Targeting In The Gastrointestinal Tract And To Other Mucosal Surfaces

The alimentary canal has been and continues to be the preferred route for drug administration for systemic drug action. Thus, there is a growing interest in developing oral dosage forms that can either (i) exert a therapeutic effect at a specific site in the GI tract (see Ref. 42 for diseases of the GI tract) or (»') allow systemic absorption of drugs or prodrugs utilizing a specific region of the alimentary canal, without being affected by the GI fluid, pH fluctuations, enzymes, and microflora, while traveling along the GI tract. The various anatomical, physiological, physicochemical, and biochemical features of various regions of the alimentary canal, including intestinal transporters that influence drug targeting and possible formulation approaches that can be used, have been reviewed by Ritschel (43) and Oh et al. (358) The theoretical rationale and potential for targeting various microflora that reside in the GI tract as possible therapeutic and prophylactic strategies has been recently described by Jia et al. (359).

Depending on the site in the GI tract where drug release is sought, a variety of approaches can be used. Bioadhesive polymers are used to prepare adhesive tablets and films for use in the buccal cavity and other regions of the alimentary canal (360). These polymers adhere to a biological tissue for an extended period, thereby providing increased local therapeutic effect or prolonged maintenance of therapeutic amounts of drug in the blood. Examples of bioadhesive polymers commonly used include hydroxypropylcellu-lose, poly(acrylic acid) (Carbopol®), and sodium carboxymethylcellulose. Enteric polymers (e.g., cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, polyvinyl acetate phthalate, methacrylate-methacrylic acid copolymers, and others), which remain insoluble in the stomach but dissolve at higher pH of the intestine, are used to deliver drugs to the small intestine. Enteric coating also prevents drugs from degradation by gastric fluid and enzymes and protects the gastric mucosa from the irritating properties of certain drugs. Using coating solutions containing a mixture of cellulose acetate phthalate, Eudragit® SI00 (Rohm Pharma GmbH, Darmstadt, Germany), and Eudragit L30D and an acidic coating system containing succinic acid in a solution of ethylcellulose (Aquacoat) and hydroxypropylcellulose, Klokkers-Bethke and Fisher (361) developed a novel multiunit delivery system capable of targeting both the lower part of the bowel and the colon. Drug delivery to the stomach can be achieved using hydrodynamically balanced (floating) dosage forms (362). Because of lower bulk density, such dosage forms stay buoyant in the stomach, thereby resisting gastric emptying. Drug delivery systems that contain inflatable chambers (these become gas filled at body temperature) or solids (e.g., carbonates and bicarbonates) that form gases when in contact with gastric fluid also stay buoyant and are used to target drugs for release in the stomach

(363). A variety of techniques have been advocated for drug targeting the small intestine, including the use of polysaccharide swellable hydrogels (364).

Targeting drugs to the colon is of significance not only for local treatment of colonic diseases, such as ulcerative colitis, irritable bowel syndrome, and colon cancer, but also for drugs that are not well absorbed from other regions of the GI (365,366). Some examples of drugs that have shown enhanced efficacy upon delivery to colon are aminosalicylates, corticosteroids, and immunosuppressive agents. The successful delivery to the colon can be achieved by using prodrugs or by drug entrapment within or by coating with polymers that undergo enzymatic degradation in the colon. A number of pH-dependent polymers, such as enteric polymers (e.g., Eudragit S in Asacol®, from Proctor & Gamble Pharmaceuticals, Inc., Ohio, U.S., under license from Medeva Pharma Schweiz AG) have also been used to deliver drugs to the colon. However, because of a small difference in the pH of the small and large intestines and the fact that pH in the proximal and distal bowel, cecum, and colon can vary from 2.9 to 9.2, (frequently between 5.9 and 9.2), in patients with inflammatory bowel disease, ulcerative colitis, and Crohn's disease (367-371), such preparations may fail to produce the intended dose in the colon. The prodrug approach relies on the ready susceptibility of the prodrug carrier-drug linkages to enzymatic hydrolysis (e.g., hydrolysis of glycosides by glycosidases). Over 400 distinct microbial species, predominantly anaerobic, exist in the colon. They produce enzymes responsible for hydrolysis and redox reactions. Examples of hydrolytic enzymes are P-glucuronidases, P-xylosidase, and P-galactosidase and those of reductive enzymes include nitroreductase, azoreductase, and deaminase. Sinha and Kumaria (372) recently reviewed and listed several examples of prodrugs evaluated for colon-specific delivery. Macromolecule-based prodrugs are advantageous in that they remain intact and excreted with feces and hence pose no concerns of toxicity. Of particular importance are azo polymers [e.g., azo-linked poly(acrylic acid), poly(ester-ester), and copolymers of methylmetha-crylate and 2-hydroxyethyl methacrylate] (373-380). They have been used as a coating material or as a macromolecular prodrug carrier. The azo linkage is resistant to proteolytic digestion in the stomach and small intestine but degrades in the colon by the indigenous microflora [concentration 10n-1012 CFU/mL vs. mainly gram-positive <103 — 104 CFU/ mL microflora present in the upper part of GIT (381)] to produce the corresponding amines, causing the release of free drug. Several hydrogel formulations using azo-cross-linked polymers have also been developed (382-385), but they may be limiting because of the low drug-loading capability. It has been reported that differences in the redox potential between the colon and the other regions of the upper GI tract (stomach, -65 mV; proximal small intestine, —67±90 mV; distal small intestine, —196±97 mV; and colon, —415±72 mV), caused by microflora present in the respective segments, make these polymers susceptible to degradation in the colonic environment (372). Targeting in the colon is specifically important for polypeptide delivery, because there are no digestive enzymes in the colon, and the duration of residence is longer in the colon than in other regions of the GI tract [esophagus, 9-15 seconds; stomach, 0.4-4.5 hours; duodenum, jejunum, and ileum, 1-4 hours; cecum and colon, 4-16 hours; and rectum, 2-8 hours (43)]. Targeting in the colon is also feasible by pH and time-dependent pulsatile systems (386-388). The use of lectins (plant or microbial origin), neoglycoconjugates, and a number of natural polysaccharides (e.g., chitosan, pectin and its salts, chondroitin sulfate, cyclodextrin, dextrans, guar gum, inulin, amylose, and locust bean gum) as colon-specific drug carriers has been recently reviewed by Minko (389) and Sinha and Kumria (372). A number of colonic microflora are known to secrete polysaccharidases (e.g., P-d-glucosidase, amylase, pectinase, etc.), which can degrade polysaccharides and release the drug. Lectins, the naturally occurring proteins, are bioadhesives and show high specificity for sugar residues (e.g., d-Gal, GalNac, GlcNAc, a-d-Man, a-d-Glc, and Gal) attached to proteins and lipids of epithelial cells. They can trigger vesicular uptake by epithelial cells (41) and are hence ideally suited to target drugs to the intestine and buccal cavity. Lectins are also found on the epithelial cell surfaces and can hence be targeted as well by using synthetic polymers (e.g., HPMA) bearing sugars as ligands (390). Bridges et al. (391) reported that proximal regions of the gut showed greater accumulation of polymers bearing galactose, while fucose-containing polymers were more specific to distal regions of the gut. Uptake of polymeric particles in the inflamed colon has been found to be size dependent.

Rectal delivery, depending on the position of the dosage form in the rectum, can be used to target either the systemic circulation or the liver. For systemic targeting, the dosage form should be placed and located directly behind the internal rectal sphincter, whereas targeting the liver requires the dosage form to be placed in the ampulla recti (about 12-15 cm up the rectum) (50).

Targeting esophageal mucosa and other regions of the GI tract can also be achieved by using bioadhesive magnetic granules (392). The various parameters that influence targeting a specific site using bioadhesive magnetic granules include the composition of the formulation, the amount of the magnetic material in the granules, and the magnitude of the magnetic field. This approach can be used for local chemotherapy of esophageal cancer and for other diseases in the alimentary canal.

Although most drugs are absorbed from the intestine by the blood capillary network in the villi, they can also be taken up by the lymphatic system, predominantly by M cells that reside in the Peyer's patch regions of the intestine. Uptake of particles by M cells may involve specific fluid-phase pinocytosis or receptor-mediated phagocytosis. Various intestinal-uptake mechanisms of particles and their implications in drug and antigen delivery have been reviewed by O'Hagan (393) and Rieux (39). Peyer's patches have also been implicated in the regulation of the secretory immune response. Wachsmann et al. (394) reported that an antigenic material encapsulated within a liposome, when administered perorally, was taken up by these M cells and exhibited better saliva and serum IgA (primary and secondary) immune response than a simple solution of antigen (Fig. 11). In an attempt to demonstrate the use of microparticles as potential oral

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