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Colon Specific Medication Delivery

ABSRACT

The colon is a niche site where both local and systemic delivery of drugs can takes place. Colon specific medication delivery has achieved importance for the delivery of drugs for the treating local diseases associated with the colon like crohn's disease, ulcerative colitis etc. as well for the systemic delivery of protein, therapeutic peptides, antiasthmatic drugs, antihypertensive drugs and antidiabetic real estate agents. A drug need to be protected from degradation, release and absorption in the top part of GIT and then to be made certain abrupt and controlled release in the proximal colon. This article reviews an in depth research about need of digestive tract specific medicine delivery, restriction and problems, factors impacting on colonic medicine delivery, different techniques of bowel including some successful book solutions such as CODESTM, Pulsinicap system, Interface system, Colal pred system, Multiparticulate system and also a study on analysis for site specific medicine delivery to intestines.

INTRODUCTION

Drug administration through an oral course is the most convenient and important route of administering drugs for systemic effect. At about 50% of the medication delivery systems available in the market are oral drug delivery systems and these systems have more benefits credited to patient acceptance and simple administration. Over the last decade considerable interest has been given in growing site-specific formulations for focusing on drugs to the bowel. Colon specific medicine delivery has achieved increased importance not limited to the delivery of the drugs for the treatment of local disorders associated with the digestive tract like Crohn's disease, ulcerative colitis, irritable colon syndrome and constipation also for the systemic delivery of proteins and peptides, antihypertensive drugs, antiasthmatic drugs and antidiabetic providers. The colon specific medicine delivery system must have capacity to protect the drug on the way to the digestive tract i. e. drug release and medicine absorption shouldn't appear in the abdomen as well as the small intestine, and the bioactive agent should not be degraded in either of the dissolution sites but only released and absorbed once the system grows to the digestive tract. 1

Colon targeted drug delivery would on top of that be valuable whenever a delay in absorption is desired from a therapeutically perspective in the treatment of diseases which have peak symptoms early in the morning, such as nocturnal asthma, angina or arthritis. The immediate advancement of biotechnology and hereditary anatomist resulted into option of peptides and proteins at affordable costs; there has been an increased fascination with utilizing the bowel as site for medication absorption. The potential applicants in this admiration include analgesic peptides, oral vaccines, contraceptive peptides, growth hormones, insulin, erythropoietin, interferon, and interleukins (Saffran et al. , 1988; Mackay and Tomlinson, 1993). 2

The colon is a suitable absorption site for peptides and necessary protein drugs anticipated to: i) less diversity and power of digestive enzymes ii) less proteolytic activity of colon mucosa resulting in better protection from hydrolysis and enzymatic degradation in duodenum and jejunum iii) increased systemic bioavailability iv) long intestines property time (5 days) and high responsiveness to absorption enhancers.

There are amount of methods or techniques by which colon drug targeting may be accomplished, such as formation of prodrug, covering with pH very sensitive polymers, covering with biodegradable polymers, planning formulations using polysaccharides, timed release system, pressure-controlled drug delivery systems, osmotic pressure handled systems etc.

Need of digestive tract targeted drug delivery

  • Colon targeted medication delivery system would asssure direct treatment at the condition site, lower dosing and fewer systemic area effects.
  • Site-specific drug delivery system allows oral supervision of health proteins and peptide drugs, colon-specific formulation may be used to prolong the drug delivery.
  • Colon-specific medicine delivery system is useful in the treatment of intestines diseases.
  • The bowel is a site where both local or systemic medicine delivery could be achieved. Localized treatment of inflammatory bowel disease, e. g. ulcerative colitis or Crohn's disease. These inflammatory conditions are majorly cared for with glucocorticoids and sulphasalazine (targeted).
  • A quantity of others serious disorders of the bowel, e. g. colorectal cancer, may also be with the capacity of being treated more effectively if drugs were targeted to the digestive tract.
  • Formulations for colonic delivery are also well suited for delivery of drugs which can be polar and/or susceptible to substance and enzymatic degradation in top of the GI tract, highly damaged by hepatic first cross metabolism, specifically, therapeutic proteins and peptides. 3

Limitations and challenges in colon targeted drug delivery system

  • A challenge in the introduction of colon specific drug delivery systems is to set up a proper dissolution testing way for in-vitro evaluation of the designed system. That is due to the rationale after having a colon specific medicine delivery system is quite different.
  • As a site for drug delivery, the digestive tract provides a near natural pH, low digestive enzymatic activity, an extended transit time and improved awareness 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 intestines is mostly difficult to access. In addition to that the variant in pH values and various enzymes present throughout the gastrointestinal area, through which the medication dosage form must pass before achieving the concentrate on site, further complicate the reliability and delivery efficiency.
  • Successful delivery through this web site also needs the drug to maintain solution form before it grows to the bowel or alternatively, it will dissolve in the luminal essential fluids of the bowel, but this is often a restricting factor for terribly soluble drugs as the substance content in the bowel is a lot lower which is more viscous than in the top part of the GI area.
  • The stability of the medication is also taken into consideration while building a medicine delivery system, since it may bind nonspecific way to dietary residues, intestinal secretions, mucus or faecal subject.
  • Low surface area and comparative tightness of the tight junctions in the colon can also limit medication transport across the mucosa and in to the systemic blood flow. 4

Anatomy and physiology of colon

The gastrointestinal tract is hollow muscular tube. It takes in nutrition and eliminate misuse by such physiological techniques as secretion, motility, digestion, absorption and excretion. Based on structure and functions, the gastrointestinal system is divided into the mouth, pharynx, oesophagus, stomach, small intestine and large intestine. The large intestine is roughly 1. 5m long and extends from the ileocaecal junctions to the anus. It really is divided into four parts: caecum, digestive tract, rectum and anal canal. 5

The entire digestive tract is about 5 legs (150 cm) long, and is split into five major helpings. Peritoneal folds called as mesentery which is backed by ascending and descending bowel. The right intestines includes the caecum, ascending bowel, hepatic flexure and the right 1 / 2 of the transverse digestive tract. The left bowel includes the left 1 / 2 of the transverse bowel, descending bowel, splenic flexure and sigmoid. The rectum is the last anatomic segment before the anus. The individuals digestive tract were shown in Amount1. The primary functions of the intestines is to make suitable environment for the growth of colonic microorganisms, safe-keeping reservoir of faecal items, expulsion of the material of the colon at a proper time and absorption of potassium and normal water from the lumen. The absorptive capacity is very high, at about 2000ml of fluid enters the colon through the ileocecal valve that more than 90% of the fluid is soaked up6.

The intestines is involved in fermentation of polysaccharides and protein, absorption of drinking water and electrolytes and the formation, storage and reduction of faecal materials. As a consequence of the functions of the colon, the colonic environment is normally viscous in character. This could impact on the performance of drugs and delivery systems in this area of gut. Quick water absorption in the ascending bowel results in the distal colonic material being more viscous. It's been approximated that the human colon consists of only 220g of wet contents. In addition digestive tract has a next to neutral pH and houses a feasible microflora. These bacteria are involved in the fermentation of polysaccharides and proteins which have escaped digestive function in the upper gut. Moreever the citizen bacteria can also metabolize medication. The protein based mostly drugs, insulin and calcitonin are speedily degraded in simulated colonic articles5.

Fig 1: Anatomy of colon

Factors influencing colonic medication delivery:

Physiological factors:

1. Transit through gastro intestinal tract

Orally taken dose forms first enters into tummy and small intestine via oral cavity and then reach intestines. The nature and pH of the tummy affects the medicine release and absorption. To be able to effectively deliver tablet to colon within an intact form, the medicine delivery systems should bypass the barriers in the tummy and small intestine. Gastrointestinal transit can vary from 1 hr to 3 hrs depending after the problem fasting or non-fasting respectively. Generally, the small intestinal transit is not influenced by the physical point out, size of the dose form. The mean transit time of the dosage form is approximately 3-4 hours to be able to attain the ileocecal junction and the period of time is inconsistent. During this time the dosage form is exposed to enzymes within small intestine. Compared to the other region of GIT, movements of materials through the intestines is sluggish. Total time for transit tends to be highly adjustable and affected by number of factors such as diet especially nutritionary fibre content, ability to move, stress, disease condition and drugs. The colonic transit time is ranging from 20 to 30 time, can be upsurge in presence of active disease 50 to 70 hours. Longer residence time with following longer transit time and the contact of medication dosage form

with micro flora in intestines govern the release and improve absorption of medicine from dose form. 7

Table 1: Transit time of medication dosage forms in GIT

Organ

Transit time(hr)

Stomach

>3 (given)

Small intestine

3-4

Large intestine

20-30

2. pKa of the medicine, lipophilicity and gastrointestinal pH:

The pH partition theory points out the procedure of medication absorption from the GIT and its own syndication across all biological membranes. It expresses that for drug substances of molecular weight greater than 100, that happen to be mainly transported across the natural membranes by unaggressive diffusion,

the process of absorption is governed by:

1) The dissociation continuous (pKa) of the medication.

2) The lipophilicity of unionized medication.

3) The pH at the absorption site.

Since almost all of the drugs are weak electrolytes (weakened acids or weakened bases), their amount of ionization depends upon the pH of the natural fluid. In the event the pH on the either aspect of the membrane is different, then the area in which pH favors increased ionization of the medication will contain better amount of medication, and only the unionized form of medicine, if adequately lipid soluble, permitted to permeate the membrane passively before attention of unionized drug on both side of the membrane becomes similar i. e. until equilibrium is achieved.

The above statement of the hypothesis was based on the assumptions that:

1) The GIT is a straightforward lipoidal hurdle to the transportation of drug.

2) Bigger the portion of unionized drug, faster the absorption(D. M. Brahmankar et al 2009).

3. pH of colon

The pH of GIT varies in every individual. The food intakes, diseased point out, etc. affects the pH of the GIT. This change in the pH in different regions of GIT is the foundation for the development of colon targeted drug delivery systems. Finish with different polymers is performed to target the medication to the website.

Table 2: pH in several regions of gastrointestinal tract

Part of GIT

Ph

Stomach (before food)

1-2

Stomach (during digestion)

4

Smll intestine

6-7

Duodenum

6. 6+0. 5

Ileum

7. 5+0. 4

Caecum

6. 4+0. 4

Colon

5. 5-7

Rectum

7

4. Colonic microflora

A variety of anaerobic and aerobic bacteria can be found throghout entire length of the human being GI system. Over 400 different bacterial varieties have been found, 20-30% of which are of the genus bacteroids. The upper region of the GIT has a very few bacteria and mainly includes gram positive bacterias. The rate of microbial development is best in the proximal areas because of high attentiveness of energy source.

Concentration of microflora is generally about1011-1022 CFU/ml.

It contains Bacteroids, Bifidobacterium, Ruminococcus, Eubacterium and Clostridium.

Chief metabolic reactions transported by the enzymes released from colonic microflora are hydrolysis and lowering.

Stand 3: Different microflora, enzymes and their actions

Enzyme

Microorganism

Metabolic reactions catalysed

Nitroreductase

E. coli, Bacteroids

Reduced aromatic and heterocyclic nitro compounds

Azoreductase

Clostridia, Lactobacilli, E. coli

Reduced cleavage of azo compounds

N oxide reductase,

Sulphoxide reductase

E. coli

Reduced N oxides and sulphoxides

Hydrogenase

Clostridia, Lactobacilli

Reduced carbonyl organizations and aliphatic double bonds

Esterases and amidases

E. coli, P. vulgaris, B. subtilis, B. mycoides

Cleavage of esters or amidases of carboxylic acid

Glucosidase

Clostridia, Eubacteria

Cleavage of b- glycosidase of alcohols and phenols

Glucoronidase

E. coli, A. aerogenes

Cleavage of b glycosidase of alcohols and phenols

Sulphatase

Eubacteria, streptococci

Cleavage of O-sulfates and sulfamates

Phamaceutical factors

a) Medication candidate

Drugs which show poor absorption in the stomach and intestine are most ideal for bowel delivery. Drugs such as theophylline, nifedipine, diclofenac, ibuprofen, metoprolol, isoosorbide dinitrate, oxyprenolol and low molecular weight peptides and Peptide like drugs have been proven to be effectively ingested from the bowel.

b) Drug carrier

The selection of carrier for a specific drug candidate depends upon the physicochemical nature of the medicine as well as the disease for which the machine is to be employed. The factors such as substance nature, balance and partition coefficient of drug and the type of absorption enhancers affects the carrier selection. 9

Table 3: Drugs in bowel targeted drug delivery

Sr. No.

Criteria

Pharmacological class

Drug and lively agents

1

Drug used for local impact in colon

Anti-inflammatory Drugs

Oxyprenolol, Metoprolol, Nifedipine, Diclofenac, Sodium, Amylin, Antisense Oligonucleotide,

2

Drugs poorly soaked up from higher GIT

Antihypertensive and antianginal drugs

Ibuprofen, Isosorbides, Theophylline, Desmopressin Cyclosporine A,

3

Drugs for intestines cancer

Antineoplastics

Pseudoephedrine, epoetin, Glucagon

4

Drugs that degrade in belly and small intestine

Peptides and proteins

Bromopheniramine, 5 Flurouracil, Doxorubicin, Gonadoreline, Insulin, Interferones

5

Drugs that experience extensive first cross metabolism

Nitroglycerin and corticosteroids

Nimustine, Bleomycin, Nicotine, Dexamethasone, protirelin, Sermorelin, Molgramoatim, Salotonin.

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