Jurnal International amilum

Vol. 3 (4) Oct – Dec 2012 www.ijrpbsonline.com 1597

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

____________________________________________Review Article

Natural Polymers – A Comprehensive Review

Kulkarni Vishakha S*, Butte Kishor D and Rathod Sudha S.

Oriental College of Pharmacy, Sanpada, Navi Mumbai , Maharashtra, India. _____________________________________________________________________________________ ABSTRACT Any pharmaceutical formulation contains two ingredients one is the active ingredient and other is an excipients. An excipients help in the manufacturing of dosage form and it also improves physicochemical parameters of the dosage form. Polymers play an important role as excipients in any dosage form. They influence drug release and should be compatible, non-toxic, stable, economic etc. They are broadly classified as natural polymers and synthetic polymers. They have wide range of applications so selection of polymer is the main step in designing any dosage form. Nowadays, due to many problems associated with drug release and side effects manufacturers are inclined towards using natural polymers. Natural polymers are basically polysaccharides so they are biocompatible and without any side effects. This review discusses various natural polymers, their advantages over synthetic polymers and role of natural polymers in designing novel drug delivery systems. Keywords: Agar, Cellulose, Chitin, Locust bean gum, Starch. INTRODUCTION A polymer is a large molecule (macromolecules) composed of repeating structural units. These subunits are typically connected by covalent chemical bonds. Both synthetic and natural polymers are available but the use of natural polymers for pharmaceutical applications is attractive because they are economical, readily available and non-toxic. They are capable of chemical modifications, potentially biodegradable and with few exceptions, also biocompatible.1 Substances of plant origin pose several potential challenges such as being synthesized in small quantities and in mixtures that are structurally complex, which may differ according to the location of the plants as well as other variables such as the season. This may result in a slow and expensive isolation and purification process. Another issue that has become increasingly important is that of intellectual property rights.2, 3 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.4-6 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.7

NEED OF HERBAL POLYMERS 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 material.

4. Safe and devoid of side effects – They are from a natural source and hence, safe and without side effects.

5. Easy availability – In many countries, they are produced due to their application in many industries. 8

DISADVANTAGES OF HERBAL POLYMERS

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. 8

4. Slow Process – As the production rate is 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. 9

CLASSIFICATION OF NATURAL POLYMERS

1. Plant origin - Cellulose, Hemicellulose, Glucomannan, Agar, Starch, Pectin, Inulin, Rosin, Guar gum, Locust bean Gum, Gum Acacia, Karaya gum, Gum Tragacanth, Aloe Vera gel.

2. Animal origin - Chitin, Alginates, Carageenans, Psyllium, Xanthum gum.

NATURAL POLYMERS FROM PLANT ORIGIN Cellulose Cellulose was discovered in 1838 by the French chemist Anselme Payen, who isolated it from plant matter and determined its chemical formula. Cellulose is an organic polysaccharide with the formula (C6H10O5)n, consisting of a linear chain of several hundred to over ten thousand β(1→4) linked D-glucose units.10

The polysaccharides of the plant cell wall consist mainly of cellulose, hemicelluloses and pectin.11 Cellulose is an essential structural component of cell walls in higher plants and is the most abundant organic polymer on earth. Many parallel cellulose molecules form crystalline microfibrils that are mechanically strong and highly resistant to enzymatic attack. These are aligned with each other to provide structure to the cell wall. Cellulose is insoluble in water and indigestible by the human body.12, 13

Fig. 1: Cellulose derivatives

Microcrystalline cellulose is mainly used in the pharmaceutical industry as a diluent/binder in tablets for both the granulation and direct compression processes.14

Controlled release applications for cellulose derivatives include the formulation of membrane

controlled drug release systems or monolithic matrix systems. Film coating techniques for the manufacture of membrane controlled release systems include enteric coated dosage forms and the use of semi-permeable membranes in osmotic pump delivery systems.



Hydroxypropylmethylcellulose is a partly O-methylated and O-(2-hydroxypropylated) cellulose ether derivative that has been extensively investigated as an excipient in controlled release drug delivery systems due to its gel forming ability. In a study where two cellulose ethers; hydroxypropylmethylcellulose and carboxymethylcellulose were employed as polymeric carrier materials in matrix tablets for controlling the release of a soluble drug, diltiazem, it was found that each polymer on its own could sustain drug release over an extended period of time in these systems.

More importantly, a mixture of the two cellulose ethers in the matrix type tablets enabled zero order drug release kinetics at both pH 4.5 and 6.8.15 Hydroxypropylmethylcellulose monolithic matrix systems showed similar dissolution profiles as a commercial osmotic pump system for glipizide, a drug with low solubility. It was further found that the hydroxypropylmethylcellulose matrix systems have a stronger gel structure than those made of polyethylene oxide, which may provide superior in vivo performance in terms of matrix resistance to the destructive forces within the gastrointestinal tract.16

Fig. 2: Structure of Cellulose

Hemicellulose A hemicellulose is a heteropolymer (matrix polysaccharides), such as arabinoxylans, present along with cellulose in almost all plant cell walls. While cellulose is crystalline, strong, and resistant to hydrolysis, hemicellulose has a random, amorphous structure with little strength. Unlike cellulose, hemicellulose (also a polysaccharide) consists of shorter chains - 500-3,000 sugar units. In addition, hemicellulose is a branched

polymer, while cellulose is unbranched. Hemicellulose polysaccharides consist of xyloglucans, xylans and mannans that can be extracted from the plant cell wall with a strong alkali. They have backbones made up of β-1,4-linked D-glycans. Xyloglucan has a similar backbone as cellulose, but contains xylose branches on 3 out of every 4 glucose monomers. The β-1,4-linked D-Xylan backbone of arabinoxylan contains arabinose branches.12, 13

Fig. 3: Structure of Hemicellulose



Glucomannan Glucomannan is a hydrocolloidal polysaccharide of the mannan family consisting of β-1,4 linked D-mannose and D-glucose monomers (with acetyl side branches on some of the backbone units), but the mannose:glucose ratio may differ depending on the source. The acetyl groups contribute to its solubility and swelling capacity and assist in making it a soluble natural polysaccharide with the highest viscosity and water-holding capacity. It is very abundant in Nature and this polysaccharide is specifically derived from softwoods, roots, tubers and plant bulbs. The most commonly used type of Glucomannan is referred to as konjac Glucomannan, which is extracted from the tubers of Amorphophallus konjac and is a very promising polysaccharide for incorporation into drug delivery systems. Since konjac Glucomannan by itself forms very weak gels, it has been investigated as an effective exponent in controlled release drug delivery devices in combination with other polymers or by modifying its chemical structure.17, 18 It was shown that konjac Glucomannan gel systems were able to maintain the integrity and control the

release of theophylline and diltiazem for 8 hours. This was, however, dependent on the country of origin (i.e. Japan, Europe or America) due to differences in the degree of acetylation of the konjac Glucomannan.18 Matrix tablets prepared from konjac glucomannan alone showed the ability to sustain the release of cimetidine in the physiological environments of the stomach and small intestines but the presence of β-mannanase (colon) accelerated the drug release substantially. Mixtures of konjac Glucomannan and xanthan gum in matrix type tablets showed high potential to sustain and control the release of the drug due to stabilization of the gel phase of the tablets by a network of intermolecular hydrogen bonds between the two polymers to effectively retard drug diffusion.19 Konjac Glucomannan was used to form hydrophilic cylinders and particles for controlled release of DNA.20 Konjac Glucomannan cross-linked with trisodium trimetaphosphate formed hydrogel systems that could sustain hydrocortisone release dependent on cross-linking density and enzymatic degradation.21

Fig. 4: Structure of Glucomannan

Agar Agar or agar-agar is the dried gelatinous substance obtained from Gelidium amansii (Gelidaceae) and several other species of red algae like, grailaria (Gracilariaceae) and Pterocladia (Gelidaceae).22 Agar consists of a mixture of agarose and agaropectin. The predominant component, agarose, is a linear polymer, made up of the repeating monomeric unit of agarobiose. Agarobiose is a disaccharide made up of D-galactose and 3,6-anhydro-L-galactopyranose. Agaropectin is a heterogeneous mixture of smaller acidic molecules that gel poorly. Its great gelling power in an aqueous environment allows it to form gels which are more resistant (stronger) than those of any other gel-forming agent, assuming the use of equal concentrations. It can be used over a wide range of pH, from 5 to 8, and in some cases beyond these limits. It withstands thermal treatments very well, even above 100°C which allows good sterilization. A 1.5% aqueous solution gels between 32°C-43°C and

does not melt below 85°C. This is a unique property of agar, compared to other gelling agents. Agar gives gels without flavour and does not need the additions of cations with strong flavours (potassium or calcium) it can be used without problems to gel food products with soft flavours. Its gel has an excellent reversibility allowing it to be repeatedly gelled and melted without losing any of the original properties. Agar is used as Suspending agent, emulsifying agent, gelling agent in suppositories, surgical lubricant, tablet disintegrants, medium for bacterial culture, laxative.

Fig. 5: Structure of Agar



Starches Starch or amylum is a carbohydrate consisting of a large number of glucose units joined together by glycosidic bonds. This polysaccharide is produced by all green plants as an energy store. It is the principal form of carbohydrate reserve in green plants and especially present in seeds and underground organs. Starch occurs in the form of granules (starch grains). A number of starches are recognized for

pharmaceutical use. These include maize (Zea mays), rice (Oryza sativa), wheat (Triticum aestivum), and potato (Solanum tuberosum).23 It is comprised of two polymers, namely amylose (a non-branching helical polymer consisting of α-1, 4 linked D-glucose monomers) and amylopectin (a highly branched polymer consisting of both α-1,4 and α-1,6 linked D-glucose monomers).

Fig. 6: Structure of a) Amylose b) Amylopectin

Modified Starch It was tested for general applicability of a new pregelatinized starch product in directly compressible controlled-release matrix systems. It was prepared by enzymatic degradation of potato starch followed by precipitation (retrogradation), filtration and washing with ethanol. The advantages of the material include ease of tablet preparation, the potential of a constant

release rate (zero-order) for an extended period of time and its ability to incorporate high percentages of drugs with different physicochemical properties. Release rates from retrograded pregelatinized starch tablets can be enhanced or decreased to the desired profile by different parameters like geometries of the tablet, compaction force and the incorporation of additional excipients.24

Fig. 7: Structure of Modified Starch



Native Starch It may not be suitable in controlled release drug delivery systems due to substantial swelling and rapid enzymatic degradation resulting in too fast release of many drugs. This has led to the use of derivatives of starch that are more resistant to enzymatic degradation as well as crosslinking and formation of co-polymers. Starch acetate prepared by acetyl esterification has shown retarded enzymatic degradation with the potential to be used as a colon-targeted drug delivery carrier. 25 High amylase carboxymethyl starch produced by spray drying showed a high loading capacity for the soluble drug, acetaminophen, in controlled release direct compressible matrix systems. 26 To deliver proteins or peptide drugs orally, microcapsules containing a protein and a proteinase inhibitor were prepared. Starch/bovine serum albumin mixed-walled microcapsules were prepared using interfacial cross-linking with terephthaloyl chloride. The microcapsules were loaded with native or amino-protected aprotinin by incorporating protease inhibitors in the aqueous phase during the cross-linking process. The protective effect of microcapsules with aprotinin for bovine serum albumin was revealed in vitro. 27

Pectin Pectin is the purified carbohydrate product obtained by acid hydrolysis from the inner portion of the rind of citrus peels i.e. Citrus Simon or Citrus Aurantium, (Rutaceae). The main component of pectin is a linear polysaccharide composed of α-1,4-linked D-galacturonic acid residues interrupted by 1,2- linked L-rhamnose residues with a few hundred to about one thousand building blocks per molecule, corresponding to an average molecular weight of about 50,000 to about 1,80,000. 28 The galacturonic acid polysaccharides are rich in neutral sugars such as rhamnose, arabinose, galactose, xylose and glucose. The composition of pectin can vary based on the botanical source, for example pectin from citrus contains less neutral sugars and has a smaller molecular size as compared to pectin obtained from apples. 29, 30 Pectin has been investigated as an excipient in many different types of dosage forms such as film coating of colon-specific drug delivery systems when mixed with ethyl cellulose, microparticulate delivery systems for ophthalmic preparations and matrix type transdermal patches. It has high potential as a hydrophilic polymeric material for controlled release matrix drug delivery systems, but its aqueous solubility contributes to the premature and fast release of the drug from these matrices.9

It was investigated that the suitability of amidated pectin as a matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. The results suggest that the pectin-chloroquine patch matrix preparation has potential applications for the transdermal delivery of chloroquine and perhaps in the management of malaria. 31 Calcium pectinate nanoparticles to deliver insulin were prepared as a potential colonic delivery system by ionotropic gelation.32 Micro particulate polymeric delivery systems have been suggested as a possible approach to improve the low bioavailability characteristics shown by standard ophthalmic vehicles (collyria). In this context pectin microspheres of piroxicam were prepared by the spray drying technique. In vivo tests in rabbits with dispersions of piroxicam-loaded microspheres also indicated a significant improvement of piroxicam bioavailability in the aqueous humour (2.5-fold) when compared with commercial piroxicam eye drops.33 Depending on the type and structure of the pectin molecule, pectins can gel in various ways. Gelling can be induced by acid or cross-linking with calcium ion or by reaction with alginate. When a pectin solution is titrated with acid, the ionization of carboxylate groups on pectins is repressed causing pectin molecules to no longer repel each other over their entire chains. The pectins can thus associate over a portion of their chains to form acid-pectin gels. Gel forming systems have been investigated widely for sustained drug delivery. A mixture of xyloglucan with pectin resulted in an in situ gel forming system with sustained paracetamol drug delivery in rats.34, 35 In relation to cosmetics, using citronella as a model compound, pectin gel formulations were evaluated for controlled fragrance release by kinetic and static methods. These formulations showed a prolonged duration of fragrance release and limitation of fragrance adsorption to the receptor skin layers. The increase in pectin concentrations suppressed the fragrance release by a diffusion mechanism, thereby proving that pectin/calcium microparticles are promising materials for controlled fragrance release.36 In relation to the food industry, folic acid incorporated microcapsules were prepared using alginate and combinations of alginate and pectin polymers so as to improve stability of folic acid. Folic acid stability was evaluated with reference to encapsulation efficiency, gelling and hardening of capsules, capsular retention during drying and storage. The blended alginate and pectin polymer matrix increased the folic acid encapsulation efficiency and reduced leakage from the capsules as



compared to those made with alginate alone, they showed higher folic acid retention after freeze drying and storage.37

Fig. 8: Structure of Pectin

Inulin It is a polysaccharide from the bulbs of Dehlia, Inula Helenium (Compositae), roots of Dendelion, Taraxacum officinale (Compositae). Burdock root, Saussurea lappa (Compositae) or chicory roots, Cichonium intybus (Compositae).22 Inulin consists of a mixture of oligomers and polymers that belong to the group of gluco-fructans and occur in plants such as garlic, onion, artichoke and chicory. The inulin molecules contain from two to more than 60 fructose molecules linked by β-2,1- bonds. Inulin is resistant to digestion in the upper gastrointestinal tract, but is degraded by colonic microflora.38, 39 Inulin with a high degree of polymerization was used to prepare biodegradable colon-specific films in combination with Eudragit® RS that could withstand break down by the gastric and intestinal fluids. 38 It was shown in another study where different Eudragits® were formulated into films with inulin that when a combination of Eudragit® RS and Eudragit® RL was mixed with inulin it exhibited better swelling and permeation properties in colonic medium rather than other gastrointestinal media.40 Methylated inulin hydrogels were developed as colon-specific drug delivery systems and investigated for water uptake and swelling. The hydrogels exhibited a relatively high rate of water uptake and anomalous dynamic swelling behaviour.39 Inulin derivatised with methacrylic anhydride and succinic anhydride produced a pH sensitive hydrogel by UV irradiation that exhibited a reduced swelling and low chemical degradation in acidic medium, but it had a good swelling and degradation in simulated intestinal fluid in the presence of its specific enzyme, inulinase.41

Fig. 9: Structure of Inulin

Rosin Rosin, also called colophony or Greek pitch (Pix græca), is a solid form of resin obtained from pines and some other plants, mostly conifers, produced by heating fresh liquid resin to vaporize the volatile liquid terpene components. Rosin is a natural polymer with a low molecular weight of 400 Da obtained from the oleoresin of pine trees, with the principle sources being Pinus soxburghui, Pinus longifolium and Pinus toed a. Rosin is primarily composed of abietic and pimaric acids and has excellent film-forming properties. Rosin and its derivatives are biopolymers that are increasingly used for their pharmaceutical applications. In the pharmaceutical context it has been investigated for microencapsulation, film-forming and coating properties, matrix materials in the tablets for sustained and controlled release.1 Derivatives of rosin synthesized by a reaction with polyethylene glycol 200 and maleic anhydride proofed suitable for sustaining the drug release from matrix tablets and pellets.42 Polymerized rosin films containing hydrophobic plasticizers showed excellent potential as coating materials for the preparation of sustained release dosage forms. 43 Different studies on the film forming and coating properties of rosin and the glycerol ester of maleic rosin demonstrated their potential to be used as coating materials for pharmaceutical products as well as in sustained-release drug delivery systems. It was shown that hydrocortisone loaded nanoparticles prepared from rosin could slowly release this model drug, which was dependent on the rosin content. This in vitro study demonstrated the potential of rosin for the production of effective nanoparticulate drug delivery systems.44



Fig. 10: Structure of Rosin

Guar Gum Guar gum is the powder of the endosperm of the seeds of Cyamopsis tetragonolobus Linn. (Leguminosae). 22 Guar gum is also called guaran, clusterbean, Calcutta lucern, Gum cyamposis, Cyamopsis gum, Guarina, Glucotard and Guyarem. It is a galactomannans which is a linear polysaccharide consisting of (1→4)-diequatorially linked β-D-mannose monomers, some of which are linked to single sugar side-chains of α-D-galactose attached. 45 Guar gum has a backbone composed of β-1,4 linked- D-mannopyranoses to which, on average, every alternate mannose an α-D-galactose is linked 1→6. 46

The FDA has affirmed guar gum as generally safe.47 Guar gum has recently been highlighted as an inexpensive and flexible carrier for oral extended release drug delivery.48 Guar gum is particularly

useful for colon delivery because it can be degraded by specific enzymes in this region of the gastrointestinal tract. The gum protects the drug while in the stomach and small intestine environment and delivers the drug to the colon where it undergoes assimilation by specific microorganisms or degraded by the enzymes excreted by these microorganisms. Guar gum on its own showed high potential to serve as a carrier for oral controlled release matrix systems. In addition, it was found that inclusion of excipients can be used as a tool to modulate drug release from these matrix systems. 49 Guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as trimetazidine dihydrochloride. 50 The same study was carried out by using metoprolol tartrate a model drug with high solubility. The results indicated that guar gum, in the form of three-layer matrix tablets, is a potential carrier in the design of oral controlled drug delivery systems for highly water-soluble drugs such as metoprolol tartrate. 51 Another water soluble drug, diltiazem HCl has given controlled release comparable with marketed sustained release diltiazem HCl tablets (D-SR tablets), which are prepared in the form of matrix tablets with guar gum using the wet granulation technique.52

Fig. 11: Structure of Guar Gum

Locust Bean Gum Locust bean gum also known as Carob bean gum is derived from the seeds of the leguminous plant Ceratonia siliqua Linn (Leguminosae). The brown pods or beans of the locust bean tree are processed by milling the endosperms to form locust bean gum and it is therefore not an extract of the native plant but flour. Locust bean gum consists mainly of a neutral

galactomannan polymer made up of 1,4-linked D-mannopyranosyl units and every fourth or fifth chain unit is substituted on C6 with a D-galactopyranosyl unit. Locust bean gum is a neutral polymer and its viscosity and solubility are therefore little affected by pH changes within the range of 3-11.53 Locust bean gum was used to produce matrix tablets with and without the cross-linker, glutaraldehyde that



showed similar drug release profiles for different model drugs as guar gum and scleroglucan. 46 In another study, sustained release of diclofenac sodium could be obtained for minimatrix systems made from locust bean gum.54 A commercially available tablet

system (TIMERx®) developed by the Penwest Pharmaceuticals Company consisting of locust bean gum and xanthan gum showed both in vitro and in vivo controlled release potential.55

Fig. 12: Structure of Locust Bean Gum

Gum Arabic Gum acacia or gum Arabic is the dried gummy exudation obtained from the stem and branches of Acacia Arabica wild, belonging to (Leguminosae). The gum has been recognized as an acidic polysaccharide containing D-galactose, L-arabinose, L-rhamnose, and D-glucuronic acid. Acacia is mainly used in oral and topical pharmaceutical formulations as a suspending and emulsifying agent, often in combination with tragacanth. It is also used in the preparation of pastilles and lozenges and as a tablet binder.56 Gum Arabic was successfully used as a matrix microencapsulating agent for the enzyme, endoglucanase, which proofed to give a slow release of the encapsulated enzyme and in addition increased its stability.57 Gum Arabic was used as an osmotic suspending and expanding agent to prepare a monolithic osmotic tablet system. The optimum system delivered the water-insoluble drug, naproxen, at a rate of approximately zero order for up to 12 hours at a pH of 6.8.58 Sustained release of ferrous sulphate was achieved for 7 h by preparing gum Arabic pellets. The release was further sustained for more than 12 h by coating the pellets with polyvinyl acetate and ethylene vinyl acetate, respectively. An increase in the amount of gum Arabic in the pellets decreased the rate of release due to the gelling property of gum Arabic. The gel layer acts as a barrier and retards the rate of diffusion of FeSO4 through the pellet. 59 Karaya Gum Karaya gum is obtained from Sterculia urens (Sterculiaceae) is a partially acetylated polymer of galactose, rhamnose, and glucuronic acid. Swellable hydrophilic natural gums like xanthan gum and

karaya gum were used as release-controlling agents in producing directly compressed matrices. Caffeine and diclofenac sodium, which are having different solubilities in aqueous medium were selected for gum erosion, hydration and drug release studies using a dissolution apparatus (basket method) at two agitation speeds. It was concluded that drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of the drug. Both xanthan and karaya gums produced near the zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices. 60 It was shown that mucoadhesive tablets prepared by karaya gum for buccal delivery, had superior adhesive properties as compared to guar gum and was able to provide zero-order drug release, but concentrations greater than 50% w/w may be required to provide suitable sustained release. 61 Tragacanth This gum is obtained from the branches of Astragalus gummifer (Leguminosae). 22 Tragacanth contains from 20% to 30% of a water-soluble fraction called tragacanthin (composed of tragacanthic acid and arabinogalactan). It also contains from 60% to 70% of a water-insoluble fraction called bassorin. Tragacanthic acid is composed of D-galacturonic acid, D-xylose, L-fructose, D-galactose, and other sugars. Tragacanthin is composed of uronic acid and arabinose and dissolves in water to form a viscous colloidal solution (sol), while bassorin swells to form a thick gel.62 Tragacanth when used as the carrier in the formulation of 1- and 3-layer matrices produced satisfactory release prolongation either alone or in combination with other polymers.63 As with other water-soluble gums, there is some preliminary evidence that concomitant ingestion of



tragacanth with a high sugar load can moderate the blood sugar levels in patients with diabetes,64 although this effect has not been demonstrated consistently65 and requires much more detailed investigation. Although gum tragacanth swells to increase stool weight and decrease the GI transit time, it appears to have no effect on serum cholesterol, triglyceride or phospholipid levels after a 21-day supplementation period as do other soluble fibers.64, 66 Tragacanth has been used since ancient times as an emulsifier, thickening agent, and suspending agent.67 Aloe Gel The inner part of the leaves of Aloe Vera (L.) Baum. f. (Aloe barbadensis Miller) consists of the parenchyma tissue that contains the mucilaginous gel. 68 After extraction of the A. Vera gel from the leaves and a filtration step, the acetone precipitate was directly compressed in matrix systems with diclofenac sodium as a model drug. The mucilage produced direct compressible matrix tablets that showed good swelling and sustained release of the model drug. 69 Many of the health benefits associated with Aloe Vera have been attributed to the polysaccharides contained in the gel of the leaves. These biological activities include promotion of wound healing, antifungal activity, hypoglycemic or antidiabetic effects antiinflammatory, anticancer, immunomodulatory and gastroprotective properties. These effects include the potential of whole leaf or inner fillet gel liquid preparations of A. Vera to enhance the intestinal absorption and bioavailability of co-administered compounds as well as enhancement of skin permeation. In addition, important pharmaceutical applications such as the use of the dried A. Vera gel powder as an excipient in sustained release pharmaceutical dosage forms.70

Fig. 13: Structure of Aloin

NATURAL POLYMERS FROM ANIMAL ORIGIN Chitin Chitin is the polysaccharide derivative containing amino and acetyl groups and are the most abundant organic constituent in the skeletal material of the invertebrates. It is found in mollusks, annelids, arthropods and also as a constituent of the mycelia and spores of many fungi. 22 It may be regarded as a derivative of cellulose, in which the hydroxyl groups of the second carbon of each glucose unit have been replaced with acetamido (-NH(C=O)CH3) group. The new polyelectrolyte complex gel beads based on Phosphorylated Chitosan (PCS) were developed for controlled release of ibuprofen in oral administration. The PCS gel beads were readily prepared from soluble phosphorylated chitosan by using an ionotropic gelation with counter polyanion, tripolyphosphate (TPP), at pH 4.0. Ibuprofen was highly loaded, around 90%, in the PCS gel beads. The release percents of ibuprofen from PCS gel beads were found to be increased as the pH of dissolution medium increased. 71 Chitosan and their derivatives (N-trimethyl chitosan, mono-N-carboxymethyl chitosan) are effective and safe absorption enhancers to improve mucosal (nasal, peroral) delivery of hydrophylic macromolecules such as peptide and protein drugs and heparins. This absorption enhancing effect of chitosan is caused by the opening of the intercellular tight junctions, thereby favouring the paracellular transport of macromolecular drugs. Chitosan nano- and microparticles are also suitable for controlled drug release. Association of vaccines to some of these particulate systems has shown to enhance the antigen uptake by mucosal lymphoid tissues, thereby inducing strong systematic and mucosal immune responses against the antigens. The aspecific adjuvant activity of chitosans seems to be dependent on the degree of deacetylation and the type of formulation. From the studies reviewed it is concluded that chitosan and chitosan derivatives are promising polymeric excipients for mucosal drug and vaccine delivery. 72



Fig. 14: Structure of Chitin

Alginates Alginates or alginic acids is an anionic polysaccharide are linear, unbranched polysaccharides found in brown seaweed and marine algae such as Laminaria hyperborea, Ascophyllum nodosum and Macrocystis pyrifera. Alginic acid can be converted into its salts, of which sodium alginate is the major form currently used. These polymers consist of two different monomers in varying proportions, namely β-D-mannuronic acid and α-L-guluronic acid linked in α- or β-1,4 glycosidic bonds as blocks of only β-D-mannuronic acid or α-L-guluronic acid in homopolymers or alternating the two in heteropolymeric blocks. Alginates have high molecular weights of 20 to 600 kDa.12, 73 Alginates have been used and investigated as stabilizers in emulsions, suspending agents, tablet binders and tablet disintegrants.47 The in vivo delivery of anti-tuberculosis drugs were investigated in mice for alginate nanoparticles prepared by cation induced gelation. A single oral dose achieved therapeutic drug concentrations in the blood plasma for 7-11 days and in organs such as the lungs, liver and spleen for a total of 15 days. The drugs encapsulated in these nanoparticles resulted in significantly higher bioavailability compared to the

free drug. Furthermore, in M. Tuberculosis infected mice only three oral doses of the nanoparticles that were spaced 15 days apart resulted in complete bacterial clearance from specific organs, which is comparable to 45 conventional doses of the free drug.74 Bioadhesive sodium alginate microspheres of metoprolol tartrate for intranasal systemic delivery were prepared to avoid the first-pass effect, as an alternative therapy for injection, and to obtain improved therapeutic efficacy in the treatment of hypertension and angina pectoris. The microspheres were prepared using emulsification-cross linking method. In vivo studies indicated significantly improved therapeutic efficacy of metoprolol from microspheres, with sustained and controlled inhibition of isoprenaline-induced tachycardia as compared with oral and nasal administration of drug solution.75 In a comparative study, alginate formulation appeared to be better than the polylactide-co-glycolide (PLG) formulation in improving the bioavailability of two clinically important antifungal drugs-clotrimazole and econazole. The nanoparticles were prepared by the emulsion-solvent-evaporation technique in case of PLG and by the cation-induced controlled gelification in case of alginate.76

Fig. 15: Structure of Alginates



Carrageenans Carrageenan is sulphated polysaccharide extract of the seaweed called carrageen; or Irish moss, the red algae obtained from Chondrus Crispus (Rhodophyceae). 22 Carrageenan extracted from seaweed is not assimilated by the human body and provides only bulk but no nutrition. There are three basic types of carrageenan - kappa (κ), iota (ι) and lambda (λ) respectively.12 The λ-type carrageenan results in viscous solutions but are non-gelling, while the κ- type carrageenan forms a brittle gel. The ι-type carrageenan produces elastic gels.47 A study where the compaction ability of two κ-carrageenans (Gelcarin® GP-812 NF and GP-911NF) and one ι-carrageenan (Gelcarin® GP-379 NF) was

investigated showed that these carrageenans are able to form strong compacts with a high elastic recovery. It was finally concluded from the results that the carrageenans investigated were suitable tableting excipients for the manufacturing of controlled-release tablets.77 Hydrogel beads were prepared from a mixture of cross-linked κ-carrageenan with potassium and cross-linked alginate with calcium and they exhibited a smoother surface morphology than that of the one-polysaccharide network beads. The carrageenan parts of the hydrogen pronouncedly enhanced the thermostability of the polymeric network. These beads were introduced as novel carriers for controlled drug delivery systems.78

Fig. 16: Structure of a) kappa (κ), b) iota (ι) and c) lambda (λ)

Psyllium Psyllium mucilage is obtained from the seed coat of Plantago ovata by milling the outer layer of the seeds. It has been evaluated for its tablet binding properties, 79 but also to form hydrogels through radiation-induced cross-linking for controlled release of 5-fluorouracil as a model drug.80 Psyllium and methacrylamide based hydrogels were prepared by using N,N’-methylenebisacrylamide as a cross-linker, which were then loaded with insulin.

These cross-linked hydrogels showed controlled release of the active ingredient by means of non-Fickian diffusion of the drug through polymer chain relaxation during swelling.81 Psyllium husk was used in combination with other excipients such as hydroxypropyl methylcellulose to prepare a novel sustained release, swellable and bioadhesive gastroretentive drug delivery systems for ofloxacin.82



Fig. 17: Structure of Psyllium

Xanthan Gum Xanthan gum is a high molecular weight extracellular polysaccharide produced by the fermentation of the gram-negative bacterium Xanthomonas campestris. The primary structure of this naturally produced cellulose derivative contains a cellulosic backbone (β-D-glucose residues) and a trisaccharide side chain of β-D-mannose-β-D-glucuronicacid-α-D-mannose attached with alternate glucose residues of the main chain. In one of the trials, xanthan gum showed a higher ability to retard the drug release than synthetic hydroxypropylmethylcellulose. Xanthan gum and hydroxypropylmethylcellulose were used as hydrophilic matrixing agents for preparing modified release tablets of diltiazem HCl. The amount of hydroxypropylmethylcellulose and xanthan gum exhibited significant effect on drug release from the

tablets prepared by direct compression technique. It was concluded that by using a suitable blend of hydroxypropylmethylcellulose and xanthan gum desired modified drug release could be achieved.83 By utilizing retention properties of xanthan gum and releasing properties of galactomannan, the desired release profile was achieved in delivering of theophylline. Hydrophilic galactomannan is obtained from the seeds of the Brazilian tree Mimosa scabrella (Leguminosae). The matrices made alone with xanthan gum (X) showed higher drug retention for all concentrations, compared with galactomannan (G) matrices that released the drug too fast. The matrices prepared by a combination of both gums were able to produce near zero-order drug release. The XG (conc. 8%) tablets provided the required release rate (about 90% at the end of 8 h), with zero-order release kinetics.55

Fig. 18: Structure of Xanthan Gum



CONCLUSION Polymers play a vital role in the drug delivery. So, the selection of polymer plays an important role in drug manufacturing. But, while selecting polymers care has to be taken regarding its toxicity, drug compatibility and degradation pattern. By this review, we can say that natural polymers can be good substitute for the synthetic polymers and many of the side effects of the synthetic polymers can be overcome by using natural polymers.

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