Colon-targeted drug delivery

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Chapter: Pharmaceutical Drugs and Dosage: Organ-specific drug delivery

Traditionally, colonic drug delivery is focused on the treatment of local conditions such as ulcerative colitis, colorectal cancer, irritable bowel syndrome, amebiasis, and Crohn’s disease.


Colon-targeted drug delivery

Traditionally, colonic drug delivery is focused on the treatment of local conditions such as ulcerative colitis, colorectal cancer, irritable bowel syndrome, amebiasis, and Crohn’s disease. However, it has been gaining importance for the systemic delivery of potent compounds such as proteins, peptides, and oligonucleotides that are unstable in the harsh conditions of the upper GI tract. As colon is rich in lymphoid tissues, it offers opportuni-ties for the oral delivery of vaccines targeted for release and absorption in the lower GI tract. In addition, colon delivery can be exploited to improve the bioavailability of drugs that are extensively metabolized by cytochrome P450 enzymes in the upper GI tract, because the activity of these metabo-lizing enzymes are relatively lower in the colonic mucosa. Colon-specific drug delivery may also help overcome GI side effects of drugs. For example, conversion of flurbiprofen to a glycine prodrug, hydrolysable by colonic microfloral enzymes (amidases), reduced its ulcerogenic activity in rats. Targeted drug delivery to the colon has been extensively studied.

Colon-specific drug delivery is challenged by its distal location in the GI tract. Even localized delivery through the rectum, however, only reaches a small part of the colon and is not a patient-friendly mode of adminis-tration. Therefore, oral delivery has been explored, utilizing physiological differences in the colonic microenvironment and physiology. The aspects of colon physiology that have been exploited to develop drug-targeting strategies include the presence of unique colonic microflora, high pH, the relatively predictable transition time in the small intestine, and high intra-luminal pressure inside the colon. In addition, osmotically and oxidation potential controlled DDSs, and bioadhesive polymers have been used for colonic drug delivery.


Utilization of the unique colonic microflora

Human colonic microflora consists predominantly of bacteria, which also make up to 60% of the dry mass of feces. The metabolic activities of this microflora results in the salvage of absorbable nutrients from diet by fermenting unused energy substrates, trophic effects on the epi-thelium, and protection of the colonized host against invasion by alien microbes. Colonic bacteria are mostly gram negative and anaerobic, except cecum, which can have high amount of aerobic bacteria. Bacteria in the proximal part of the colon are primarily involved in ferment-ing carbohydrates, whereas the latter part breaks down proteins and amino acids.

The unique metabolic ability of these microbes has been exploited to develop polymerics and prodrugs that are degraded by the unique enzy-matic activities of colonic microflora. In particular, the azo reductase and glycosidase activities of the microflora help degrade the azo bound and glycosidic linkages. Prodrug strategy for colonic drug delivery utilizes drug conjugation with a promoiety through an azo bond, which is degraded by the colonic bacteria. Examples of such prodrugs include sulfasalazine, balsalazide, ipsalazide, olsalazide, and salicylazosulfapyridine for the treatment of inflammatory bowel disease. As shown in Figure 15.5, these prodrugs contain an azo bond, which is reductively cleaved by the colonic anaerobic bacteria to release the anti-inflammatory compound 5-amino salicylic acid (5-ASA). 


Figure 15.5 Colon-targeted drug delivery by prodrug strategy. Prodrug strategy for colonic drug delivery utilizes drug conjugation with a promoiety through an azo bond, which is reductively cleaved by the colonic anaerobic bacteria to release the parent compound. This figure shows the structure of several prodrugs of 5-amino salicylic acid (5-ASA), an anti-inflammatory compound used for the treatment of inflammatory bowel disease.

Sulfasalazine was first introduced for the treatment of rheumatoid arthritis and inflammatory bowel disease. In the colon, it degrades into 5-ASA and sulfapyridine, which is responsible for most of the side effects of sulfasalazine. This problem was overcome by the use of other promoieties, such as 4-amino benzoyl glycine in ipsalazine and 4-aminobenzoyl-β-alanine in balsalazide, or azo bond conjugation of sul-fasalazine with itself to form olsalazine. In addition, the drug has been covalently conjugated to a polymeric backbone of polysulfonamidoethylene by azo bond (Figure 15.5).

Polymers that degrade specifically in the colon have been used for drug targeting by surface coating to form a barrier to drug release or as matrix systems embedding the drug substance. For example, azo-linked acrylate copolymers and poly(ester-ether) copolymers have been used for the delivery of protein and peptide drugs, and small molecular weight compounds such as ibuprofen, sulfasalazine, and betamethasone. For embedding the drug in polymer matrices, natural polysaccharides have been used in oral solid dosage forms to protect the drug during GI transit and release in the colon on polymer degradation by the microflora. They offer advantages such as the presence of derivatizable functional groups and a range of molecular size, in addition to their low toxicity. The hydrogel (hydrophilic and swelling) prop-erties of these polymers, however, can lead to the dosage form swelling and disintegration in the presence of water before reaching the colon. Therefore, these dosage forms require protection from the aqueous environment during upper GI transit. This is usually accomplished by the use of protective surface coating or chemical cross-linking with linkers that are degraded in the colon. Polymers that are stable in the upper GI tract and degraded by colonic micro-flora include azo cross-linked synthetic polymers and plant polysaccharides, such as amylose, pectin, inulin, and guar gum.

A disadvantage of polymeric coating or embedding approaches for colonic drug delivery is their dependence on the bacterial microflora in the large intestine. Although the microflora is fairly constant in the healthy population, it can be affected by the dietary fermentation precursors, type of diet consumed, and coadministration of antibiotics. In addition, the nat-ural polymers are often not available in pure form, which can lead to physi-cochemical incompatibility with the drug substance and/or inconsistency of product performance.


pH-dependent dosage forms

pH-sensitive polymers have been widely used for enteric coating of dosage forms to facilitate pH-dependent drug release. As the pH increases progres-sively from stomach (pH 1–2) to small intestine (pH 6–7), and the distal ileum (pH 7–8), dosage forms can be coated with polymers that dissolve only the aforementioned specific pH ranges. For colon targeting, the poly-meric coating should be able to withstand the acidic pH of the stomach and higher pH of the proximal small intestine, but dissolve in the neutral to slightly basic pH of the terminal ileum. However, most of the commonly used enteric coating polymeric systems have a pH threshold of 6.0 or lower for dissolution. These include the methacrylic acid/methyl methacrylate copolymers, (Eudragits® L100, L-30D, L100-55), polyvinylacetate phthal-ate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), and cellulose acetate trimelliate (CAT). Only Eudragit® S100 and FS 30D have a higher pH threshold of 6.8 and 7.0, respectively.

Eudragit® S100 coating is used, for example, in the mesalamine (Asacol®, Procter &Gamble)-delayed release tablets for topical anti-inflammatory action in the colon. Eudragit® L100 and S100 are copolymers of meth-acrylic acid and methyl methacrylate with the ratio of carboxyl to ester groups of 1:1 or 1:2, respectively. The carboxylate groups form salts, lead-ing to polymer dissolution at basic pH. Drug release from these acrylate polymers also depend on the plasticizer, nature of the salt in the dissolu-tion medium, and permeability of the film. Colon-targeted dosage forms utilizing methacrylate resins for coating or matrix formation have been reported in several molecules such as bisacodyl, indomethacin, 5-FU, and budesonide.

The use of pH trigger for drug delivery to the colon, however, has the disadvantage of inconsistency in dissolution of the polymer at the desired site due to inter- and intraindividual pH variation, among other factors. For example, Ashford et al. observed significant variability in the disintegration time and location of Eudragit® S coated tablets in human volunteers. In addition, based on GI motility, polymer dissolution can complete toward the end of the ileum or deep in the colon. In addition, factors such as the presence of short-chain fatty acids and residues of bile acids in the luminal contents, and the locally formed fermentation products can reduce the local pH, thus influencing the drug release mechanism.


Time-dependent drug release

Human small intestinal transit time for pharmaceutical dosage forms was measured using gamma scintigraphy and found to be about 3–4 h. Although the transit time does vary with the amount of food and the type of dosage form, it is less variable than the gastric emptying time. Timed release of dosage forms to target the colon are, thus, typically formulated to prevent drug release in the acidic gastric environment and to prevent the release of drug until 3–4 s after leaving the acidic gastric environment.

An example of such timed-release dosage form is the Pulsincap® device. In this device, the drug formulation is sealed in an impermeable capsule body with a hydrogel polymer plug. The hard gelatin capsule body may be made insoluble by exposure to formaldehyde vapor, which cross-links gelatin. The plug expands in the aqueous GI tract fluid and exits the body, thus releasing drug, after a time delay determined by the rate of expansion and the length of the plug.

Another approach utilized a three-layer coated dosage form with an inner coating of an acid-soluble polymer, Eudragit® E; followed by a water-soluble coat, and the outer enteric coating of Eudragit® L. An organic acid (succinic acid) was used as a part of the formulation. On oral administra-tion, the dosage form is protected in the acidic gastric environment by the enteric coating. In intestinal conditions, water ingress into the formulation lowers the pH inside the dosage form by the dissolution of the organic acid.

This, in turn, causes the inner, acid-labile coat to dissolve, thus releasing the drug. Drug release rate and lag time is controlled by the coating thickness of the acid-soluble layer and the amount of organic acid in the formulation. Using this approach, Fukui et al. prepared timed-release press-coated tablets with the core tablets containing diltiazem hydrochloride (DIL) and the outer, water soluble, layer containing phenylpropanolamine hydrochlo-ride (PPA), as a marker for gastric emptying time. On administration to beagle dogs, the gastric emptying time and lag time after gastric empty-ing were evaluated by determining the times at which PPA and DIL first appeared in the plasma, which were about 4 and 7 h, respectively. The 3 h lag time between the time of appearance of these drugs in the plasma correlated well with the expected intestinal transit time.

An inherent limitation of the time-dependent drug release systems inter-and intraindividual variability in gastric emptying, and small intestinal and colonic transit time. This can result in variations in the site of drug release in the small intestine or within the colon, which can impact drug absorp-tion as absorption by the transcellular route diminishes in the distal colon.


Osmotically controlled drug delivery systems

Osmotic DDSs, such as the OROS-CT® system of Alza Corporation, are based on the incorporation of an osmotic agent, such as a salt, in the dos-age form. The dosage form is encapsulated in a semipermeable membrane with an orifice for drug release. On ingestion, osmotic pressure gradient forces the ingress of water, which leads to the formation of flowable gel in the drug compartment and generates pressure to force the drug gel out of the orifice at a controlled rate. Amount of the osmotic agent, rate of water permeation, and size of the laser-drilled orifice primarily determine the drug release rate. The release rate can be extended for 4–24 h in the colon and the each osmotic unit is designed for a 3–4 hpostgastric delay for drug release.

A modification of the osmotic pump suitable for colonic drug delivery involves microbially triggered release mechanism. Liu et al. exploited the gelation of chitosan under acidic conditions and its degradation in the colon to use it as an osmotic agent and as a pore-forming agent in the impermeable cellulose acetate membrane. The authors designed a dosage form containing citric acid and chitosan in the drug containing core, which had a coating of cellulose acetate and chitosan, followed by an enteric coat of methacrylic acid/ methyl methacrylate copolymer, Eudragit® L100. As shown in Figure 15.6a, on reaching the small intestine, the enteric coat dissolves followed by water permeation into the core, leading to the formation of a flowable gel through dissolution of citric acid and swelling of chitosan. However, chitosan in the cellulose acetate membrane is completely dissolved only in the colonic microenvironment, thus preventing significant drug release until the dos-age form reaches the colon. Figure 15.6b shows drug (budesonide, used as a model drug)-release inhibition at gastric and intestinal pH and controlled release in the simulated colonic fluid (SCF), which was a function of the amounts of chitosan and citric acid, and the coating thickness. On similar lines, Kumar et al. designed a metronidazole delivery system using guar gum as a pore-forming agent and showed in vitro drug-release characteristics that demonstrated its potential for colon targeting.


Figure 15.6 Drug delivery to the colon. An osmotic pump colonic drug delivery system that utilizes gelation of chitosan under acidic conditions and its degradation in the colon by the local microflora: (a) core tablets contain both the drug and chitosan. Cores are coated with a semipermeable membrane of cellulose acetate and chitosan, followed by the outermost enteric coating of Eudragit® L 100. The dosage form stays intact in the stomach environment (Figure A1). Dissolution of the enteric coat in the small intestine is followed by water penetration into the core and formation of a flowable gel (Figure A2). When the dosage form arrives in the colon, the colonic microflora degrade chitosan particles in the coating leading to pore formation in the coat (Figure A3). This allows the flowable gel in the core of the tablet to extrude out from the semipermeable cellulose acetate coating in the colon and (b) in vitro drug release from this formulation was inhibited in the simulated gastric and intes-tinal fluids, which represent the first 6 h of dissolution profile. 

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