Natural and Synthetic Polymers for Colon Targeted Drug Delivery

 

Babli Thakur, Vinay Pandit, Mahendra Singh Ashawat, Pravin Kumar*

Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Kangra (H.P)-177101

*Corresponding Author E-mail: kumar3785@gmail.com

 

ABSTRACT:

Colon targeted drug delivery system have recently gained importance in delivery of number of therapeutic agents for both local and systemic action. Colon targeted drug delivery system is useful for delivery of proteins and peptides, drugs undergoing degradation in stomach and small intestine. Targeting of drugs to colon is also favorable for the chronotherapy of diseases. To achieve successful, colonic delivery, a drug is needed to be protected from absorption in upper gastrointestinal tract (GIT). Out of the several approaches for colon targeting, coating the drug core with a polymer or polymer combinations is an important strategy. Coating of drug core with a pH dependent polymer or a polymer biodegraded in colon by colonic flora has been widely investigated approach for colonic delivery. Polysaccharides are important polymers from either natural or synthetic origin which have been exhaustively studied for successful colon targeting. This review describes some important natural and synthetic polysaccharides and polymers investigated for colonic drug delivery by coating the drug core.

 

KEY WORDS: Colon, polymer, coating, biodegradation, polysaccharide.

 

 


INTRODUCTION:

Oral route is most widely used for controlled delivery of drugs. It offers several advantages such as prevention of peak and valley fluctuation, reduced dosing frequency, reduced dose, improved patient compliances and nearly constant level at the site of action.1, 2In past decades, via oral route colon has been exhaustively investigated as a specific site for delivery and absorption of drugs.

 

Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon like Crohn’s disease, ulcerative colitis, irritable bowel syndrome and constipation but also for the systemic delivery of proteins, therapeutic peptides, anti-asthmatic drugs, antihypertensive drugs and anti-diabetic agents.3, 4 Because of near neutral pH and longer transit time colon offer several therapeutic advantages as a site of drug delivery.5

 

Colon specific release of drug either immediate release or controlled release for local treatment, will help in reduction of drug dose and doing frequency.6It will further reduce the cost of therapy, lower incidence of adverse effects and thus, improved patient compliance. Moreover, the timed release of drug to colon can be used for the chronotherapy of diseases such as nocturnal asthma, depression, diabetes mellitus etc.7 Bioavailability of certain drugs viz. NSAIDs (irritant to gastrointestinal tract) and drugs having high first pass metabolism can be improved by delivering directly to colon. The prolong retention time (6-12hours) and more hostile environment of colon (less enzymatic activity) compared to stomach and small intestine, also helps in the absorption of poorly water soluble drugs. Further, colon can also be used as site for delivery and absorption of proteins and peptides due to absence of peptidase.8,9 There are certain limitations associated with the development of colonic drug delivery system such as multiple manufacturing steps and incomplete drug absorption due to interference from dietary residues, intestinal secretions, mucus and fecal matter.10 Certain approaches (e.g. pH sensitive coating) used to develop colon targeted drug delivery system showed uncertainty of location and environment in which formulation may start to dissolve.11

 

There are several approaches which had been widely investigated for the design of colon targeted drug delivery systems (Table 1). The desired properties of a colon targeted drug delivery system can be achieving by using some polymer either alone or in combination because it is now recognized that polymer can potentially influence the rate and absorption of drug release and play an important role in the formulation of colon targeted drug delivery system.12, 13Coating of delivery systems with a polymer either sensitive to colonic pH or biodegraded by bacteria in colon is an important approach for the formulation of colon targeted drug delivery system.14 In the present paper, the authors have tried to explain the basic mechanism of colon targeting by polymer coating, important polymers of natural or synthetic or semisynthetic origin and patents granted for drug delivery to colon by coating approach.

 

Mechanism of colon targeting using polymer coating

In this approach, the drug is present in the core of the formulation which is coated with layers of polymer. The change of pH along the gastrointestinal tract has been used as a mean for the solubilization of polymer coating and drug release in colon (Fig 1). This can be achieved by means of coating that remain intact at lower pH of the stomach but should dissolve at neutral pH of the colon. The pH in the gastrointestinal tract varies from 1.2 in the stomach, 6.6 in the proximal small intestine, about 7.5 in the distal part of small intestine and 6.7 in colon.16-18

 

The pH variation in the stomach and small intestine has previously been used to deliver drugs to small intestine by way of pH sensitive enteric coating. These polymer coats are recalcitrant to the acidic condition of the stomach but ionized and get dissolved above a certain threshold alkaline pH found in small intestine. Thus, it was possible to apply same concept to deliver drugs to the terminal of ileum or colon by use of enteric polymers with a relatively high threshold pH for dissolution and subsequent drug release.19


Table 1. Different approaches used for colon targeted drug delivery system15

Approaches

Basic features

1.Prodrug (covalent linkage with carrier)

 

1.1 Azo conjugated e.g. sulphasalazine with 5-ASA

Drug is conjugated with an azo bond

1.2 Glycoside conjugate e.g. dexamethasone

Drug is conjugated with glycoside

1.3 Glucuronide conjugated

Drug is conjugated with glucuronide

1.4 Polypeptide conjugated

Drug is conjugated with polypeptide

1.5 polymeric conjugation

Drug is conjugated with polymer

2. Approaches to deliver the intact drug to the colon

 

2.1 Coating with polymer

 

2.1 (a) Coating with pH sensitive polymer

Formulation coating with enteric coated polymers release polymer when pH moves toward alkaline pH

2.1 (b) Coating with biodegradable polymer

 

Drug released with degradation of polymer due  to the action of  colonic bacteria

2.2 Embedding in matrices

 

2.2 (a) Embedding in biodegradable polymer and hydrogel

Drug release depend upon the swelling and biodegradation action of the polymer

2.2 (b) embedding with pH sensitive polymer

Release depend upon the degradation of pH sensitive polymer

2.3 Time released system 

Once multicoated formulation passes the stomach, drug is released after lag time 3- 5 h i.e. equivalent to transit time of small intestine

2.4 Redox sensitive polymer

Drug formulated with azo and disulfide polymer that selectively response to the redox potential of  colon

2.5 Bioadhesive system

Bioadhesive polymer selectively target and release the drug in colon   

2.6 Osmotic controlled drug delivery

Drug is released through semipermeable membrane due to osmotic pressure

 

Fig 1.Mechanism of drug release from pH sensitive polymer coating

 

Fig 2. Mechanism of drug release from biodegradable polymer coating

 


Drug can be also administered locally and selectively to the colon if they are enclosed in an azo-aromatic cross-linked polymer subject to cleavage by azo-reductase of the colonic micro flora. This approach of coating a drug with biodegradable material for the colon targeting was reported to deliver large amount of the drug. Biodegradable polymers degrade in vivo, either in presence of enzyme or non-enzymatically, to produce products which are non-toxic and biocompatible (Fig 2).20 The colonic bacterias will enzymatically degrade the polymers (mainly polysaccharides) into organic acid. Various bacteria present in the colon secrete many enzymes which can cause hydrolysis of glycosidic bonds e.g.C-D glactosidase, amylase, pectinase, C-D glucodase, dextranase and D-D xylosidase.21The micro flora composition remains relatively constant across a diverse human population.

 

Natural polymers:

Natural polymers mainly polysaccharide has gain importance for the formulation of solid oral dosage forms for colonic delivery of drugs because these are non-toxic, safe and economical. Polysaccharides are biodegradable polymers having limited swelling characteristic in acidic pH due to their hydrophilic nature.22These polymer are economical and are available in a variety of structures. Linear polysaccharides remains intact in stomach and small intestine, but the bacteria of human colon degrades them and thus make them potentially useful in colon targeted drug delivery systems.23Pectin, inulin, xanthan gum, starch, guar gum, amylose and khaya gum etc. are few polysaccharides investigated for colon targeting of drugs.

 

PECTIN:

Pectin (Fig. 3a) are non-starch linear heterogeneous polysaccharide that consist of D-1, 4 D-glacturonic acid and 1, 2 D-rhamnose with glactose and darabinose side chains. It is refractory to gastric and small intestine enzymes but is almost completely degraded by the colonic bacterial enzyme to produce a series of soluble oligalactorunate.24, 25 Pectin is soluble in water, monovalent cations (alkali) metal salt of pactinic and pactinic acid are soluble in water, di and tri-valiant cations are weakly soluble or insoluble. If used alone it swells, when it comes in contact with gastric fluids and intestinal fluid.26

 

Dupuis et al. had investigated zinc pectinate beads for colonic delivery of ketoprofen. This study revealed that zinc pectinate beads protected the entrapped drug sufficiently from the upper gastro-intestinal conditions and release was controlled by pectin degradation with colonic microflora.27

 

Lee CM et al. had used spray drying method to prepare pectin microspheres for oral colon delivery of indomethacin. The prepared microspheres were cross-linked with calcium chloride. The release of indomethacin from the cross linked pectin microspheres was more suppressed than its release from non-cross linked microspheres. Drug release from pectin microspheres was increased by the addition of pectinase. Release of indomethacin from pectin microsphere was less in acidic pH while it was stimulated at neutral pH (pH 7.4). The results of the study clearly demonstrated that pectin microspheres prepared by spray drying and crosslinking methods are potential carriers for colon-specific drug delivery.28

 

Momin M et al. mixed film of pectin: ethyl cellulose for colon targeted drug delivery of sennosides and triphala was prepared using non aqueous solvent like acetone and isopropyl alcohol. The results of the study indicated that under simulated colonic conditions, drug release was more pronounced from coated formulations containing higher proportion of pectin.29

 

Wei H et al. performed in vitro and in vivo study of pectin/ethyl cellulose film-coated pellets of 5-fluorouracil for colon targeting. The pellet cores were coated to different film thicknesses with three different pectin: ethylcellulose formulations. The pectin: ethylcellulose (1:2) coated pellets with 30% total weight gain produced more satisfactory drug-release profiles in simulated gastric, intestinal and colonic fluids.30

 

Ravi V et al. formulated and evaluated a novel colon targeted tablet using pectin as a carrier. The release of drug was limited in stomach and small intestine; and was maximum in the colon. The study revealed that pectin can be used effectively for colon targeting of both water soluble and insoluble drugs.31

 

CHITOSAN:

Chitosan (Fig 3b) is a high molecular weight polycationic polysaccharide derived from chitin by alkaline deacetylation. Chitosan is consisting of a repeated unit of (2-amino-2-deoxy-D-gluco-pyranose) which is linked by (1-4) C-bond. Chitosan is a nontoxic, biodegradable, biocompatible, and bioactive polymer. It is used as colon targeted drug delivery because it has tendency to dissolve in acidic pH of stomach but get swollen in the intestinal pH.32

 

Orienti I et al. developed a colon specific drug delivery system composed of drug reservoir and the outer drug release regulating layer by dispersing chitosan powder in a hydrophobic polymer. It was observed that the thickness of the outer layer control the drug release rate since the dispersed chitosan dissolves easily under acidic conditions. An additional outer enteric coating was also provided to prevent the release of drug from chitosan dispersed system in the stomach.33

 

Shimono N et al. investigated chitosan to control the release of many drugs and to improve the bioavailability of degradable substances such as protein, as well as to improve the uptake of hydrophilic substances across the epithelial layer in colon.34

 

Zhang H et al. formulated and investigated hydrogel beads of chitosan with tripolyphosphate and protein release was investigated in vitro under different conditions. It was observed that under colonic environment, protein release was high due to the degradation of the beads.35

 

Shu X et al. used chitosan capsules for colonic delivery of an antiulcerative colitis drug. 5-Aminosalicylic acid (5-ASA) was used as model drug. A marked increase in the release of drug from chitosan capsule was observed in the presence of the rat cecal content. It was concluded, that chitosan capsules could be an effective carrier for the colon targeted delivery of anti-inflammatory drugs.36

 

GUAR GUM:

Guar gum (Fig 3c) is a polysaccharide composed of the sugars galactose and mannose. The backbone is a linear chain of C 1, 4-linked mannose residues to which galactose residues are 1, 6-linked at every second mannose, forming short side-branch.37

 

Al- Saidan SM et al. investiated guar gum in colon targeted drug delivery systems due to its drug release retarding property and susceptibility to microbial degradation in large intestine. Guar gum has a gelling property which retards the release of drug from the dosage form, making it more likely that degradation will occur in the colon. Guar gum was found to be a colon-specific drug carrier in the form of matrix and compression coated tablets as well as microspheres.38

 

Krishnaiah YS et al. prepared core tablets containing 5-aminosalicylic acid (5-ASA) by wet granulation with starch paste. The tablets were compression coated with different quantities of guar gum. The study confirmed that selective delivery of 5-ASA to the colon can be achieved using guar gum as a carrier in the form of compression coating over the drug core.39

 

Ji CM et al. evaluated the potential of guar gum as a film coating material for colonic delivery of 5-flourouracil. Guar gum based pellet systems were prepared by coating guar gum and pH-sensitive polymer Eudragit FS 30 D sequentially around drug-loaded cores. The study revealed that guar gum coating worked as a time-controlled retardant and offered additional protection to the pellets until it is degraded by microbial enzymes at the proximal colon. In vitro results indicated that guar gum is a feasible coating material to achieve timed and enzyme-triggered fluorouracil release.40

 

Krishnaiah et al. has performed the pharmacokinetic evaluation of guar gum-based colon-targeted tablets of mebendazole against an immediate release tablet in six healthy human volunteers. Colon-targeted tablets showed delayed tmax (9.4±1.7 h) and absorption time, and decreased Cmax (25.7±2.6 μg/ml) and absorption rate constant when compared to the immediate release tablets. The results indicated that the guar gum-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon.41

 

AMYLOSE:

Amylose (Fig 3d) is the polysaccharide which is obtained from the plant extracts and a component of starch. Amylose is unbranched linear polymer of glucopyranose units (α-1, 4-D-glucose) linked through α–D-(1-4) linkage. Amylose is resistant to pancreatic amylases in its glassy amorphous form but it gets degraded by the bacteroids, bifidobacterium.42

 

Milojevis S et al. formed an amylose film by gelation, which can be used for tablet coating purpose. But, coating made up of amylose solely becomes porous and release the drug under simulated gastrointestinal conditions. To avoid this problem, water insoluble polymers are added to the amylose film as these water insoluble polymers control the amylose swelling. Addition of ethyl cellulose to amylose gives a suitable polymer mixture for colon targeting. In vitro dissolution of various coated pellets was performed under simulated gastric and intestinal conditions and it was concluded that amylose: ethyl cellulose coat (1:4) resist these conditions over a period of 12 h.43

 

Cumming et al. used a mixture of amylose and ethocel (1:4) to prepare microspheres of [13C] glucose which was used as a surrogate for drug delivery. The results of the study revealed that combination of amylose and ethylcellulose can be used for coating of pellets which results in controlled release of contents for targeted delivery of drug to the large bowel during a period of 12–24 h.44

 

LOCUST BEAN GUM:

Locust bean gum (Fig 3e) contains natural polysaccharides which have a molecular weight of 310000. Locust bean gum is also known as ‘Carob gum’ as it is derived from the endosperm of the seed of the ‘Carob’ (Ceratonia Siliqua Linn, Fam: Leguminosae). It is irregular shaped molecule with branched β-1, 4-D-galactomannan units. Locust bean contains about 88% D-galacto-D mannoglycan, 4% of pentane, 6% of protein, 1% of cellulose and 1% of ash.45

 

Raghavan et al. investigated a combination of locust bean gum and chitosan, as a coating material for protecting the core tablet containing mesalazine during the condition mimicking mouth to colon transit. The coating was susceptible to the colonic bacterial enzymes which causes the release of drug.45

 

Bashardoust et al. formulated compression-coated tablets of ibuprofen by a direct compression method using locust bean gum (LBG) at 300, 250, 200 and 175 mg. Tablets were evaluated for their physicochemical properties and in vitro drug release. In vitro drug release studies were performed with and without rat caecal contents. In rat caecal contents, tablets showed enhanced drug release due to degradation of the LBG coating by colonic enzymes. The in vitro release studies in pH 6.8 phosphate buffer containing 2% w/v rat caecal contents showed the cumulative percentage release of ibuprofen after 26 h as 39.91 ± 0.05%, 53.21 ± 0.37%, 69.17 ± 0.19% and 94.46 % ± 0.92%. Coating thickness and the amount of locust bean gum control the release rate.46

 

INULIN:

Inulin (Fig 3f) is a naturally occurring glucofructan and consists of C 2-1linked D-fructose molecule having a glycosul unit at the reducing end. It can resist the hydrolysis and digestion in the upper gastrointestinal tract.47 Inulin is not hydrolysed by the endogenous secretion of human digestive tract. However, bacteria harbouring in the colon and more specially bifidobacteria are able to ferment inulin.48

 

Maris B et al. synthesized and characterized new hydrogel systems composed of methacrylated inulin, copolymerized with the aromatic azo agent BMAAB and HEMA or MA. Inulin hydrogels have been developed and characterized for dynamic and equilibrium swelling properties and in vitro degradation study. The rate of water transport into the inulin hydrogels was quite high (mean swelling time <1.2 h) and the hydrogels exhibited anomalous dynamic swelling behavior. The enzymatic digestibility of the prepared inulin hydrogels was assessed by performing an in vitro study using an inulinase preparation derived from Aspergillus Niger. The amount of fructose liberated from the inulin hydrogels by the action of inulinase was quantified using the anthrone method. The equilibrium swelling ratio as well as the mechanical strength of the hydrogels was studied before and after incubation in inulinase solutions. The data obtained by these different methods indicate that enzymatic digestion of the inulin hydrogels appeared to be enhanced by a prolonged degradation time, a higher inulinase concentration, and a lower degree of substitution and feed concentration of the hydrogel polymer. The inulin hydrogels exhibited an increase in equilibrium swelling after degradation compared with the swelling before degradation, suggesting that inulinase enzymes diffuse into the inulin hydrogel networks causing bulk degradation.49


 

 

Fig 3. Chemical structure (a) Pectin (b) Chitosan (c) Guar gum (d) Amylose (e) Locust bean gum (f) Inulin

 


XANTHAN GUM:

Xanthan gum (Fig 4a) is a high molecular weight extra cellular polysaccharide produced by the fermentation of the gram negative bacterium Xanthomonas campestral. It is a free flowing powder soluble in both hot and cold water and gives viscous solution at low concentration. It is a very effective thickener and stabilizer because it gives highly viscous solutions even at low concentration in comparison to the other polysaccharide solution. Its solution offer very good stability. They are least affected by change in pH and are stable in both alkaline and acidic conditions.50

 

Shun YL et al. used xanthan gum and hydroxypropyl methyl cellulose as hydrophilic matrixing agent for preparing modified release tablets of diazepam HCl. The amount of hydroxy propyl methyl cellulose and xanthane gum exihibited significant effect on drug release from the tablets prepared by direct compression technique. It was concluded that by using a stable blend of hydroxy propyl methyl cellulose and xanthane gum desired modified drug release could be achieved.51

 

Musukula YR et al. developed compression coated tablets of Ketorolac tromethamine (KTM) for colon targeting. Thenatural polymers like Xanthan Gum, Guar Gum, Khaya Gum and Combination of Xanthan Gum/ Guar Gum with HPMC K100M were investigated as a compression coat over the KTM core tablets. The tablets were evaluated for their pre and post compression parameters. In vitro drug release studies were conducted in pH1.2 buffer, pH7.4 phosphate buffer and in enzyme free simulated intestinal fluid (pH6.8) and also in pH 6.8 phosphate buffer containing 2% and 4% w/v of rat caecal contents, respectively. A significant difference was observed in the amount of KTM released at the end of 24hin medium with rat caecal content when compared to the without rat caecal content.52

 

KHAYA GUM:

Khaya gum (Fig 4b) is a polysaccharide obtained from the incised trunk of tree Khayagrandulifolia, family Maliaceae. Odeku O.A. et al., evaluated the effect of khaya gum on the mechanical release properties of paracetamol tablets in comparision with two standard binding agents, poly vinyl pyrrolidone and gelatin. It has been found that the crushing strength, friability ratio, disintegration time, dissolution time t50, t90 and t1hr all increase in binder concentration.

 

It was also found that khaya gum is capable of protecting the drug from being released in the acidic environment prevailing in the stomach and small intestine. They are degraded by the colonic bacterial enzyme, there by releasing the drug in colon where there is local action and improved absorption.53

 

Prabhakara P et al. prepared fast disintegrating core tablets of budesonide by direct compression technique. These tablets were coated with khaya gum. These tablets were further coated using eudragit S-100 by dip coating technique. In vitro drug release studies were carried out in presence and absence of rat caecal contents and revealed that khayagum, protected the drug from being released in the upper parts of the GIT to little extent. But, the enteric coated formulations completely protected the drug from being released in the upper parts of the GIT, and released the drug only in the colon by bacterial degradation of gum. Khaya gum alone cannot be used either for targeting the drug to the colon or for sustaining or controlling the release of drugs.54

 

SYNTHETIC POLYMERS:

The polymer used for colon targeting, however, should protect the drug from the environment and absorption in upper gastrointestinal tract. It should not be affected by the lower pH of stomach and the proximal part of the small intestine and also able to disintegrate at the neutral slightly alkaline pH of terminal ileum and preferably at the ileocecal junction. These can be called as pH dependent polymer. The most commonly used pH dependent polymers are derivatives of acrylic acid and cellulose. Thus, drug is targeted with pH sensitive polymer to the colon.55

 

EUDRAGIT:

Eudragit products are pH-dependent methacrylic acid polymers containing carboxyl groups. The number of esterified carboxyl groups affects the pH level at which dissolution takes place. Eudragit are of three types: Eudragit L, Eudragit S and Eudragit RS.56

 

Euragit L

Eudragit L (Fig 4c) is an anionic polymer synthesized from methacrylic acid and methyl methacrylate having a pH dependent solubility. Eudragit® L 100 would release the drug at pH rang 6-6.5 i.e. ileum and large intestine. It is a white powder having faint characteristic odor.57

 

It provides an effective and stable enteric coating with a fast dissolution in the upper bowel. It is also used to form a site specific drug delivery system to the intestine by combination with Eudragit® S100. Eudragit L coating have been investigated in the development colon targeted single unit tablets of 5-ASA in patients with ulcerative colitis.58

 

Eudragit S

Eudragit S (Fig 4d) is an anionic copolymer synthesized from methacrylic acid and methyl methacrylate. It is available only in the form of organic solution i.e. isopropanol and solid. Eudragit® S 100 releases the drug at pH rang above 7.0.57

 

It is used in powder form for granulation of drug substance in order to form a controlled release drug delivery system. It is used for the delivery of drug in the intestine by combination of drug with other grades of Eudragit S such as Eudragit® S12.5 Eudragit® FS 30 D. When sites of disintegration of Eudragit S coating single-unit tablets were investigated using a gamma camera they were found to lie between ileum and splenic flexure. Eudragit S has been used in combination with Eudragit L 100-55, in colon specific drug delivery.58

 

Pruthviraj S et al. prepared colon targeted tablets of budesonide using pectin, guar gum as enzyme dependent polymers along with HPMC, HEC as time dependent polymers followed by pH dependent polymers like Eudragit S100 and Cellulose acetate phthalate. The compression coating was done over the core tablets by using pectin, guar gum, HPMC and HEC in different ratios by direct compression method. The enteric coating was done on the compression coated tablets by using ES100 and CAP in different ratios by dip coating method. In vitro swelling and in vitro drug release studies were carried out at different pH (1.2, 6.8 and 7.4). The compression coated formulation C1 (pectin: guar gum =1:2), C2 (HPMC: HEC =1:2) and C3 (HPMC and HEC: pectin and guar gum =2:1) showed good swelling (493.42%, 411.08% and 393.61%) up to 18, 20 and 21 h, respectively. pH dependent polymers ES100: CAP in the ratio 2:1 as an enteric coating material applied over compression-coated tablets was capable of protecting the drug from being released in the stomach and small intestine. This study proved that Budesonide compression-coated tablet, enteric coated with ES100: CAP in the ratio 2:1 may be beneficial in the treatment of irritable bowel syndrome and nocturnal asthma.59

 

SELLAC

Shellac (Fig 4e) is the purified product of natural resin lac which the hard secretion of small, parasitic insects Kerrialaca. It is the only kwon commercial resin of animal origin. It is a hard, brittle and resinous solid which is insoluble in water. It is practically odorless, but evolve characteristic odor on heating. The shellac coating remains intact during passage through stomach and intestine until it reaches in the colon. This allows the transfer of drug into the colon. Moreover, activity of peptidase in the colon is lower in the upper GI tract allowing for oral administration of peptide and proteins.60

 

Shellac films prepared from alcoholic solution shows pronounced hardening including by continuing polymerization process. This results in a loss of gastric resistance time and a decrease in intestinal fluid solubility. These are disadvantages when compared with synthetic or partially synthetic polymer such as polymethacrylate and cellulose derivatives.61

 

Das M et al. prepared matrix tablets with Pectin and Hydroxy propyl methylcellulose (HPMC) K4M and compression coated with Eudragit S100, Shellac and HPMC K100M. The prepared tablets were evaluated by compatibility studies. The tablets passed the physical parameter tests. The in-vitro release studies revealed that the release pattern of the tablets was mainly influenced by the type of coating, the release being minimum for HPMC K100M coated tablets and maximum for Eudragit S100 coated tablets. Shellac coated tablets gave an average rate of release throughout the 8 hour study. It was concluded that among the various batches prepared, FBC1 (HPMC K4M tablets coated with HPMC K100M), FAC1(Pectin tablets coated with HPMC K100M) and FAC2 (Pectin tablets coated with Shellac) were found to avoid significant drug release in the first 5 hours of dissolution and released 35%, 10% and 54% drug throughout the 8 hour dissolution study.62


 

 

Fig 4. Chemical structure (a) Xanthane gum (b) khaya gum (c) Eudragit® L 100 (d) Eudragit ® S 100 (e) Shellac

 

Table 2. Patents granted in relation to polymer coating for colon targeted drug delivery systems

Patents

 Details of patents

US70488945

It explained a time controlled drug delivery system. The inventor coated the drug particle with a plasticized enteric coating cellulose acetate phthalate, HPMC phthalate etc.  The inventors also added an option of applying an organic acid (such as fumaric or succinic acid) for further modulation of lag time and release profile of the drug.

CA2215378

It is assigned to Andrx Pharmaceuticals Inc., US describes unit dosage forms of diltiazem hydrochloride which comprise a two fraction system of enteric polymeric membrane coated pellets and delayed pulse polymeric membrane coated pellets. This invention relies on the biological system for subject-to-subject and dissolution of the complete enteric coat for bio-response in the initial phase.

US6217904

It described a pharmaceutical dosage form for pulsatile delivery of a CNS stimulant. The formulation included three fractions of beads; first fraction of beads being prepared by coating an inert support material such as lactose with the drug which provides immediate release. A second fraction of beads was prepared by coating immediate release beads with an amount of enteric coating material. A third fraction was prepared by coating immediate release beads having half dose of the first fraction of beads with a greater amount of enteric coating material, sufficient to provide  lag phase of 7-9 h and thereafter releasing the drug in the colon.

US5439689

It disclose once-a-day oral formulation of diltiazem hydrochloride having a stair stepped release profile generated by two populations of diltiazem beads which released the drug at two different intervals of time i.e. 3-9 h following lag times of 3 h and 15-21 h following a lag time of 15 h. Although such a formulation releases diltiazem hydrochloride over 24 h.

US655136

It explains the use of hydrocolloid gums which are effective to provide for colonic delivery e.g. guar gum, locust bean gum, tragacanth etc. Other material suitable for colonic delivery includes polysaccharide and related compounds e.g. pectin, chitosan, chondroitin sulfate etc. The invention is based on pharmaceutical dosage form for pulsatile delivery of methylphenidate by using three kinds of mini-tablets or bead or particle fractions in a capsule which have different drug and polymer coating levels. Out of which the third tablet or bead or particle fraction provides for release of the active agent in the colon.

 


 

 

Important patents granted for polymer coating

There have been several patents granted for polymer coating approach for colon targeted drug delivery systems (Table 2).63

 

CONCLUSION:

Colon targeted drug delivery system is a novel approach to improve the patient compliance and therapeutic effect. During the last decade several natural and synthetic polymers have been investigated for delivery of drugs to the colon. Formulations coated with natural or synthetic biodegradable and pH sensitive polymer passes intact from upper GIT (stomach and small intestine) and release the drug in colon. One of important class of natural polymers is the polysaccharides having a wide application for the development of colon targeted drug delivery systems by coating. Eudragit and shellac have also shown some promising results for delivering the drug to the colon.

 

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Received on 30.12.2015          Accepted on 21.01.2016        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2016; Vol. 6: Issue 1, Jan. - Mar., Pg 35-44

DOI: 10.5958/2231-5713.2016.00006.4