Colon Specific Drug Delivery

colon Specific Drug DeliveryABSRACTThe colon is a site where both local and governanceic delivery of doses can takes place. Colon limited medicate delivery has achieved importance for the delivery of doses for the treatment of local diseases associated with the colon like crohns disease, ulcerative colitis etc. as considerably as for the dodgingic delivery of proteins, therapeutic peptides, antiasthmatic medicates, antihypertensive medicates and antidiabetic agents. A do drugs need to be protected from degradation, release and absorption in the velocity grapheme of lowlife and then to be ensured abrupt and controlled release in the proximal colon. This article re stares a detailed study nigh need of colon specific drug delivery, limitation and challenges, factors affecting colonic drug delivery, different approaches of colon including some successful novel approaches such as CODESTM, Pulsinicap system, Port system, Colal pred system, Multiparticulate system and likewis e a study on evaluation for site specific drug delivery to colon.INTRODUCTIONDrug administration by an oral route is the most convenient and important route of administering drugs for systemic effect. At about 50% of the drug delivery systems available in the market are oral drug delivery systems and these systems get more benefits due to patient acceptance and ease of administration. During the last decade considerable interest has been given in growth site-specific formulations for targeting drugs to the colon. Colon specific drug delivery has achieved increased importance not only for the delivery of the drugs for the treatment of local disorders associated with the colon like Crohns disease, ulcerative colitis, irritable bowel syndrome and constipation but also for the systemic delivery of proteins and peptides, antihypertensive drugs, antiasthmatic drugs and antidiabetic agents. The colon specific drug delivery system should have capability to protect the drug en route to t he colon i.e. drug release and drug absorption should not occur in the stomach as well as the small gut, and the bioactive agent should not be degraded in either of the dissolution sites but only released and absorbed once the system reaches the colon.1Colon targeted drug delivery would additionally be valuable when a delay in absorption is desired from a therapeutically point of view in the treatment of diseases that have peak symptoms early in the morning, such as nocturnal asthma, angina or arthritis. The rapid advancement of biotechnology and hereditary engineering resulted into availability of peptides and proteins at reasonable costs there has been an increased interest in utilizing the colon as site for drug absorption. The potential candidates in this respect include analgesic peptides, oral vaccines, contraceptive peptides, growth hormone, insulin, erythropoietin, interferon, and interleukins (Saffran et al., 1988 Mackay and Tomlinson, 1993).2The colon is a satisfactory absorption site for peptides and protein drugs due to i) less diversity and specialty of digestive enzymes ii) less proteolytic activity of colon mucosa resulting in better prevention from hydrolysis and enzymatic degradation in duodenum and jejunum iii) increased systemic bioavailability iv) capacious colon residence time (5 days) and high responsiveness to absorption enhancers.There are event of methods or techniques through which colon drug targeting can be achieved, such as formation of prodrug, coating with pH sensitive polymers, coating with biodegradable polymers, designing formulations using polysaccharides, timed release system, pressure-controlled drug delivery systems, osmotic pressure controlled systems etc.Need of colon targeted drug deliveryColon targeted drug delivery system would asssure direct treatment at the disease site, write down dosing and fewer systemic side effects.Site-specific drug delivery system would allow oral administration of protein and peptide drugs, colon-specific formulation could also be used to prolong the drug delivery.Colon-specific drug delivery system is useful 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 Crohns disease. These inflammatory conditions are majorly treated with glucocorticoids and sulphasalazine (targeted).A number of others serious disorders of the colon, e.g. colorectal cancer, may also be capable of being treated more effectively if drugs were targeted to the colon.Formulations for colonic delivery are also suitable for delivery of drugs which are polar and/or susceptible to chemical and enzymatic degradation in the upper GI tract, highly affected by liverwort front pass metabolism, in particular, therapeutic proteins and peptides.3Limitations and challenges in colon targeted drug delivery systemA challenge in the development of colon specific drug d elivery systems is to set up an catch dissolution testing method for in-vitro evaluation of the designed system. This is due to the rationale after a colon specific drug delivery system is quite different.As a site for drug delivery, the colon provides a near neutral pH, low digestive enzymatic activity, a long transit time and enhanced sensitivity to absorption enhancers however, the targeting of drugs to the colon is very complicated. Owing to its location in the distal part of the alimentary canal, the colon is predominantly difficult to access. In addition to that the variation in pH values and different enzymes present throughout the gastrointestinal tract, through which the dosage form has to pass before reaching the target site, further complicate the consistency and delivery efficiency.Successful delivery through this site also needs the drug to be in solution form before it reaches the colon or alternatively, it should dissolve in the luminal mobiles of the colon, but th is 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.The stability of the drug is also taken into consideration while designing a drug delivery system, because it may contain nonspecific way to viandsary residues, intestinal secretions, mucus or faecal matter.Low surface area and relative tightness of the tight junctions in the colon can also limit drug transport across the mucosa and into the systemic circulation.4Anatomy and physiology of colonThe gastrointestinal tract is hollow muscular tube. It takes in nutrients and eliminate waste by such physiological processes as secretion, motility, digestion, absorption and excretion. Depending on structure and functions, the gastrointestinal tract is divided into the mouth, pharynx, oesophagus, stomach, small intestine and hulking intestine. The large intestine is approximately 1.5m in length and extends from the ileocaecal j unctions to the anus. It is divided into four parts caecum, colon, rectum and anal canal.5The entire colon is approximately 5 feet (150 cm) long, and is divided into tail fin major portions. Peritoneal folds called as mesentery which is supported by ascending and descending colon. The right colon consists of the caecum, ascending colon, hepatic flexure and the right half of the transverse colon. The left colon consists of the left half of the transverse colon, descending colon, splenic flexure and sigmoid. The rectum is the last anatomic segment before the anus. The human colon were shown in Figure1.The main functions of the colon is to make suitable environment for the growth of colonic microorganisms, storage reservoir of faecal contents, expulsion of the contents of the colon at an appropriate time and absorption of potassium and water from the lumen. The absorptive capacity is very high, at about 2000ml of fluid enters the colon through the ileocecal valve from which more than 90% of the fluid is absorbed6.The colon is involved in fermentation of polysaccharides and proteins, absorption of water and electrolytes and the formation, storage and elimination of faecal material. As a consequence of the functions of the colon, the colonic environment is broadly speaking viscous in nature. This could impact on the performance of drugs and delivery systems in this theatrical role of gut. Rapid water absorption in the ascending colon results in the distal colonic contents being more viscous. It has been estimated that the human colon contains only 220g of wet contents. In addition colon has a near neutral pH and is home to a viable microflora. These bacterium are involved in the fermentation of polysaccharides and proteins that have escaped digestion in the upper gut. Moreever the resident bacteria can also metabolize drug. The protein based drugs, insulin and calcitonin are rapidly degraded in simulated colonic contents5.Fig 1 Anatomy of colonFactors influenci ng colonic drug deliveryPhysiological factors1. Transit through gastro intestinal tractOrally taken dosage forms first enters into stomach and small intestine via mouth and then reach colon. The nature and pH of the stomach affects the drug release and absorption. In order to effectively deliver tablet to colon in an intact form, the drug delivery systems should bypass the roadblocks in the stomach and small intestine. Gastrointestinal transit varies from 1 hr to 3 hrs depending upon the condition fasting or non-fasting respectively. In general, the small intestinal transit is not influenced by the physical state, size of the dosage form. The mean transit time of the dosage form is about 3-4 hours in order to reach the ileocecal junction and the time period is inconsistent. During this time the dosage form is exposed to enzymes present in small intestine. Compared to the other region of GIT, movement of material through the colon is slow. Total time for transit tends to be highly va riable and influenced by number of factors such as diet particularly dietary fibre content, mobility, stress, disease condition and drugs. The colonic transit time is ranging from 20 to 30 hours, can be increase in front of active disease 50 to 70 hours. Longer residence time with subsequent longer transit time and the contact of dosage formwith micro flora in colon govern the release and improve absorption of drug from dosage form.7Table 1 Transit time of dosage forms in GITOrganTransit time(hr)Stomach3 (fed)Small intestine3-4Large intestine20-302. pKa of the drug, lipophilicity and gastrointestinal pHThe pH partition theory explains the process of drug absorption from the GIT and its distribution across all biological membranes. It states that for drug molecules of molecular weight greater than 100, which are mainly transported across the biological membranes by passive diffusion,the process of absorption is governed by1) The dissociation constant (pKa) of the drug.2) The lipophi licity of unionized drug.3) The pH at the absorption site.Since most of the drugs are worn electrolytes (weak acids or weak bases), their degree of ionization depends upon the pH of the biological fluid. If the pH on the either side of the membrane is different, then the compartment in which pH favors greater ionization of the drug will contain greater amount of drug, and only the unionized form of drug, if adequately lipid soluble, allowed to permeate the membrane passively until the concentration of unionized drug on both side of the membrane becomes equal i.e. until equilibrium is attained.The above statement of the hypothesis was on the basis of the assumptions that1) The GIT is a simple lipoidal barrier to the transport of drug.2) Larger the fraction of unionized drug, faster the absorption(D. M. Brahmankar et al 2009).3.pH of colonThe pH of GIT varies in each individual. The food intakes, diseased state, etc.influences the pH of the GIT. This miscellanea in the pH in differe nt regions of GIT is the basis for the development of colon targeted drug delivery systems. Coating with different polymers is done to target the drug to the site.Table 2 pH in different regions of gastrointestinal tractPart of GITPhStomach (before meal)1-2Stomach (during digestion)4Smll intestine6-7Duodenum6.6+0.5Ileum7.5+0.4 cecum6.4+0.4Colon5.5-7Rectum74. Colonic microfloraA number of anaerobic and aerobic bacteria are present throghout entire length of the human GI tract. everyplace 400 different bacterial species have been found, 20-30% of which are of the genus bacteroids. The upper region of the GIT has a very small number of bacteria and predominantly consists of gm positive bacteria. The rate of microbial growth is greatest in the proximal areas because of high concentration of energy source.Concentration of microflora is generally about1011-1022 CFU/ml.It consists of Bacteroids, Bifidobacterium, Ruminococcus, Eubacterium and Clostridium.Chief metabolous reactions carried by the enzymes released from colonic microflora are hydrolysis and reduction. Table 3 Different microflora, enzymes and their actionsEnzymeMicroorganismMetabolic reactions catalysedNitroreductaseE. coli, BacteroidsReduced aromatic and heterocyclic nitro compoundsAzoreductaseClostridia, Lactobacilli, E.coliReduced cleavage of azo compoundsN oxide reductase,Sulphoxide reductaseE. coliReduced N oxides and sulphoxidesHydrogenaseClostridia, LactobacilliReduced carbonyl groups and aliphatic double bondsEsterases and amidasesE. coli,P. vulgaris, B.subtilis, B. mycoidesCleavage of esters or amidases of carboxylic acidGlucosidaseClostridia, EubacteriaCleavage of b- glycosidase of alcohols and phenolsGlucoronidaseE.coli, A. aerogenesCleavage of b glycosidase of alcohols and phenolsSulphataseEubacteria, streptococciCleavage of O-sulfates and sulfamatesPhamaceutical factorsa) Drug candidateDrugs which show poor absorption in the stomach and intestine are most suitable for colon delivery. Drug s such as theophylline, nifedipine, diclofenac, ibuprofen, metoprolol, isoosorbide dinitrate, oxyprenolol and low molecular weight peptides and Peptide like drugs have been shown to be effectively absorbed from the colon.b) Drug carrierThe selection of carrier for a particular drug candidate depends on the physicochemical nature of the drug as well as the disease for which the system is to be utilized. The factors such as chemical nature, stability and partition coefficient of drug and the type of absorption enhancers influences the carrier selection.9Table 3 Drugs in colon targeted drug deliverySr. No.CriteriaPharmacological casteDrug and active agents1Drug used for local effect in colonAnti-inflammatory DrugsOxyprenolol, Metoprolol, Nifedipine, Diclofenac, Sodium, Amylin, Antisense Oligonucleotide,2Drugs poorly absorbed from upper GITAntihypertensive and antianginal drugsIbuprofen, Isosorbides, Theophylline, Desmopressin Cyclosporine A,3Drugs for colon cancerAntineoplasticsPseudo ephedrine, epoetin, Glucagon4Drugs that degrade in stomach and small intestinePeptides and proteinsBromopheniramine, 5 Flurouracil, Doxorubicin, Gonadoreline, Insulin, Interferones5Drugs that undergo extensive first pass metabolismNitroglycerin and corticosteroidsNimustine, Bleomycin, Nicotine, Dexamethasone, protirelin, Sermorelin, Molgramoatim, Salotonin.