Veiga et al., 1997). It is soluble both in organic solvent as well as in water. Thermoplasticity and surface activity with aqueous thickening and stabilizing properties are the other characteristics of this polymer. It has a long standing history of safe and effective use in the pharmaceutical industry. The pharmaceutical grades of HPC (Klucel®) comply with the monograph requirements of the National Formulary, the European Pharmacopoeia, and the Japanese Pharmacopoeia.

Hydroxyethylcellulose (HEC) is non-ionic water-soluble cellulose ether, formed by reacting cellulose with ethylene oxide. It is used as a sustained release tablet matrix forming material, film former, thickener, stabilizer and suspending agent for oral and topical applications when a non-ionic material is desired (Veiga et al., 1998). HEC is easily dispersed in cold or hot water to give solutions of varying viscosities and desired properties. The pharmaceutical grades of HEC (Natrosol®) comply with the monograph requirements of the National Formulary and the European Pharmacopoeia.

Carbopol is a derivative of polyacrylic acid. It is a synthetic, high molecular weight, crosslinked polymer. It readily hydrates, absorbs water and swells making it a potential candidate for controlled release drug delivery systems (Khan and Jiabi, 1998; Goskonda et al., 1998; Wong et al., 1999; Juang and storey, 2003; Ikinci et al., 2004; Tapia-Albarran and Villafuerte-Robles, 2004). In the case of tablets formulated with Carbopol the drug is entrapped in the glassy rubbery core in the dry state. It forms a gelatinous layer upon hydration. However, this gelatinous layer is significantly different structurally from the traditional matrix tablets. The hydrogel is not entangled chains of polymer, but discrete microgel made up of many polymer particles in which the drug is dispersed. The crosslinked network enables the entrapment of drug in the hydrogel domains. Since these hydrogels are not water soluble, they do not dissolve and erode. Rather, when the hydrogel is fully hydrated, osmotic pressure from within works to break up the structure, essentially by sloughing off discrete pieces of the hydrogel. This hydrogel remains intact and the drug continues to diffuse through the gel layer at a uniform rate (Khan and Jiabi, 1998).

It is well recognized that the key formulation variables are matrix dimension and shape, polymer level and molecular weight, as well as drug loading and solubility. Other factors such as tablet hardness, type of inactive ingredients and processing normally play secondary roles. The choice of manufacturing process such as direct blending or granulation typically does not affect product performance significantly, although exception does exist. In general, processing and scale up associating with hydrophilic matrices are more robust than other controlled release systems (Upadrashta et al., 1993; Velasco et al., 1999; Venkatraman et al., 2000; Soliman et al., 2005).

1.3.2 (b) Hydrophobic matrix systems

Hydrophobic matrix systems are constructed using water insoluble polymeric materials. The hydrophobic matrix formers include waxes (Vergote et al., 2001; Hayashi et al., 2005), glycerides (Yuksel et al., 2003), fatty acids and polymeric materials such as ethyl cellulose (Crowley et al., 2004) and acrylate copolymer (Azarmi et al., 2002; Krajacic and Tucker, 2003). To modulate drug release, it may be necessary to incorporate soluble ingredients such as lactose into the formulations. The presence of insoluble ingredient in the formulations helps to maintain the physical integrity of the hydrophobic matrix during drug release. As such, diffusion of active ingredients from the system is the release mechanism (Kincl et al., 2004) and the corresponding release characteristics can be described by Higuchi equation known as square root of time release kinetics (Higuchi, 1963). The square root of time release profile is expected with a porous monolith, where the release from such system is proportional to the drug loading. In general, hydrophobic matrix systems are not suitable for water insoluble drugs because the concentration gradient is too low to render adequate drug release. As such, depending on actual ingredient properties or formulation design, incomplete drug release within the gastrointestinal transit time is a potential risk and need to be delineated during the developmental stages.

Polymers used in hydrophobic matrices

Ethylcellulose is one of the most widely used water insoluble hydrophobic polymer. It can be applied either as an organic solution or as an aqueous colloidal dispersion. Ethylcellulose is essentially tasteless, odorless, colorless, noncaloric and physiologically inert (Donbrow and Friedman, 1974; Spited and Kinget, 1980; Iyer et al., 1990). Ethylcellulose contains 44 to 51% of ethoxy groups manufactured by reacting ethyl chloride or ethyl sulfate with cellulose dissolved in hydroxide. Depending on the degree of ethoxy substitution, different viscosity grades are obtained and available. This material is completely insoluble in water and gastrointestinal fluids, and thus cannot be used alone for tablet coating. It is usually combined with water soluble additives, such as hydroxypropyl methylcellulose, to prepare films with reduced water solubility properties (Lachman et al., 1986; Sadeghi et al., 2000).

Kollidon® SR is a newly developed sustained release matrix excipient based on a mixture of polyvinyl acetate and povidone. Due to its excellent flow and compression properties, it is highly suitable for tablets made by direct compression (Draganoiu et al., 2001). Polyvinyl acetate is a very plastic material that produces a coherent matrix even under low compression forces. When the tablets are introduced into dissolution media, the water soluble povidone is leached out to form pores through which the active ingredient slowly diffuses outwards.

1.4 Advantages and disadvantages of oral controlled release dosage forms

1.4.1 Advantages

Oral controlled release dosage forms offer great advantages due to better therapeutic success than with conventional dosage forms of the same drug (Reza et al., 2003). The advantages include (1) remarkable decrease in dosing frequency and improved patient compliance, (2) minimized in vivo fluctuation of drug concentrations and maintenance of drug concentrations within a desired range (Urquhart, 1982), (3) reduced side effects, and (4) reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing and reduction in personnel time to dispense, administer and monitor patients.

This is of great importance, especially for drugs used in long term treatment of chronic diseases. Moreover, controlled release dosage forms are useful for delivering drugs with narrow therapeutic indices since they can reduce the peak trough fluctuations in blood concentration, being characteristic of multiple dosing using conventional immediate release dosage forms (George et al., 1978; Longer and Robinson, 1990). A better efficacy and toxicity ratio of drug during the complete dosing interval could be obtained. Large fluctuations in the blood levels may produce high peak drug levels associated with toxicity while low trough levels result in the loss of efficacy. Hence, a better disease management and reliable therapy can be achieved with the controlled release dosage forms (Chaffman and Brogden, 1985).

1.4.2 Disadvantages

Oral controlled release dosage forms also suffer from a number of potential disadvantages which generally include (1) higher cost, (2) reduced bioavailability, (3) possible dose dumping, (4) reduced potential for dose change or withdrawal in the event of toxicity, allergy or poisoning, and (5) increased first pass metabolism for certain drugs. Unpredictable and poor in vitro/in vivo correlations and bioavailability are often observed with such formulations, especially when the drug release rate is very low or drug absorption from the colon is involved. Dose dumping is a phenomenon where a large amount of the drug is released from a controlled release formulation in a short period of time, resulting in undesired high plasma drug levels and potential toxicity. Basically, this can occur due to a breakdown of the rate controlling mechanism, such as rapid disintegration of the matrix tablet.

1.5 Tableting Methodologies

Solid pharmaceutical single unit dosage forms encompassing therapeutic substances with or without suitable excipients and prepared by several methods. Tablets significantly vary in size and weight which depend on the dosage of APIs and the mode of administration.

Ordinarily, tablets are prepared in disk shaped with biconvex surfaces however they too are available in different shapes like oval, oblong, cylindrical, square, triangular etc. Perhaps, the most extensively used solid dosage form of medicament are the tablets since they present a number of advantages to the patient and the manufacturing pharmacist (Chien, 1978; Chien, 1983; Patel and Amiji, 1996; Streubel et al., 2000; 2006). Tablets can be prepared by compressing a powder mixture with the help of a suitable die and punches at high compression force. Usually, the powder mixture comprises of APIs, bulking agents or diluents, binders, disintegrants, lubricants and glidants.

1.5.1 Direct compression method

The simplest method for tablet production is direct compression. In direct compression, the API is blended with the excipients to form a uniform mixture and then directly compressed into tablets without any modification or adopting any special process. Addition of lubricating agents is necessary to avoid the mixture from adhering to the tools in the course of compression. Powder mixtures having adequate physico-chemical properties, good flow and compaction properties are necessary for direct compression (Kristensen et al., 1993).

Tableted drug delivery systems can range from relatively simple immediate release formulations to complex extended or modified release dosage forms. The role of an oral drug delivery system is to deliver the drug in sufficient amount and at appropriate rate at the site of absorption. However, it must also meet a number of other essential criteria. These include physical and chemical stability, ability to economically mass produce and patient acceptability (Augsburger and Zellhofer, 2002).

1.5.2 Granulation method

Granulation process imparts excellent physico-chemical properties such as flowability, and compactibility, which is the basic requirement in the production of high quality tablets on commercial scale. The two methods used in granulation process are dry granulation and wet granulation.

1.5.2 (a) Dry Granulation method

In dry granulation technique, the dry powder blend might be compressed together by using larger size dies and punches to form hard slugs through high speed compression machine, the resulted slugs are then crushed to obtain the required size granules for final dosage form or more precisely through compaction by a roller compactor, specially designed for high scale dry granulation process. This technique has been employed when one of the ingredients, either the API or the diluent has inadequate flow properties to be directly compressed into the final dosage form. Dry granulation is a precious technique in circumstances where the dose of the active substances is excessively high to be compressed directly or the APIs are unstable at high temperature and humidity, which excludes need for wet granulation process. (Banaker, 1979; 1991).

1.5.2 (b) Wet Granulation method

Wet granulation involves some additional procesing steps that are necessary to produce a granular mass of having desired compression properties. In wet granulation method after dry blending of the API with suitable diluent, a paste or solution of a suitable binder is added to the mixture to wet the powder blend. This wet mass is then dried by different techniques and crushed to obtain the granules of required size and density. Introduction of the binder to the bulk powder changes its physico-chemical properties and improves binding of the granules and thus can produce robust tablets.

Appendix 2.21 Statistical analysis of T50%, and MDT results for in vitro release profiles of Theophylline containing various amount of Kollidon® SR matrix formulation F17 to F20. Mean ± SD, N = 3.

Appendix 2.22 Statistical analysis of T50%, and MDT results for in vitro release profiles of Theophylline containing various amount of Plasdone S-630 matrix Formulation F21 to F24. Mean ± SD, N = 3.

Appendix 2.29 Kinetic plots of Theophylline release from formulation F1 10% hydroxypropyl methylcellulose (HPMC K4M). Mean, N = 3.