Colon Specific Drug Delivery

Colon Specific Drug DeliveryABSRACTThe colon is a come out where twain local and systemic pitching of medicines foot takes place. Colon ad hoc do medicates voice communication has achieved grandness for the speech communication of medicines for the interference of local diseases associated with the colon ilk crohns disease, ulcerative colitis and so on as well as for the systemic actors line of proteins, therapeutic peptides, antiasthmatic doses, antihypertensive medicate drugs and antidiabetic agents. A drug need to be protected from degradation, douse and soaking up in the upper discussion section of GIT and then to be ensured abrupt and controlled clit in the proximal colon. This article reviews a expand study about need of colon specific drug legal transfer, terminus ad quem and challenges, parts affecting colonic irrigation drug oral communication, different approaches of colon including some lucky novel approaches much(prenominal) as CODESTM, Pulsini cap system, Port system, Colal pred system, Multiparticulate system and alike a study on valuation for site specific drug saving to colon.INTRODUCTIONDrug administration by means of an spoken route is the close convenient and important route of administering drugs for systemic effect. At about 50% of the drug delivery systems available in the market are oral exam drug delivery systems and these systems expect much benefits due to patient word meaning and ease of administration. During the last decade considerable interest has been given in developing site-specific formulations for prating drugs to the colon. Colon specific drug delivery has achieved alter magnitude importance non only for the delivery of the drugs for the treatment of local disorders associated with the colon like Crohns disease, ulcerative colitis, irritable catgut syndrome and constipation but also for the systemic delivery of proteins and peptides, antihypertensive drugs, antiasthmatic drugs and an tidiabetic agents. The colon specific drug delivery system should have capability to protect the drug en route to the colon i.e. drug release and drug absorption should not occur in the stomach as well as the slim intestine, and the bioactive agent should not be degraded in either of the extravagance sites but only released and absorbed once the system reaches the colon.1Colon targeted drug delivery would auxiliaryally 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, much(prenominal) as nocturnal asthma, angina or arthritis. The rapid advancement of biotechnology and genic 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 drop candidates in this respect include analgesic peptides, oral vaccines, contraceptive peptides, emergence h ormone, insulin, erythropoietin, interferon, and interleukins (Saffran et al., 1988 Mackay and Tomlinson, 1993).2The colon is a suitable absorption site for peptides and protein drugs due to i) less(prenominal) diversity and intensity of digestive enzymes ii) less proteolytic activity of colon mucous membrane resulting in better prevention from hydrolysis and enzymatic degradation in duodenum and jejunum iii) increased systemic bioavailability iv) long colon residence date (5 days) and higher(prenominal) responsiveness to absorption enhancers.There are spot 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 exploitation polysaccharides, sequenced release system, pressure-controlled drug delivery systems, osmotic pressure controlled systems etc.Need of colon targeted drug deliveryColon targeted drug delivery system would asssur e direct treatment at the disease site, lower dosing and few 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 tempered 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 first crystalise m etabolism, in particular, therapeutic proteins and peptides.3Limitations and challenges in colon targeted drug delivery systemA challenge in the evolution of colon specific drug delivery systems is to set up an appropriate 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 sensibility 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 GI tract, through which the back breaker form has to pass before hit the target site, further complicate the consistency and delivery efficiency.Successful deli very 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 rovings 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.The stability of the drug is also taken into consideration term designing a drug delivery system, because it may bind nonspecific way to dietary residues, intestinal secretions, mucus or faecal matter. impoverished surface area and relative tightness of the tight junctions in the colon can also limit drug get off crosswise the mucosa and into the systemic circulation.4Anatomy and physiology of colonThe gastrointestinal tract is hollow knock-down(a) tube. It takes in nutrients and eliminate waste by such physiological sufficees as secretion, motility, digestion, absorption and excretion. Depending on structure and functions, the gastrointestinal tr act is divided into the mouthpiece, pharynx, oesophagus, stomach, infinitesimal intestine and large intestine. The large intestine is around 1.5m in space and extends from the ileocaecal junctions 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 five major portions. Peritoneal folds called as mesentery which is support by advance and descending colon. The right colon consists of the caecum, ascending colon, hepatic flexure and the right half of the transverse colon. The leftover 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 surround for the growth of colonic microorganisms, shop reference of faecal contents, expulsion of the contents of the colon at an appropriate ti me 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 generally viscous in nature. This could impact on the performance of drugs and delivery systems in this region 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 feasible micro botany. These bacteria are involved in the fermentation of polysaccharides and proteins that have fly digestion in the upper gut. Moreever the resident bacter ia can also metabolize drug. The protein based drugs, insulin and calcitonin are rapidly degraded in fake colonic contents5.Fig 1 Anatomy of colonFactors influencing colonic drug deliveryPhysiological factors1. Transit through gastro intestinal tractby word of mouth taken dosage forms first enters into stomach and humiliated 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 barriers in the stomach and minor(ip) intestine. Gastrointestinal transit varies from 1 hr to 3 hrs depending upon the condition continence or non-fasting respectively. In general, the flyspeck 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 variable and influenced by number of factors such as diet particularly dietary part content, mobility, stress, disease condition and drugs. The colonic transit time is ranging from 20 to 30 hours, can be increase in presence of active disease 50 to 70 hours. Longer residence time with subsequent chronic 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 intestine3-4 gargantuan 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 biologic membranes. It states that for drug molecules of molecular weight g reater than 100, which are mainly transported across the biologic membranes by passive diffusion,the process of absorption is governed by1) The disassociation constant (pKa) of the drug.2) The lipophilicity of unionized drug.3) The pH at the absorption site.Since most of the drugs are weak 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 infiltrate 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 venture 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 change in the pH in different 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+0.4Caecum6.4+0.4Colon5.5-7Rectum74. Colonic microfloraA number of anaerobic and aerobic bacteria are present throghout entire length of the human GI tract. Over 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 gram positive bacteria. The rate of microbial growth is greatest in the proximal areas because of high concentration of suscep tibility source.Concentration of microflora is generally about1011-1022 CFU/ml.It consists of Bacteroids, Bifidobacterium, Ruminococcus, Eubacterium and Clostridium.Chief metabolic reactions carried by the enzymes released from colonic microflora are hydrolysis and reduction. Table 3 Different microflora, enzymes and their actionsEnzymeMicroorganismMetabolic reactions catalysedNitroreductaseE. coli, Bacteroids trim down aromatic and heterocyclic nitro compoundsAzoreductaseClostridia, Lactobacilli, E.coli cut down 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 phenolsSulphataseE ubacteria, strepCleavage of O-sulfates and sulfamatesPhamaceutical factorsa) Drug candidateDrugs which show poor absorption in the stomach and intestine are most suitable for colon delivery. Drugs 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 classDrug and active agents1Drug used for local effect in colonanti-inflammatory drug DrugsOxyprenolol, Metoprolol, Nifedipine, Diclofenac, Sodium, Amylin, Antisense Ol igonucleotide,2Drugs poorly absorbed from upper GITAntihypertensive and antianginal drugsIbuprofen, Isosorbides, Theophylline, Desmopressin Cyclosporine A,3Drugs for colon cancerAntineoplasticsPseudoephedrine, 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.