RESEARCH NATURAL POLYMERS USED IN … in the design of novel drug delivery systems such as those that target delivery of the drug to a specific region in the gastrointestinal tract

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Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: 2231-6876

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INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH

NATURAL POLYMERS USED IN SUSTAINED DRUG DELIVERY SYSTEMS Yogendra S. Mohare*, Atul S. Pratapwar, Dinesh M. Sakarkar, Aqueel Sheikh

*Department of Pharmaceutics, S. N. Institute of Pharmacy, Pusad, Dist. Yavatmal, India.

Corresponding author: Yogendra S. Mohare Research Scholar,

Department of Pharmaceutics, S.N. Institute of Pharmacy, Pusad, Yavatmal, India. Contact no: +91-9579164495 Email id: [email protected]

Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT Article history Received 11/04/2013 Available online 12/05/2013 Keywords Natural polymers, Biodegradable, Compatible, Resources and Eco-friendly.

The use of natural polymers and their semi-synthetic derivatives in drug delivery continues to be an area of active research despite the advent of synthetic polymers. Natural polymers remain attractive primarily because they are inexpensive, readily available, capable of multitude of chemical modifications and potentially biodegradable and compatible due to their origin. The products from natural sources have become an integral part of human health care system because of some side effects and toxicity of synthetic drugs and polymers. Applications of natural polymers in pharmacy are comparable to the synthetic polymers and they possess wide scope in drug, food and cosmetic industries. In spite of that, natural resources are also eco-friendly, renewable and if cultivated or harvested in a sustainable manner, they can provide a constant supply of raw material. 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. The increasing research interests in this group of materials are indications of their increasing importance.

Please cite this article in press as Mohare et.al. NATURAL POLYMERS USED IN SUSTAINED DRUG DELIVERY SYSTEMS. Indo American Journal of Pharm Research.2013:3(2).

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Vol 3, Issue 6, 2013. Mohare et al. ISSN NO: 2231-6876

Introduction: Protein, enzymes, muscle fibers, polysaccharides and gummy exudates are the natural polymers being used effectively in formulating the variety of pharmaceutical products. The well-known natural polymers used in pharmacy and other fields are chitosan, carrageenan, ispaghula, acacia, agar, gelatin, shellac, guar gum and gum karaya. These natural polymers are widely used in pharmaceutical industry as emulsifying agent, adjuvant and adhesive in packaging; and also well suited for pharmaceutical and cosmetic product development. The specific application of plant-derived polymers in pharmaceutical formulations include their use in the manufacture of solid monolithic matrix systems, implants, films, beads, microparticles, nanoparticles, inhalable and injectable systems as well as viscous liquid formulations like ophthalmic solutions, suspensions, implants[1-3]. Within these dosage forms, polymeric materials have fulfilled different roles such as binders, matrix formers or drug release modifiers, film coating formers, thickeners or viscosity enhancers, stabilizers, disintegrants, solubilisers, emulsifiers, suspending agents, gelling agents and bioadhesives [4].

Sustained drug delivery systems significantly improve therapeutic efficacy of drugs. Drug-release-retarding polymers are the key performers in sustained release drug delivery system for which various natural, semi-synthetic and synthetic polymeric materials have been investigated. Besides this several polymers are often utilized in the design of novel drug delivery systems such as those that target delivery of the drug to a specific region in the gastrointestinal tract or in response to external stimuli to release the drug. Need of Natural Polymers [5]:

1. Biodegradable – Naturally occurring polymers produced by all living organisms. They show no adverse effects on the environment or human being. 2. Biocompatible and non-toxic – Chemically, nearly all of these plant materials are carbohydrates in nature and composed of repeating monosaccharide units. Hence they are non-toxic. 3. Economic – They are cheaper and their production cost is less than synthetic materials. 4. Safe and devoid of side effects – They are from a natural sources and hence, safe and without side effects. 5. Easy availability – In many countries, they are produced due to their application in many industries. Disadvantages of Natural Polymers [5,6]: 1. Microbial contamination – During production, they are exposed to external environment and hence, there are chances of microbial contamination. 2. Batch to batch variation – Synthetic manufacturing is controlled procedure with fixed quantities of ingredients while production of natural polymers is dependent on environment and various physical factors. 3. The uncontrolled rate of hydration – Due to differences in the collection of natural materials at different times, as well as differences in region, species, and climate conditions the percentage of chemical constituents present in a given material may vary. 4. Slow Process – As the production rate depends upon the environment and many other factors, it can’t be changed. So natural polymers have a slow rate of production. 5. Heavy metal contamination – There are chances of Heavy metal contamination often associated with herbal excipients.

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Classification of Natural Polymers [7]:

1. Plant origin – Rosin, Cellulose, Hemicellulose, Glucomannan, Agar, Starch, Pectin, Inulin, Guar gum, Locust bean Gum, Gum Acacia, Karaya gum, Gum tragacanth, Aloe Vera gel. 2. Animal origin – Chitin, Alginates, Carageenans, Psyllium, Xanthum gum. Natural Polymer Approach in Sustained Release Drug Delivery Systems: The use of natural polymers and their semi-synthetic derivatives in drug delivery continues to be an area of active research. Drug-release retarding polymers are the key performer in matrix systems. Various polymers have been investigated as drug retarding agents, each presenting a different approach to the matrix system. Based on the features of the retarding polymer, matrix systems are usually classified into three main groups: hydrophilic, hydrophobic and plastic. Hydrophilic polymers are the most suitable for retarding drug release and there is growing interest in using these polymers in sustained drug delivery [8]. There are various numbers of natural polymers which have been investigated as sustained release agent.

Examples of Natural Polymers:

1. Pectin: (Polysaccharide of the Plant Cell Wall) Biological Source: Pectins are non-starch, linear polysaccharides present in the walls that surround growing and dividing plant cells. Pectin was first isolated in the 1820s and the first commercial production of a liquid pectin extract was recorded in 1908 in Germany, and the process spread rapidly to the United States.

Physico-chemical properties: Pectin is widely found in plant tissues where it serves, in combination with cellulose, as intercellular structural substance (membranes, middle lamellae). It is soluble in water, insoluble in ethanol (95%) and other organic solvents. The main sources of commercial pectin are citrus peel (lemon, lime and grapefruit), apple pomace and sugar beet pulps. Pectin polysaccharides are predominantly linear polymers of primarily α-(1,4)-linked D-galacturonic acid residues interrupted by 1,2-linked L-rhamnose residues having an average molecular weight of about 50,000 to about 180,000. Chemical modifications of pectin can lead to new products with significant physicochemical and biological properties. Pectin is classified according to its degree of esterification (DE). Pectin with at least 50% DE or greater is high-methoxy pectin, and the one with DE below 50% is low-methoxy pectin. These two types of pectin possess different properties; for example, low-methoxy pectin requires calcium to gel, and high-ester pectins are capable of forming gels in aqueous systems with high contents of soluble solids and low pH values.

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fig: structure of Pectin Applications: Pectins from different sources are widely used as gelling agents, thickeners, texturisers, emulsifiers and stabilizers in food, pharmaceutical, and many other industries. Pectin gel beads have been shown to be an effective medium for controlling the release of a drug within the gastrointestinal tract. Literature Review: This polysaccharide is extensively used and studied by many researchers for various floating drug delivery systems. Some important examples are described below. Badve et al developed hollow calcium pectinate beads for floating-pulsatile release of diclofenac sodium intended for chronopharmaco therapy. Floating beads obtained were porous and hollow in nature with bulk density less than 1. In vivo studies by gamma scintigraphy determined on rabbits showed gastroretention of beads upto 5 h[9]. Washington et al investigated the floating behaviour of pectin containing anti-reflux formulation by means of gamma scintigraphy. Formulation was shown to float and form a discrete phase on top of the stomach contents and emptied from the stomach more slowly than the food[10]. Mishra et al formulated gastroretentive controlled release system of loratadine to increase the residence time in stomach and to modulate the release behaviour of the drug. Low methoxy polysaccharide, pectin, was employed as one of the polymers in the formulation of oil entrapped floating microbeads. Designed therapeutically efficacious gastroretentive formulation of drug showed an excellent buoyant ability along with suitable drug release pattern [11]. Sriamornsak et al investigated the use of pectin as a carrier for intragastric floating drug delivery. They concluded that the drug release could be prolonged using this polymer with lower degree of esterification, calcium carbonate, acidified gelation medium, and high drug loading.36 Significant efforts by various scientists on this material have been carried out for the development of floating drug delivery systems. This reveals the most exciting opportunities in the area of pectin based floating dosage forms[12].

Ispaghula[13,14,15,16,17]: Biological Source: Ispaghula husk consist of dried seeds of the plant Plantago ovate Forsk. (Family ⎯ Plantaginaceae) commonly known as Isabgol or Ispaghula or Spogel seeds. It contains mucilage, which is present in the epidermis of seeds. It contains no toxic principles and when taken with water or milk most of it pass out of gastro-intestinal tract in 6 to 12 hours. Larger doses are essential as their action is produced partly by lubricating action of mucilage and

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partly by the increase in bulk of intestinal contents, which mechanically stimulates the intestinal peristalsis.

fig: Ispaghula

Applications: 1. The seed and husk of the isabgol are widely used in pharmaceutical industry as demulcent, emollient, laxative, as an adjunct to dietary and drug therapy on lipid and glucose levels, in patients with type II diabetes and in the treatment of dysentery. 2. The seed and husk of the isabgol contains mucilage which is present in the epidermis of the seed. It is official in IP, BP, and USP. It is used in food and pharmaceuticals at a dose level of 5-6 g twice a day. 3. Mucilage is used as binding agent in the granulation of material for preparation of compressed tablets. It is used as a suspending and thickening agent due to its high swelling factor and ability to give a uniform viscous solution. 4. It is much sought in pharmaceutical industry as enteric coating material, tablet disintegrator and also used in sustained release drug formulations.

Literature Review: Khanna M. et al, carried out standardization of isabgol mucilage. They observed that the aqueous dispersion (1%, w/v) of mucilage has a pH of 4-5 and contains not more than 0.01% (w/v) crude fibres. The kinematic viscosity of (0.5%, w/v) aqueous dispersion was found to be 4-6 centistokes. The mucilage was found to contain not more than 0.1% (w/w) of chloride and 20 ppm of heavy metals [1]. On comparative evaluation, isabgol mucilage (0.5%, w/w) was found to posses higher suspending and emulsifying power than methylcellulose (1%, w/v) and tragacanth (1%, w/v) aqueous suspensions. Further, the binding power of aqueous dispersion (2%, w/v) of isabgol was found to be equivalent to the methylcellulose and tragacanth. Prajapati S.T. et al, evaluated the disintegrating property of Plantago ovata mucilage by preparing dispersible tablet of nimesulide using wet granulation technique. The study revealed that the mucilage is effective at low concentration as superdisintegrant. Further, the results revealed that disintegrant property of isabgol mucilage is equivalent to Ac-Di-Sol and superior to sodium starch glycolate. Similar results were obtained in an another study, Chakraborty S. et al, prepared fast dissolving tablets of acelofenac by direct compression method employing microcrystalline cellulose as a diluents and isabgol or Ac-

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Di-Sol or sodium starch glycolate as the disintegrant. The study attributed the better disintegrating property of isabgol mucilage over the Ac-Di-Sol and sodium starch glycolate, to the higher swelling index of isabgol mucilage as compared to the Ac-Di-Sol and sodium starch glycolate. Apart from the disintegrating property, Desai A. et al, evaluated the psyllium husk has a sustained release property. The capsules containing sustained release granules and tablets of amoxicillin trihydrate were formulated using various combinations of psyllium husk and HPMC K4M. It was observed that in case of granules, a faster release of amoxicillin occurred from the formulation containing only psyllium husk as the release retardant while use of a combination of Psyllium husk and HPMC K4M provided a sustained release of the drug. The incorporation of HPMC K4M into psyllium husk granule was observed to reduce the immediate swelling of the matrix and thus reduce its release. Fischer M.H. et al, reported the laxative and cholesterol-lowering activity of the psyllium husk due to its gel-forming ability. A method of extracting gel forming fraction of psyllium husk has been described in one of the patent claim. The method involves suspending the husk in dilute aqueous alkali, followed by separation of alkali-soluble fraction and acidifying to a pH of 4.5, which yields the gel and an acid – insoluble fraction. The gel fraction can be dehydrated by washing with organic solvents and dried. Further, the patient describes the use of gel forming fraction of psyllium husk in the form of tablets, capsules or liquid dosage form for its laxation and hypocholesterolemic effects. Hibiscus Mucilage: The mucilage is extracted from the fresh leaves of Hibiscus rosa-sinensis, family Malvaceae. Physico-chemical properties: Hibiscus rosa-sinensis, commonly known as China rose is a popular landscape shrub, creates a bold effect with its medium-textured, glossy dark green leaves and with 4-6 inch wide and up to 8 inch long, showy flowers, produced throughout the year and grows up to 7-12 feet[18].

fig: Hibiscus Plant

Literature Review: Jani G.K. et al designed matrix tablets of Diclofenac sodium using Hibiscus rosa-sinensis leaves mucilage and study its release retardant activity in prepared sustained release formulations. Hibiscus rosa-sinensis leaves were evaluated for physicochemical properties. Different matrix tablets of Diclofenac sodium Hibiscus rosa-sinensis leaves mucilage were formulated. The matrix tablets found to have better uniformity of weight, hardness, friability and drug content with low deviated values. The swelling behavior, release rate characteristics and the in- vitro dissolution study proved that the dried Hibiscus rosa-sinensis leaves mucilage can be used as a matrix forming material for preparing sustained release matrix tablets. The kinetics of selected formulation followed zero order. It was concluded that, Hibiscus rosa-sinensis

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leaves mucilage can be used as an effective matrix forming polymer, to sustain the release of Diclofenac sodium from the formulation[19]. Aloe Mucilage: Biological Source: Aloe is the dried juice of the leaves of Aloe barbadensis Miller, belonging to family Liliaceae. Physico-chemical properties: Many compounds with diverse structures have been isolated from both the central parenchyma tissue of Aloe vera leaves and the exudates arising from the cells adjacent to the vascular bundles. The bitter yellow exudates contains 1,8 dihydroxyanthraquinone derivatives and their glycosides[20]. The aloe parenchyma tissue or pulp has been shown to contain proteins, lipids, amino acids, vitamins, enzymes, inorganic compounds and small organic compounds in addition to the different carbohydrates. Many investigators have identified partially acetylated mannan (or acemannan) as the primary polysaccharide of the gel, while others found pectic substance as the primary polysaccharide. Other polysaccharides such as arabinan, arabinorhamnogalactan, galactan, galactogalacturan, glucogalacto-mannan, galactoglucoarabinomannan and glucuronic acid containing polysaccharides have been isolated from the Aloe vera inner leaf gel part[21].

fig: Aloe leaf

Literature Review: Jani G. K. et al, directly compressed dried A. vera leaf gel (acetone precipitated component of the pulp) in different ratios with a model drug to form matrix type tablets, including ratios of 1:0.5, 1:1, 1:1.5 and 1:2. These matrix systems showed good swelling properties that increased with an increase of aloe gel concentration in the formulation. The directly compressed matrix type tablets also showed modified release behavior with 35.45% and 30.70% of the dose released during the first hour and the remaining of the dose was released over a 6 hour period for those formulations containing the lower ratios of gel to drug, namely 1:0.5 and 1:1. The formulation that contained the highest ratio of gel to drug, namely 1:2 exhibited only a 23.25% drug release during the first hour with the remaining of the dose being released over an 8 hour period. The dried A. vera gel polysaccharide component therefore showed excellent potential to be used as an excipient in the formulation of direct compressible sustained- release matrix type tablets[22]. Hindustan Abdul et al, formulated matrix tablets of Glimepiride with Aloe barbadensis miller leaves mucilage and Povidone and studied its functionality as a matrix forming agent for sustained release tablet

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formulations. Physicochemical properties of dried powdered mucilage of Aloe barbadensis miller mucilage and Povidone tablet blend were studied. Various formulations of Glimepiride Aloe barbadensis miller mucilage and Povidone were prepared. They found to have better satisfactory physicochemical properties with low SD values. The swelling behavior and release rate characteristics were studied. The dissolution study proved that the dried Aloe barbadensis miller mucilage and Povidone combination can be used as a matrix forming material for making Sustained release matrix[23]. Fenugreek Mucilage: Trigonella Foenum-graceum, commonly known as Fenugreek, is an herbaceous plant of the leguminous family. Physico-chemical properties: Fenugreek seeds contain a high percentage of mucilage (a natural gummy substance present in the coatings of many seeds). Although it does not dissolve in water, mucilage forms a viscous tacky mass when exposed to fluids. Like other mucilage- containing substances, fenugreek seeds swell up and become slick when they are exposed to fluids[24]. Extraction of Mucilage: The husk from the seeds is isolated by first reducing the size, and then separated by suspending the size reduced seeds in chloroform for some time and then decanting. Successive extraction with chloroform removes the oily portion which is then air dried[25]. A different extraction procedure is also reported to isolate the mucilage from the husk. The powdered seeds are extracted with hexane then boiled in ethanol. The treated powder is then soaked in water and mechanically stirred and filtered. Filtrate is then centrifuged, concentrated in vacuum and mixed with 96% ethanol. This is then stored in refrigerator for 4 hrs to precipitate the mucilage [26].

Powdered husk is extracted with hexane

Boiled in ethanol

Soaked in water and mechanically stirred and filtered

Filtrate is then centrifuged, concentrated in vacuum and

mixed with 96% ethanol

Stored in refrigerator for 4 hrs to precipitate the mucilage

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fig: Fenugreek seeds

Literature review: Ali N. et al, derived the mucilage from the seeds of fenugreek and investigated for use in matrix formulations containing propranolol hydrochloride. Methocel® K4M was used as a standard controlled release polymer for comparison purposes. A reduction in the release rate of propranolol hydrochloride was observed with increase in concentration of the mucilage in comparison to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug: mucilage ratio. Fenugreek mucilage at a concentration of about 66% w/w was found to be a better release retardant compared to hypomellose at equivalent content[26] Guar Gum: Guar gum comes from the endosperm of the seed of the legume plant Cyamopsis tetragonolobus. Physico-chemical properties: Chemically, guar gum is a polysaccharide composed of the sugars galactose and mannose. The backbone is a linear chain of 1, 4-linked mannose residues to which galactose residues are 1, 6-linked at every second mannose, forming short side- branches[27]. Guar gum is more soluble than locust bean gum and is a better emulsifier as it has more galactose branch points. It is insoluble in most hydrocarbon solvents. It degrades at extremes of pH and temperature (e.g. pH 3 at 50°C) [28]. Guar gum is prepared by first drying the pods in sunlight, then manually separating from the seeds. Gum remains stable in solution over pH range 5-7. Strong acids cause hydrolysis and loss of viscosity, and alkalies in strong concentration also tend to reduce viscosity. Extraction of gum: The gum is commercially extracted from the seeds essentially by a mechanical process of roasting, differential attrition, sieving and polishing. The seeds are broken and the germ is separated from the endosperm. Two halves of the endosperm are obtained from each seed and are known as Guar Splits. Refined guar splits are obtained when the fine layer of fibrous material, which forms the husk, is removed and separated from the endosperm halves by polishing. The refined Guar Splits are then treated and finished into powders by a variety of routes and processing techniques depending upon the end product desired [29].

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fig: Cyamopsis seeds

Applications: Guar gum is used and investigated as a thickener in cosmetics, sauces, as an agent in ice cream that prevents ice crystals from forming and as a fat substitute that adds the "mouth feel" of fat and binder or as disintegrator in tablets. Literature review: Sourabh Jain et al, fabricated Sustained release tablets of furosemide using pectin, guar gum and xanthan gum. The tablets were evaluated for physical characteristic like hardness, weight variation, fraibilty, and drug content. In-vitro release of drug was performed in PBS pH 7.2 for fifteen hours. All the physical characters of the fabricated tablet were within acceptable limits. The tablet with guar gum exhibited greater swelling index than those with pectin and xanthan gum. A better controlled drug release (80.74%) was obtained with the matrix tablet (G4) made-up of the guar gum than with the pectin and xanthan gum. It is cleared through the dissolution profile of furosemide from matrix tablets prepared using different natural polymers were retarded approx 15 hrs [30]. Besides being used as a matrix former for sustained release tablets Satyanarayana S. et al, investigated guar gum as a carrier for indomethacin for colon-specific drug delivery using in vitro methods Studies in pH 6.8 phosphate buffered saline (PBS) containing rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release. The pre-treatment of rats orally with 1 ml of 2% w/v aqueous dispersion of guar gum for 3 days induced enzymes specifically acting on guar gum thereby increasing drug release. A further increase in drug release was observed with rat caecal contents obtained after 7 days of pre-treatment. The presence of 4% w/v of caecal contents obtained after 3 days and 7 days of enzyme induction showed biphasic drug release curves. The results illustrate the usefulness of guar gum as a potential carrier for colon-specific drug delivery [31]. Amit S.Yadav et al, formulated the oral controlled release zidovudine matrix tablets by using Guar gum as rate controlling polymer and to evaluate drug release parameters as per various release kinetic models. The tablets were prepared by wet granulation method. Granules were prepared and evaluated for loose bulk density, tapped density, compressibility index and angle of repose, shows satisfactory results. All the granules were lubricated and compressed using 12.6 mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, in vitro release studies and swelling index. All the formulations showed compliance with Pharmacopoeial standards. The in vitro dissolution study was carried out for 12 hours using paddle (USP type II) method in phosphate buffer (pH 6.8) as dissolution media. Formulation F-1 failed to sustain release beyond 10 hours. Among all the formulation,

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F-2 shows 95.97% of drug release at the end of 12 hours. Selected formulation (F-2) was subjected to stability studies for 3 months, which showed stability with respect to release pattern. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release[32].

Swati Singh et al, formulated sustained release matrix tablets of phenytoin sodium. The tablets were fabricated by the wet granulation method using water as granulating agent along with matrix materials like guar gum, sodium alginate, tragacanth and xanthan gum with varying percentage. The granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to weight variation test, drug content, hardness, friability, and in vitro release studies. The swelling behavior of matrix was also investigated. The granules showed satisfactory flow properties, compressibility, and drug content. The I.R. spectral analysis studies confirmed no interaction between phenytoin with used natural gums. All the tablet formulations showed acceptable pharmacotechnical properties and complied with in‐house specifications for tested parameters. In the further formulation development process, F8 (55% guar gum with 10% acacia), the most successful formulation of the study, exhibited satisfactory drug release and could extend the release up to 12 hours. The mechanism of drug release from all the formulations was diffusion coupled with erosion[33,34].

Karaya Gum: Biological source: It is the dried gummy exudates obtained from the tree Sterculia urens Roxb. (Family ⎯ Sterculiaceae). It is also known as Sterculia, Karaya, Indian Tragacanth or Bassora Tragacanth gum. It is produced in India, Pakistan and to a small extent in Africa. Karaya also differs from tragacanth in that it contains no starch and stains pink with solution of ruthenium red. Physico-chemical properties: Gum is least soluble of commercial plant exudates, but it absorbs water rapidly and swells to form viscous colloidal solutions even at low concentrations (1%). Swelling behavior of karaya gum is dependent upon the presence of acetyl groups in its structure. The gum is glycanorhamno galacturonan type having a central backbone with a basic unit consisting of alternating α-D-galacturonic acid linked through the C-4 position and α -L-rhamnose linked through the C-2 position. The chain is substituted on the galacturonic acid hydroxyl groups in C-2 or C-3 and on some of the rhamnose hydroxyl groups in C-4 by D-galactose and D-glucuronic acid (Karaya gum consist of an acetylated, branched heteropolysaccharide with a high component of D-galacturonic acid and D-glucuronic acid residues). Applications: The granular grades are used as a bulk laxative, being only next to psyllium seed in use for this purpose. The powdered gum is used in lozenges, pastes and dental fixative powders and it has proved particularly useful as an adhesive for stoma appliances. It also acts as stimulant. It is available with frangula, as granules. The cross linked Tragacanth (Epichlorhydrin) exhibits superior wicking and swelling action and hence can be used as a potential disintegrant[35,36].

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fig: Karaya gum Literature review: Raghavendra raon G. et al, developed a sustained release matrix tablets of water soluble Tramadol hydrochloride using different polymers viz. Hydroxy propyl methyl cellulose (HPMC) and natural gums like Karaya gum (KG) and Carrageenan (CG). Varying ratios of drug and polymer like 1:1 and 1:2 were selected for the study. After fixing the ratio of drug and polymer for control the release of drug up to desired time, the release rates were modulated by combination of two different rates controlling material and triple mixture of three different rate controlling material. After evaluation of physical properties of tablet, the in vitro release study was performed in 0.1N HCl pH 1.2 for 2 hrs and in phosphate buffer pH 6.8 up to 12 hrs. The effect of polymer concentration and polymer blend concentration were studied. Different ratios like 80:20, 60:40, 50:50, 40:60 and 20:80 were taken. Dissolution data was analyzed by Korsmeyer-Peppas power law expression and modified power law expression. It was observed that matrix tablets contained polymer blend of HPMC/CG were successfully sustained the release of drug upto 12 hrs. Among all the formulations, formulation F16 which contains 20% HPMC K15M and 80% of CG release the drug which follow Zero order kinetics via, swelling, diffusion and erosion and the release profile of formulation F16 was comparable with the marketed product. Stability studies (40±2ºC/75±5%RH) for 3 months indicated that Tramadol hydrochloride was stable in the matrix tablets. The DSC and FTIR study revealed that there was no chemical interaction between drug and excipients [37]. Hakea Gum: Biological source: Hakea gum a dried 4249 exudates from the plant Hakea gibbosa family Proteaceae. Physico-chemical properties: Gum exudates from species have been shown to consist of L-arabinose and D-galactose linked as in gums that are acidic arabinogalactans (type A). Molar proportions (%) of sugar constituents Glucuronic acid, Galactose, Arabinose, Mannose, Xylose is 12:43:32:5:8. The exuded gum is only partly soluble in water. Applications: Hakea gibbosa (Hakea) was investigated as a sustained release and mucoadhesive component in buccal tablets[38].

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fig: Hakea Gibbosa plant

Literature review: Alur H.H. et al, formulated tablet with drug chlorpheniramine maleate (CPM) with either sodium bicarbonate or tartaric acid in a 1:1.5 molar ratio and different amount of Hakea were using a direct compression technique and were coated with hydrogenated castor oil (Cutina) on all but one face. The resulting plasma CPM concentration versus time profiles was determined following buccal application of the tablets in rabbits. The force of detachment for the mucoadhesive buccal tablets increased as the amount of Hakea gum was increased following application to excised intestinal mucosa. Addition of sodium bicarbonate or tartaric acid, as well as higher amounts of CPM, did not affect the mucoadhesive bond strength. These results demonstrate that the novel, natural gum, H. gibbosa, may not only be used to sustain the release but can also act as bioadhesive polymer[39]. Tamarind Gum: Tamarind xyloglucan is obtained from the endosperm of the seed of the tamarind tree, Tamarindus indica, a member of the evergreen family[40].

Physico-chemical properties: Tamarind Gum, also known as Tamarind Kernel Powder (TKP) is extracted from the seeds. The seeds are processed in to gum by seed selection, seed coat removal, separation, hammer milling, grinding and sieving. Tamarindgum is a polysaccharide composed of glucosyl : xylosyl : galactosyl in the ratio of 3:2:1. Xyloglucan is a major structural polysaccharide in the primary cell walls of higher plants. Tamarind xyloglucan has a (1 4)-!-D-glucan backbone that is partially substituted at the O-6 position of its glucopyranosyl residues with "-D-xylopyranose[41]. Some of the xylose residues are !-D-galactosylated at O-2. It is insoluble in organic solvents and dispersible in hot water to form a highly viscous gel such as a mucilaginous solution with a broad pH tolerance and adhesivety[42].

fig: Tamarind seeds

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Applications: Tamarind gum is non Newtonian and yield higher viscosities than most starches at equivalent concentrations.This has led to its application as stabilizer, thickener, gelling agent and binder in food and pharmaceutical industries. In addition to these, other important properties of tamarind seed polysaccharide (TSP) have been identified recently[43]. They include noncarcinogenicity, mucoadhesivity, biocompatibility, high drug holding capacity and high thermal stability. This has led to its application as excipient in hydrophilic drug delivery system[44].

Literature review: Rao P.S. et al, studied Magnetic microspheres of tamarind gum and chitosan. The magnetic microspheres were prepared by suspension cross-linking technique. Microspheres formed were in the size range of 230 - 460 μm.The magnetic material used in the preparation of the microspheres was prepared by precipitation from FeCl and FeSO solution basic medium[44].

R.Deveswaran et al, isolated the tamarind seed polysaccharide (TSP) from tamarind kernel powder and this polysaccharide was utilized in the formulation of matrix tablets containing Diclofenac Sodium by wet granulation technique and evaluated for its drug release characteristics. Hardness of the tablets was found to be in the range of 4.0-6.0 kg/cm2. The swelling index increased with the increase in concentration of TSP. Increase in polymer content resulted in a decrease in drug release from the tablets. The tablets showed 96.5-99.1% of the labeled amount of drug, indicating uniformity in drug content. The drug release was extended over a period of 12h. The release of the formulations matched with the marketed sustained release tablets with a similarity factor of 83.52. The in-vitro release data of the formulations followed zero order kinetics [45,46]. Okra Gum: Okra gum, obtained from the fruits of Hibiscus esculentus, is a polysaccharide consisting of D-galactose, L-rhamnose and L-galacturonic acid [47]. Okra gum is used as a binder. Extraction of gum/mucilage: Okra fruits were purchased from a local market; a variety of okra used by the Ewe tribe and noted for its sliminess was chosen. The seeds do not contain any mucilage and were removed prior to extraction. The okra was sliced, homogenised with five times its weight of water, centrifuged at 4000 rpm for 15 min and the clear, viscous solution decanted. The solution was heated at 70°C for 5 min to inactivate enzymes, and recentrifuged. The mucilage was precipitated with three volumes of ethanol and washed with more ethanol followed by acetone. The cream coloured solid was dried under vacuum (less than 1 Torr at 25°C for 12 h) and gave a yield of 16 g mucilage/kg okra.

fig: Okra fruit

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Literature review: Emeje M.O. et al, evaluated okra gum as a binder in paracetamol tablet formulations[48]. These formulations containing okra gum as a binder showed a faster onset and higher amount of plastic deformation than those containing gelatin. The crushing strength and disintegration times of the tablets increased with increased binder concentration while their friability decreased. Although gelatin produced tablets with higher crushing strength, okra gum produced tablets with longer disintegration times than those containing gelatin. In a study this was finally concluded from the results that okra gum maybe a useful hydrophilic matrixing agent in sustained drug delivery devices. Kalu V.D. et al, evaluated Okra gum as a controlled release agent in modified release matrices, in comparison with sodium carboxymethyl cellulose (NaCMC) and hydroxypropylmethyl cellulose (HPMC), using paracetamol as a model drug. Okra gum matrices provided controlled release of paracetamol for more than 6 h and the release rates followed time-independent kinetics. The release rates were dependent on the concentration of the drug present in the matrix. Okra gum compared favourably with NaCMC, and a combination of Okra gum and NaCMC, or on further addition of HPMC resulted in near zero order release of paracetamol from the matrix tablet. The results indicate that Okra gum matrices could be useful in the formulation of sustained release tablets for up to 6 h[49].

Edukondalu V. et al, optimized and evaluated the floating tablets of atenolol that prolongs the gastric residence time. Semi-synthetic polymer, HPMC K100M and natural polymer i.e. okra gum were used as release retarding agents by its swelling nature. Sodium bicarbonate was used as a gas-generating agent, Atenolol tablets were prepared by direct compression method. The prepared tablets were evaluated for physicochemical parameters and found to be within range viz. hardness, swelling index, floating capacity, thickness, and weight variation. Further, tablets were evaluated for in vitro release characteristics for 8 hrs. The concentration of okra gum with a gas-generating agent was optimized to get the sustained release of atenolol for 8hrs, drug release from all the formulations followed first order kinetics and higuchi’s mechanism. The optimized (F6) formulation has better release rate. Based on the diffusion exponent (n) value, the drug release was found to be diffusion controlled [50]. Lango K.B. et al, developed the Colon targeted tablet formulation using okra polysaccharide (Abelmuschus esculentus) as a microbially triggered material and also as the carrier. Okra polysaccharide was isolated from Abelmuschus esculentus and used for tablet formulation with Ibuprofen as model drug. The matrix tablets with four different proportions of the okra (20%, 30%, 40% & 50%) with 1% ethyl cellulose in all the four formulations and the formulations were coded as WO1, WO2, WO3, & WO4. In all the formulations constant 100 mg Ibuprofen were incorporated. The formulations were evaluated for their hardness, weight variation, friability, and drug content and were characterized by FTIR. Matrix tablets were subjected to in vitro drug release studies. The release studies were carried out for 2 hours in pH 1.2, 3 hours in pH 7.4 phosphate buffer and for 10 hours in pH 6.8 PBS. The % Release of these formulations i.e. WO1, WO2, WO3 & WO4 were found to be 20.75, 18.48, 13.37 & 11.99 respectively at 5th hour. The fifth matrix tablet (WO5) with 10% ethyl cellulose, 40% okra polysaccharide and 100 mg ibuprofen was formulated. The % cumulative release of this formulation (WO5) was found to be 4.59 at 5th hour. Among the above, WO3 was chosen as the optimized formulation for further studies. The in vitro dissolution studies were carried out with pH 1.2, pH 7.4 and the study continued in pH 6.8 PBS with rat cecal matter at 6th

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hour in simulated colonic fluid in order to mimic conditions from mouth to colon. The post five hour studies were carried out without rat cecal also as a control. The observation made was that the maximum release was 98.09% at 10th hour with rat cecal matter and a mere 32.70 % and 46.98% without rat cecal matter at 8th and 10th hour respectively. These findings were confirmed by in vivo investigation using X-ray images of rabbits ingested with okra matrix tablets (WO5) containing barium sulphate as contrast medium instead of Ibuprofen. The tablet began to disintegrate at 8th hour of tablet ingestion. These observations drive us to conclude that the okra polysaccharide under investigation has the potential to carry the drug almost intact to the intended site i.e. Colon where it undergoes degradation due to the presence of anaerobic microbes there. Thereby both the aims contemplated are achieved[51]. DhanaLakshmi B. et al, prepared and evaluated aceclofenac sustained release matrix tablets using various proportions of natural polymer Abelmoschus esculentus mucilage powder (i.e., Drug : Polymer ratio – 1:0.2, 1:0.4, 1:0.6, 1:0.8, 1:1) as release controlling factor by wet granulation method. To study the influence of different proportions of polymer on in-vitro drug release characteristics of dosage form was evaluated in 6.8 PH phosphate buffer for 12 hours. Also friability, weight variation, hardness, disintegration drug time, content uniformity was studied according to Indian Pharmacopeia. All the formulations showed good fit in zero order kinetics along with diffusion mechanisms. In vitro release showed that formulation F3 containing D: P ratio – 1:0.6 gave prolonged release for 12 hours. Analysis of drug release rate from matrix system indicated drug was release by supercase-II transport mechanism[52]. Rosin [53,54,55]: Rosin is a solid resinous material popular for its sustained release action, obtained naturally from pine trees. The principle commercial sources of rosin are Pinus Soxburghi, Pinus Longifolium and Pinus Todea. Rosin is composed of 90% of rosin acids (abietic acid& pimaric acid) and 10% non- acidic materials. The rosin acids are monocarboxilic and have a typical molecular formula C20H30O2. The prominent ones include abietic with conjugated double bonds. For modification the rosin acid molecules provide two chemically reactive centres: the double bonds and the carboxyl group. Being of natural origin, rosin and its derivatives are biocompatible and biodegradable.

Rosin derivatives and salts are polymeric biomaterials and have also been extensively evaluated for their pharmaceutical applications as coating and microencapsulating materials. Derivatives of abietic acid, principle constituent of rosin have been used for sustained release systems.

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Types of Rosin:

The major form of rosin is known as gum rosin. Gum rosin is available in large or small clumps, flakes and powder.

Other types are mainly modified rosin and rosin compound.

Gum rosin. Maliated Rosin. PEGylated Rosin. Highly hydrogenated rosin. Partially hydrogenated rosin. Glycerol ester of hydrogenated rosin. Rosin-modified Pentaerythritol ester. Non- crystalline rosin. Polymerized rosin. Disproportionated Rosin. Rosin modified Phenolic resin. Methanol ester of Gum Rosin. Methanol ester of Hydogenated Rosin.

Properties: -

1. It is typically a glassy solid, though some rosin will form crystals, especially when brought into solution. 2. The practical melting point varies with different specimens, some being semi-fluid at the temperature of boiling water, others melting at 100°C to 120°C. 3. It is very flammable, burning with a smoky flame, so care should be taken when melting it. 4. It is soluble in alcohol, ether, benzene and chloroform while insoluble in water. 5. Viscosity of rosin is very good but is less cohesive.

GGrraaddeess ooff RRoossiinn::

Grades X WW WG N M K

Color slight yellow

Light yellow Yellow Deep

yellow yellow brown

yellow red

Appearance Transparent

Softening Point (R. & B.)

76 ℃ min 75℃ min 74℃ min

Acid Value mg KOH/g

166 min 165 min 164 min

Unsaponifiable Matter

5℅ max 5℅ max 5℅ max

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TTaabbllee:: GGrraaddeess ooff RRoossiinn

UUsseess::

1. Rosin and its derivatives are used in- As microencapsulating agent. 2. Nowadays rosin is used for film forming and coating purpose due to its sustained release properties. 3. Rosin is also used as hydrophobic matrix material in sustain drug delivery. 4. As an anhydrous binder in tablet formulations. 5. As an emulsifying agent in liquid preparation of lotion. 6. Rosin is also used for enteric coatings, transdermal patches, and other sustained release formulations.

AAddvvaannttaaggeess ooff RRoossiinn PPoollyymmeerr::

1. Rosin is naturally occurring. 2. Present in abundant amount. 3. Its derivatives are expected to be eco-friendly and biocompatible. 4. Complexity of structure, so chemical modification is more elaborate. 5. Having a good film forming ability, used in preparation of sustained release and controlled release dosage form. LLiitteerraattuurree rreevviieeww::

Rosin in Microparticulate System: Morkhade D.M. et al, (2007) prepared PEGylated Rosin Derivatives as a Novel Microencapsulating Materials for Sustained Drug Delivery. Ester derivatives of rosin were synthesized by reacting rosin with PEG 400 & maleic anhydride(MA) at higher temperature. Reddy M.N. et al, (2000) prepared Microcapsules of diltiazem hydrochloride with rosin by an emulsion-solvent-evaporation technique. Different amounts of drugs were added in order to obtain various drug to polymer ratios. The physical properties, loading efficiency and release rate depended on the durg to polymer ratio. Nande V. S. et al, (2006) evaluate PEGylated Rosin Derivatives as a Novel Microencapsulating Materials for Sustained Drug Delivery. Ester derivatives of rosin were synthesized by reacting rosin with PEG 200 & maleic anhydride(MA) at higher temperature. Puranik P.K. et al, (1992) prepared Abietic acid-sorbitol derivatives and evaluated for their physicochemical properties and as material for microencapsulation by pan coating technique, using salicylic acid as a model drug. The coated microcapsules were evaluated for moisture absorption, flow properties, friability & release

Insoluble Matter in Alcohol

0.03℅ max 0.03℅ max 0.04℅ max

Ash 0.02℅ max 0.03℅ max 0.04℅ max

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characteristics. The result showed that the materials having lower acid values posses moisture protection properties and also prolong the release of the drug. Rosin as Matrix forming material: Satturwar P.M., et al, (2002) prepared Matrix tablets of diclofenac by wet granulation method using R-1 as matrix forming material in different proportions and combinations. The results suggest that the new rosin derivative R-1 is useful in developing sustained release matrix tablets; with drug release being prolonged for up to 10 h. Shirwaikar A.A. et al, (2005) used Rosin, a natural resin, was used as an insoluble matrix forming material for studying the release of sustained release tablet diltiazem HCI. The method of preparation of matrix system and its concentration were found to have a pronounced effect on the release of diltiazem HCI. Gellan Gum: (Microbial Polysaccharide) Deacylated Gellan gum (Gellan) is an anionic microbial polysaccharide, secreted from Sphingomonas elodea, consisting of repeating tetrasaccharide units of glucose, glucuronic acid and rhamnose residues in a 2:1:1 ratio: [→3)–β–D–glucose–(1→4)– β–D–glucuronic acid–(1→4)– β–D–glucose–(1→4)– –L–rhamnose– (1→]. In the native polymer two acyl substituents, L-glyceryl at O(2) and acetyl at O(6), are present on the 3-linked glucose. On average, there is one glyceryl per repeating unit and one acetyl for every two repeating units. Deacylated Gellan gum is obtained by alkali treatment of the native polysaccharide. Both native and deacylated Gellan gum are capable of physical gelation [56].

Physicochemical properties: Gelling Properties of Gellan Gum: Gelation of gellan solutions occurs abruptly upon heating and cooling of gellan gum solutions in the presence of cations. Such sol-gel transitions are considered as phase transition. The gelation of gellan gum is a function of polymer concentration, temperature, and presence of monovalent and divalent cations in solution. At low temperature gellan forms an ordered helix of double strands, while at high temperature a single-stranded polysaccharide occurs, which significantly reduces the viscosity of the solution. The transition temperature is approximately 350C, but can range from 30-500C. Below transition temperature, a stiff structure is obtained (setting point), and results in gel formation. The mechanism of gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water [57].

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Acetyl content: Acetyl content is the most important factor affecting the gel strength. Gellan gum with different acetyl content gives gels with different properties. Native gellan gum provides soft, elastic, thermoreversible gels, and is very weak because of bulky acetyl and glyceryl groups that prevent close association between gellan polymer chains in bulk-helix formation, and hinder compact packing of the cross-linked double helix. Deacetylated gellan gum forms firm, brittle and thermoreversible gel because of the absence of acetyl and glyceryl groups [58].

Type and concentration of ions: Ions have an impact on gel strength and brittleness. Gellan does not form gel in deionised water, but the addition of salts of calcium, potassium, sodium, and magnesium causes an increase in these two properties. Notably, divalent cations are more effective in achieving this; even in gellan gels of very low concentration (0.2%, by mass per volume), a high strength was achieved with a maximum at about 0.004% (by mass per volume) calcium and 0.005% (by mass per volume) magnesium [59]

Gel pH: Sanderson and Clark showed the gel strength to be enhanced within pH range of 3.5 to 8, which corresponds to the natural pH range of most foods. Change in pH does not alter the setting point of the gel, but affects melting temperature in some cases. For example, gels prepared with very low levels of monovalent ions melt at around 700C at neutral pH, but at pH=3.5 the melting temperature is slightly increased. This trend is not seen for divalent ions [60].

Presence of hydrophilic ingredients: Addition of hydrophilic ingredients like sucrose (at about 10%, by mass per volume) tends to decrease the ion concentration required for optimal gellan gel strength. Kasapis et al. used transmission electron microscopy to examine the changing nature of a polysaccharide network with increasing levels of sugar. Mixtures of deacylated gellan (<1%) with low (0-20%) and high (80-85%) levels of sugar were prepared and studied. Micrographs of the high sugar / gellan gels produced clear evidence of reduced cross linking in the polysaccharide network, which exhibits a transition from rubber to glass-like consistency upon cooling [61].

Applications: 1. Gellan gum has been used in pharmaceutical dosage forms as a swelling agent, as a tablet binder, and as a rheology modifier [62].

2. The physical gelation properties make this polysaccharide suitable as a structuring and gelling agent in food industries. Gellan is also exploited in the field of modified release of bioactive molecules. Aqueous solutions of Gellan are used as in situ gelling systems, mainly for ophthalmic preparation and for oral drug delivery [63].

3. Physical Gellan hydrogels, prepared with mono or divalent cations, are used also for the preparation of tablets, beads or microspheres [64].. Interpenetrating polymer networks [65] or co-cross linked polymer networks[66] based on Gellan and other polysaccharide systems have also been developed as drug delivery matrices.

Conclusion:

The research into and use of excipients from natural sources was reviewed and were discussed according to their classes. Natural polymeric excipients and their modifications have continued to dominate the research

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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.

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RESEARCH NATURAL POLYMERS USED IN … in the design of novel drug delivery systems such as those that target delivery of the drug to a specific region in the gastrointestinal tract