Introduction to drug delivery Introduction to ulcerative colitis: Ulcerative colitis is a disease that causes inflammation and sores, called

ulcers, in the lining of the rectum and colon. Ulcers form where inflammation has killed the cells that usually line the colon, then bleed and produce pus. Inflammation in the colon also causes the colon to empty frequently, causing diarrhea. When the inflammation occurs in the rectum and lower part of the colon it is called ulcerative proctitis. If the entire colon is affected it is called pancolitis. If only the left side of the colon is affected it is called limited or distal colitis. Ulcerative colitis is an inflammatory bowel disease (IBD), the general name for diseases that cause inflammation in the small intestine and colon. It can be difficult to diagnose because its symptoms are similar to other intestinal disorders and to another type of IBD called Crohn’s disease. Crohn’s disease differs because it causes inflammation deeper within the intestinal wall and can occur in other parts of the digestive system including the small intestine, mouth, esophagus, and stomach. Ulcerative colitis can occur in people of any age, but it usually starts between the ages of 15 and 30, and less frequently between 50 and 70 years of age. It affects men and women equally. What are the symptoms of ulcerative colitis? The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients also may experience • • • • • • • • Anemia fatigue weight loss loss of appetite rectal bleeding loss of body fluids and nutrients skin lesions joint pain

such as olsalazine. and osteoporosis. swelling . inflammation of the eye. sulfapyridine may lead to side effects such as nausea. 5-ASAs are given orally. or in a suppository. What causes ulcerative colitis? People with ulcerative colitis have abnormalities of the immune system. and severe abdominal cramps. and balsalazide. liver disease. so treatment is adjusted for each individual. The immune system is made up of blood cells and chemicals that find bacteria and viruses in the body and destroy them. Aminosalicylates. drugs that contain 5-aminosalicyclic acid (5-ASA). and to improve the quality of life for people with ulcerative colitis. Ulcerative colitis is not caused by emotional distress or sensitivity to certain foods or food products.• growth failure (specifically in children) About half of the people diagnosed with ulcerative colitis have mild symptoms. mesalamine. it can lead to inflammation. and headache. The body’s immune system is believed to react abnormally to the bacteria in the digestive tract. heartburn. Drug Therapy The goal of drug therapy is to induce and maintain remission. bloody diarrhea. The sulfapyridine component carries the anti-inflammatory 5-ASA to the intestine. Several types of drugs are available. Others suffer frequent fevers. through an enema. Each person experiences ulcerative colitis differently. diarrhea. vomiting. Other 5-ASA agents. have a different carrier. help control inflammation. The immune system reacts to virus or bacterium causing the intestinal wall to become inflamed. When the immune system fights against the intestine. However. What is the treatment for ulcerative colitis? Treatment for ulcerative colitis depends on the severity of the disease. fewer side effects. and may be used by people who cannot take sulfasalazine. nausea. depending on the location of the inflammation in the . Ulcerative colitis may also cause problems such as arthritis. destruction and scarring. but these factors may trigger symptoms in some people. Sulfasalazine is a combination of sulfapyridine and 5-ASA.

Most people with mild or moderate ulcerative colitis are treated with this group of drugs first. These drugs can cause side effects such as weight gain. Oral delivery of drugs in the colon is valuable in the treatment of diseases of colon where by high local concentration can be achieved while minimizing side effects. diabetes.colon. depending on the location of the inflammation. These drugs are used for patients who have not responded to 5-ASAs or corticosteroids or who are dependent on corticosteroids. can be given orally. and hydrocortisone also reduce inflammation. also known as steroids. Corticosteroids. and an increased risk of infection. methyl prednisone. which depends upon the physicochemical properties of the drug. they are slow-acting and it may take up to 6 months before the full benefit. they are not recommended for long-term use. Cyclosporine A may be used with 6-MP or azathioprine to treat active. For this reason. This region of the colon having a somewhat . however. acne. Immunomodulators are administered orally. or in a suppository. bone mass loss. and an increased risk of infection. although they are considered very effective when prescribed for short-term use. severe ulcerative colitis in people who do not respond to intravenous corticosteroids. mood swings. They may be used by people who have moderate to severe ulcerative colitis or who do not respond to 5-ASA drugs. hypertension. through an enema. Introduction to colon drug delivery: Among the various routes of administration. It has a serious drawback in conditions where localized delivery of the drug in the colon is required or in conditions where a drug needs to be protected from the hostile environment of upper GIT. This class of drugs is also used in cases of relapse. the oral route is considered to be most convenient for the administration of drugs to patients. intravenously. such as prednisone. a reduced white blood cell count. Dosage forms that deliver drugs in the colon rather than upper GIT has number of advantages. hepatitis. Immunomodulators such as azathioprine and 6-mercapto-purine (6-MP) reduce inflammation by affecting the immune system. Patients taking these drugs are monitored for complications including pancreatitis. Corticosteroids. On oral administration of conventional dosage forms drug normally dissolves in the gastro-intestinal fluids and is absorbed from regions of the gastro-intestinal tract. facial hair. The colon is attracting interest as a site where poorly absorbed drug molecule may have an improved bioavailability.

the drug may need to be delivered in a presolubilized form or delivery should be directed to the proximal colon. The simplest method for targeting of drugs to the colon is to obtain slower release rates or longer release periods by the application of thicker layers of conventional enteric coating or extremely slow releasing matrices. dissolution could be problematic for poorly water-soluble drugs. In addition to restricted therapy. In such instances. molecules that are degraded/poorly absorbed in the upper gut. After the several other azo-bonds containing compounds designed to locally release 5-aminosalicylicacid were synthesized bensalazine. thereby reducing the concentration of free drug. The exact mode by which the drug target itself to the colon was elucidated much latter in 1970 i. may be better absorbed from the more benign environment of the colon.less hostile environment with less diversity and intensity of activity than the stomach and small intestine. as a fluid gradient exists in the colon with more free water present in the proximal colon than in the distal colon. balsalazide and olsalazine. History: In 1942. Overall. the colon can also be utilized as a portal for the entry of drugs into the systemic circulation. Saffron and coworkers described the use of azo containing acrylic polymers to the delivery of protein drugs like insulin to the colon 1. there is less free fluid in the colon than in the small intestine and hence.e. the sulfanilamide prodrug of 5aminosalicylicacid (5-ASA) is effective in the treatment of rheumatoid arthritis and antiinflammatory disease. . For example. Svartz discovered that sulfasalazine. colon specific azoreductase splits sulfasalazine causing the release of the active moiety 5. intestinal secretions. such as peptides and proteins.aminosalicylicacid. lower dosing and less systemic side effects. In1986. These delayed mechanisms are designed to improve the efficacy of the drug by concentrating the drug molecules. Moreover. where they are needed most and also minimize the potential side effects and drug instability issues associated with premature release of drug in the upper parts of the Gastrointestinal tract. namely stomach and small intestine. the resident microflora could also affect colonic performance via degradation of the drug. the stability of the drug in the colonic environment is a further factor that warrants attention. mucus or general faecal matter. Colon targeted drug delivery would ensures direct treatment at the disease site. Aside from drug solubility.. The drug could bind in a nonspecific manner to dietary residues. the colon has a long retention time and appears highly responsible to agents that enhance the absorption of poorly absorbed drugs. Additionally.

5). 6.g. steroids like fludrocortisone. especially the affected parts of the lower GIT. Drugs suitable for CDDS: Based on literature review.5±0. Degradation by bacterial enzymes and metabolic products.4±0. 3. 4. . 3. 1. a decrease in the cecum (pH is 6.6±0. stability and permeability at the intended site of delivery. Colonic residence time as commanded by GIT motility.7. Selective and non-selective binding to mucus. Very common physiological factor which is considered in the design of delayed release colonic formulations is pH gradient of the gastrointestinal tract. Physical properties of drug such as pKa and degree of ionization. The preferred release data of the drug. prednisolone and dexamethasone.. Physico-chemical and bio-pharmaceutical properties of the drug such as solubility.4) to the end of the ileum (pH is 7. In normal healthy subjects. there is a progressive increase in luminal pH from the duodenum (pH is 6. Some reports suggested that alterations in gastrointestinal pH profiles may occur in patients with inflammatory bowel disease.0±0. 5.6) and then a slow rise from the right to the left colon with a final value of 7. delayed released dosage forms which may be designed either to provide a ‘burst release’ or a sustained/prolonged /targeted. mesalazine. budesonide. olsalazine. in general.  Drugs used to treat irritable bowel disease (IBD) require local delivery at drug to colon e. the following different categories of drugs are suitable for colon drug delivery. sulfasalazine. Pathology of disease. Local physiological action of drug. Disease state.Factors affecting Colon Absorption 5: 1. General considerations for design of Colonic Formulations: Formulations for colonic delivery are. 2. 2. which should be considered in the development of delayed release formulations 8.

In addition to that the wide range of pH values and different enzymes present throughout the gastrointestinal tract..g. the colon is particularly difficult to access. diclofencac. ibuprofen. 2. insulin. intestinal secretions. interleukin.requires site specific delivery e.  Protein and peptide drugs . 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.  To treat rheumatoid arthritis (NSAIDS). metronidazole. Successful delivery through this site also requires the drug to be in solution form before it arrives in the colon or alternatively.eliminating drug degradation e. As a site for drug delivery. reduced digestive enzymatic activity. it should dissolve in the luminal fluids of the colon. glibenclamide. nocturnal asthma. 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. theophylline. angina require delay in absorption due to circadian rhythms  Drugs showing more selective absorption in colon than small intestine due to small extent of paracellular transport e. Due to its location in the distal part of the alimentary canal. growth hormones.g. 4. . interferon and erythropoietin. This is due to the rationale after a colon specific drug delivery system is quite diverse. the targeting of drugs to the colon is very complicated.g. 5-fluorouracil. meto. calcitonin. however. and methotrexate. and oxyprenolol. mebendazole and albendazole.g. a long transit time and increased responsiveness to absorption enhancers.prolol. Drugs to treat colonic cancer require local delivery e. doxorubicin. 3. the stability of the drug is also a concern and must be taken into consideration while designing the delivery system. mucus or faecal matter. The drug may potentially bind in a nonspecific way to dietary residues. the colon offers a near neutral pH. through which the dosage form has to travel before reaching the target site. Limitations and challenges in Colon Targeted Drug Delivery: 1. further complicate the reliability and delivery efficiency. In addition.  To treat infectious diseases (amoebiasis & helminthiasis) .

2.5. The resident microflora could also affect colonic performance via metabolic degradation of the drug. 14. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon 12. 22 & 23. Reducing the adverse effects in the treatment of colonic diseases (ulcerative colitis. 19. but especially for drugs that are substrates for this class of enzyme. Preventing the gastric irritation produced by oral administration of NSAIDS. 6. 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 8. crohn’s disease etc. asthma and rheumatoid arthritis. 3. 4. 16. Minimizing extensive first pass metabolism of steroids. colorectal cancer. . The literature also suggested that the cytochrome P-450 (3A) class of drug metabolizing enzymes have lower activity in the colonic mucosa. 18. 15. 5.) 2. Advantages: Colon-specific drug delivery system offers the following therapeutic advantages 1. A longer residence time of 3 to 5 days results in elevated plasma levels of the drugs and therefore higher bioavailability in general. 20. Delayed release of drugs to treat angina. 21. By producing the ‘friendlier’ environment for peptides and proteins when compared to upper gastrointestinal tract. 9. 13. 10 & 11: 1. 17.

Polymeric prodrugs II. Chemical Approaches 1. Glycosidic conjugates 4. Embedding in pH sensitive matrices Degradation of pH sensitive polymer in the GIT releases the embedded drug 3. Coating with pH-sensitive polymer Basic feature The drug is conjugated via an azo bond The drug is conjugated with cyclodextrin The drug is conjugated with glycoside The drug is conjugated with glucuronate The drug is conjugated with dextran The drug is conjugated with polypeptide The drug is conjugated with polymer Formulation coated with enteric polymers releasedrug when pH moves towards alkaline range ii. Glucuronide conjugate 5. Coating with biodegradable polymer Drug is released following degradation of the polymer due to the action of colonic bacteria 2. Embedding in biodegradable polysaccharides The embedded drug in polysaccharide matrices is released by swelling and biodegradable action of polysaccharides. Dextran conjugates 6. Redox-sensitive polymers 5.APPROACHES FOR THE DEVELOPMENT OF COLON TARGETED DRUG DELIVERY 24 Approach I. Bioadhesive system Drug coated with bioadhesive polymer that selectively provides adhesion to colonic mucosa. Pharmaceutical Approaches 1. ii. Cyclodextrin conjugates 3. Timed released systems 4. Embedding in matrices i. Azo conjugates 2. Coating with polymer i. 6. Coating of miroparticles Drug is released through semipermeable membrane . Polypeptide conjugates 7.

Hydroxy Propyl Methyl Cellulose compression coated tablets of 5-fluorouracil were studied for colon drug delivery that based on time-dependent approach. In second approach core tablets were prepared using potassium chloride. By increasing the thickness of the coating layer. the core tablet was prepared by wet granulation method and then coated with 50% of HPMC/lactose coat powder by compression-coating method. In this. . The lag time of DS release was primarily controlled by thickness of ethycellulose coating layer. In the first approach core tablets (celicoxib as a model drug) were prepared using different concentrations of super disintegrates like cross-linked PVP. The coat weight determines the lag phase that required eliminating the release in stomach and small intestine 45. Colon targeting could be achieved by incorporating a lag time into formulation equivalent to the mouth to colon transit time. In this method the solid dosage form coated with different sets of polymers and the thickness of the outer layer determines the time required disperse in aqueous environment.7. diclofencac sodium tablets were coated with ethylcelluese in ethanol solution cooling diethyl phthalate as a plasticizer and PEG 400 as channeling agent. Osmotic controlled delivery Osmotic pressure Time-dependent system: The basic principle involved in the system is the release of drug from dosage form should be after a predetermined lag time to deliver the drug at the right site of action at right time and in the right amount 44. In this. The first one is using super disintegrate and the second one is based on osmogen. Colon drug delivery system of diclofencac sodium (DS) was developed using time dependent approach. Formulation of fast release enteric coated tablets for colon drug delivery using two different approaches. Then they are coated with Eudragit L-100:Eudragit S-100 in the ratio of 1:5 to achieve a desired thickness. sodium chloride as osmogen. Drug release characteristics were evaluated in distilled water by using a Chinese pharmacopoeia rotatable basket method 46. longer the lag time of DS release 39. The tablets with super disintegrates are fast released where the tablets with osmogen are sustain released. A nominal lag time of five hours is usually considered sufficient to achieve colon targeting.

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