2. Oral delivery of drugs to the colon is valuable in the treatment of diseases of colon like ulcerative colitis, chron’s disease, carcinomas and infections

3. The elucidation of the mode of action of some nonsteroidal anti-inflammatory drugs (NSAID) such as sulfide (metabolized in the colon to the active moiety, sulfide) that were found to interfere with the proliferation of colon polyps (first stage in colon carcinoma) possibly in local manner.

4. In some cases the colon is capable of absorbing drugs efficiently.

5. Drug absorption enhancement works better in the colon than in the small intestine.

6. Protein drugs can be absorbed better from the large bowel owing to hypothetic reduced proteolytic activity in this organ.

7. The unique metabolic activity of colon, which makes it an alternative organ for drug delivery system designer.

ADVANTAGES OF COLONIC DRUG DELIVERY:⁴

1. Local action, in case of disorders like ulcerative colitis, chron’s disease, irritable bowel syndrome, and carcinomas. Targeted drug delivery to the colon in these cases ensures direct treatment at the site with lower dosing and fewer systemic side effects.

2. In addition to local therapy colon can also be utilized as the portal entry of the drugs into systemic circulation for example molecules that are degraded/poorly absorbed in upper gut such as proteins and peptides may be better absorbed from the more benign environment of the colon.

3. The systemic absorption from colon can also be used as means of achieving chemotherapy for diseases that are sensitive to circadian rhythm such as asthma, angina and arthritis.

4. By colon targeting drug can be supplied to the biophase only when it is required and maintenance of the drug in its intact form as close as possible to the target site.

DISADVANTAGES OF COLONIC DRUG DELIVERY:⁵

1. The pH level in the small intestine and colon vary between and within individuals due to which drug may be released at undesired site due to pH variability. The pattern of drug release may differ from person to person which may cause ineffective therapy.

2. The pH level in the small intestine and cecum are similar which reduces site specificity of formulation.

3. Poor site specificity is the major disadvantage of colonic delivery of drug.

4. Diet and diseases can affect colonic microflora which can negatively affect drug targeting to colon. Nature of food present in GIT can affect drug pharmacokinetics. In diseased conditions pH level of GIT differs from pH level of healthy volunteers which alters the targeted release of formulations which release the drug according to pH of desired site.

5. Enzymatic degradation may be excessively slow which can delay the enzymatic degradation of polymer thus alters the release profile of drug.

6. Substantial variation in gastric retention time may cause drug release to undesired site in case of time dependent colonic drug delivery system.

Why colon is targeted drug delivery needed?⁶

· Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.

· Site-specific or targeted drug delivery system would allow oral administration of peptide and protein drugs, colon-specific formulation could also be used to prolong the drug delivery.

· Colon-specific drug delivery system is considered to be beneficial in the treatment of colon diseases.

· The colon is a site where both local or systemic drug delivery could be achieved, topical treatment of inflammatory bowel disease, e.g. ulcerative colitis or Crohn’s disease. Such inflammatory conditions are usually treated with glucocorticoids and sulphasalazine (targeted).

· A number of others serious diseases of the colon, e.g. colorectal cancer, might also be capable of being treated more effectively if drugs were targeted to the colon.

Colonic diseases⁷

§ Crohn’s Diseases

§ Ulcerative Colitis

§ Diversional Colitis

§ Ischemic Colitis

§ Diverticular Inflammatory Bowel Disease

§ Colon Cancer

§ Lymphoma of the Colon

Approaches to colon-specific drug delivery:⁸^-10

Colon-specific drug delivery is considered beneficial in the treatment of colon-related diseases and the oral delivery of protein and peptide drugs. Generally, each colon-specific drug delivery system has been designed based on one of the following mechanisms with varying degrees of success;

1. Coating with pH dependent polymers

2. Coating with pH independent biodegradable polymers

3. Delivery systems based on the metabolic activity of colonic bacteria.

General considerations for design of colonic formulations:

Formulations for colonic delivery are, in general, delayed-released dosage forms which maybe designed either to provide a ‘burst release’ or a sustained / prolonged / targeted.

a. Pathology and of disease, especially the affected parts of the lower GIT.

b. Physicochemical and biopharmaceutical properties of the drug such as solubility, stability and permeability at the intended site of delivery.

c. The preferred release data of the drug. Very common physiological factor which is considered in the design of delayed release colonic formulations is pH gradient of the GI tract. In normal healthy subjects, there is a progressive increase in luminal pH from the duodenum (pH is 6.6±0.5) to the end of the ileum (pH is 7.5 ± 0.4), a decrease in the cecum (pH is 6.4 ± 0.4), and then a slow rise from the right to the left colon with a final value of 7.0 ± 0.7. Some reports suggested that alterations in gastrointestinal pH profiles may occur in patients with inflammatory bowel disease, which should be considered in the development of delayed release formulations.

Types or modified release formulations for colon targeted drug delivery systems ^11-13

These are of two types:

1. Single unit colon targeted drug delivery system: It may suffer from the disadvantage of unintentional disintegration of the formulation due to manufacturing deficiency or unusual gastric physiology that may lead to drastically compromised systemic drug bioavailability or loss of local therapeutic action in the colon.

2. Multiparticulate dosage form systems: These are developed in comparison to single unit systems because of their potential benefits like increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying.

Multiparticulate approaches tried for colonic delivery includes formulations in the form of pellets, granules, microparticles and nanoparticles. The use of multiparticulate formulations in preference to single unit dosage forms for colon targeting purposes. Showed that multi particulate formulations enabled the drug to reach the colon quickly and were retained in the ascending colon for a relatively long period of time. Because of their smaller particle size as compared to single unit dosage forms these systems tend to be more uniformly dispersed in the GI tract and also ensure more uniform drug absorption. Most commonly investigated multi particulate formulations for colon specific drug delivery include pellets, granular matrices, beads, microspheres, and nanoparticles. Examples of colon targeted formulations

Limitations and challenges in colon targeted drug delivery:¹⁵^-17

Ø One challenge in the development of colon-specific drug delivery systems is to establish an appropriate dissolution testing method to evaluate the designed system in-vitro. This is due to the rationale after a colon specific drug delivery system is quite diverse.

Ø As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time and increased responsiveness to absorption enhancers; however, the targeting of drugs to the colon is very complicated. Due to its location in the distal part of the alimentary canal, the colon is particularly difficult to access. In addition to that the wide range of pH values and different enzymes present throughout the gastrointestinal tract, through which the dosage form has to travel before reaching the target site, further complicate the reliability and delivery efficiency.

Ø Successful delivery through this site also requires the drug to be in solution form before it arrives in the colon or, alternatively, it should dissolve in the luminal fluids of the colon, but this can be a limiting factor for poorly soluble drugs as the fluid content in the colon is much lower and it is more viscous than in the upper part of the GI tract.

Ø In addition, the stability of the drug is also a concern and must be taken into consideration while designing the delivery system. The drug may potentially bind in a nonspecific way to dietary residues, intestinal secretions, mucus or faecal matter.

Ø The resident microflora could also affect colonic performance via metabolic degradation of the drug. Lower surface area and relative ‘tightness’ of the tight junctions in the colon can also restrict drug transport across the mucosa and into the systemic circulation.

Current and future developments:

Currently, there are several modified release solid formulation technologies available for colonic delivery. These technologies rely on GI pH, transit times, enterobacteria and luminal pressure for site-specific delivery. Each of these technologies represents a unique system in terms of design but has certain shortcomings, which are often related to degree of site specificity, toxicity, cost and ease of scale up/manufacturing. It appears that microbially controlled systems based on natural polymers have the greatest potential for colonic delivery, particularly in terms of site-specificity and safety. In this regard, formulations that employ a film coating system based on the combination of a polysaccharide and a suitable film forming polymer represents a significant technological advancement. Further developments in this area require means to improve the coprocessing of the polymeric blend of a polysaccharide(s) and a film forming material while maintaining the propensity of the composition to microbial degradation in the colon ^18-20.

Opportunities in colon targeted drug delivery:²¹^-23

§ In the area of targeted delivery, the colonic region of the GI tract is the one that has been embraced by scientists and is being extensively investigated over the past two decades.

§ Targeted delivery to the colon is being explored not only for local colonic pathologies, thus avoiding systemic effects of drugs or inconvenient and painful transcolonic administration of drugs, but also for systemic delivery of drugs like proteins and peptides, which are otherwise degraded and/or poorly absorbed in the stomach and small intestine but may be better absorbed from the more benign environment of the colon.

§ This is also a potential site for the treatment of diseases sensitive to circadian rhythms such as asthma, angina and arthritis. Moreover, there is an urgent need for delivery of drugs to the colon that reported to be absorbable in the colon, such as steroids, which would increase efficiency and enable reduction of the required effective dose.

§ The treatment of disorders of the large intestine, such as irritable bowel syndrome (IBS), colitis, Crohn’s disease and other colon diseases, where it is necessary to attain a high concentration of the active agent, may be efficiently achieved by colon-specific delivery.

§ The development of a dosage form that improves the oral absorption of peptide and protein drugs whose bioavailability is very low because of instability in the GI tract is one of the greatest challenges for oral peptide delivery.

§ The bioavailability of protein drugs delivered at the colon site needs to be addressed.

§ More research is focused on the specificity of drug uptake at the colon site is necessary. Such studies would significant in advancing the cause of colon targeted drug delivery in future.

NEW APPROACHES:

Microbially triggered system:

These systems are based on the exploitation of the specific enzymatic activity of the microflora (enterobacteria) present in the colon. The colonic bacteria are predominately anaerobic in nature and secrete enzymes that are capable of metabolizing substrates such as carbohydrates and proteins that escape the digestion in the upper GI tract [6-8]. Bacterial count in colon is much higher around 1011-1012 CFU/ml with some 400 different species which are fundamentally aerobic, predominant species such as Bacteroides, Bifidobacterium and Eubacterum etc., whose major metabolic process occurring in colon are hydrolysis and reduction. The enzymes present in the colon are²⁴.

1. Reducing enzymes: Nitroreductase, Azoreductase, N-oxide reductase, sulfoxide reductase, Hydrogenase etc.

2. Hydrolytic enzymes: Esterases, Amidases, Glycosidases, Glucuronidase, sulfatase etc.

The vast microflora fulfills its energy needs by fermenting various types of substrates that have been left undigested in the small intestine, e.g. di- and tri-saccharides, polysaccharides etc. For this fermentation, the microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, deaminase, and urea dehydroxylase. Because of the presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery seems to be a more site-specific approach as compared to other approaches. These polymers shield the drug from the environments of stomach and small intestine, and are able to deliver the drug to the colon. On reaching the colon, they undergo assimilation by micro-organism, or degradation by enzyme or break down of the polymer back bone leading to a subsequent reduction in their molecular weight and thereby loss of mechanical strength. They are then unable to hold the drug entity any longer²⁵.

Targeted prodrug Design:

Classical prodrugs design often represents a non-specific chemical approach to mask unwanted drug properties such as low bioavailability, less site specific, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, prodrugs targeting to a specific enzymeor a specific membrane transporter, or both, have potential drug delivery system especially for cancer chemotherapy²⁶.

Polysaccharide based systems:

The polysaccharide which is polymer of monosaccharide retains their integrity, because they are resistant to digestive action of GI enzymes, matririces of polysachharide are assessed to remain intact in physiological environment of stomach and small intestine, as they reach colon they areacted upon bacterial polysaccharidases and results in degradation of the matrixes. Family of natural polysaccharide has appeal to area of drug delivery as it comprised of polymer with large number of derivitizable groups, with wide range of molecular weight, varying chemical composition and form most low toxicity and biodegradability, yet a high

Stability^27-29 (Table 1).

Delayed release oral polypeptides:³⁰^-32

In one embodiment, the composition further includes an inert core. The inert core can be, e.g., a pellet, sphere or bead made up of sugar, starch, microcrystalline cellulose or any other pharmaceutically acceptable inert excipient. A preferred inert core is a carbohydrate, such as a monosaccharide, disaccharide, or polysaccharide, i.e., a polymer including three or more sugar molecules. An example of a suitable carbohydrate is sucrose. In some embodients, the sucrose is present in the composition at a concentration of 60-75%. When the bioactive polypeptide is IL-11, the IL-11 layer is preferentially provided with a stabilizer such as methionine, glycine, polysorbate 80 and phosphate buffer, and/or a pharmaceutically acceptable binder, such as hydroxypropyl methylcellulose, povidone or hydroxypropyl ‘cellulose. The composition can additionally include one or more pharmaceutical excipients. Such pharmaceutical excipients include, e.g., binders, disintegrants, fillers, plasticizers, lubricants, glidants, coatings and suspending/ ispersing agents. In some embodiments, the composition is provided as a multiparticulate system that includes a plurality of enteric coated, IL-11 layered pellets in a capsule dosage form. The enteric coated IL-11 pellets include an inert core, such as a carbohydrate sphere, a layer of IL-11 and an enteric coat. The enteric coat can include, e.g., a pH dependent polymer, a plasticizer, and an antisticking agent/glidant.

Preferred polymers include e.g., methacrylic acid copolymer, cellulose acetate phthalate, hydroxyl propyl methylcellulose phthalate, polyvinyl acetate phthalate, shellac, hydroxylpropyl methylcellulose acetate succinate and carboxymethylcellulose. Preferably, an inert seal coat is present in the composition as a barrier between the IL-11 layer and enteric coat. The inert seal coat can be e.g. hydroxyl propyl methyl cellulose, povidone, hydroxylpropyl cellulose or another pharmaceutically acceptable binder. Suitable sustained release polymers include, e.g., amino methacrylate copolymers (Eudragit RL, Eudragit RS), ethylcellulose or hydroxypropyl methylcellulose. In some embodiments, the methacrylic acid copolymer is a pH dependent anionic polymer solubilising above pH 5.5. The methacrylic acid copolymer can be provided as a dispersion and be present in the composition at a concentration of 10-20% wt/wt. A preferred methacrylic acid copolymer Eudragit® L30D-55 19.

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Received on 14.08.2011

Accepted on 15.09.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(6): Nov.- Dec., 2011, 241-246

Polysaccharide	Chemical name	General properties	Bacterial species
Amylose	α- 1,4 D-glucose	Unbranched constituents of starch used as excipients in tablets formulation	Bacteriods, Bifidobacterium
Arabinogalactone	β-1,4 and β-1,3 D- galactose, β-1,6 and β-1,3 D-arabinose and D-galactose	Natural pectin, hemicelluloses used as thickening agents	Bifidobacterium
Chitosan	Deacetylated β-1,4 N-acetyl D-glycosamine	Deacetylated chitin used as absorption enhancing agents	Bacteroids
Chondroitin sulfate	Β-1,3, D-glucoronic acid and N-acetyl D-glycosamine	Mucosopolysaccharides contains sulphate ester group at 4 or 6 position	Bacteroids
Cyclodextran	α- 1,4 D-glucose	Cyclic structure of 6, 7 or 8 units, high stability against Amylase, used as drug solubilising agent and absorption enhancer	Bacteroids
Dextran	α- 1,6 D-glucose α- 1,3 D-glucose	Plasma expanders	Bacteroids
Guar gum	α- 1,4 D-mannose α- 1,4 D-galactose	Galactomannan used as thickening agents	Bacteroids Ruminococcus
Pectin	α- 1,4 D-galactouronic acid and 1,2 D- Rhamnose with D-galactose and D-arabinose side chains	Partial methyl ether commonly used as thickening agents	Bacteriods, Bifidobacterium Eubacterium
Xylan	β-1,4 D-xylose with β-1,3 L-arabinose side chains	Abundant hemicelluloses of plant cell wall	Bacteriods, Bifidobacterium