The current involvement shown in fresh drug bringing systems ( NDDS ) by both national and international pharmaceutical houses, open uping research to invent new schemes for effectual bringing of drugs is enormous. The current planetary market for NDDS1 is more than ˆ80 billion. The 1950s were the initial phases where the focal point was on microencapsulated drug atoms. These drug atoms were packaged in bantam shells or capsules of dimensions mensurable in microns and delivered into the organic structure.
A major face lift was brought about with the usage of polymers for the industry of the capsules or coops in the sixtiess. Besides adding to the flexibleness and versatility of the procedure of drug bringing, a few concerns sing the pulsatile nature of drug bringing were besides mitigated. The bringing of drugs to a specific site can be either sustained or pulsatile. The pulsatile manner is nevertheless preferred as it closely mimics the in vivo mechanism of release of triping of mending agents, as exemplified by the release of endocrines. The coming of transepithelial and transdermic bringing schemes in the 1990s has added to the multi dimension nature of the NDDS. The subsequent add-on of liposomes at the beginning of this decennary has added to the repertory of bing drug bringing systems. Several schemes are being tried out presently to detect fresh bearers for the drugs to be delivered specifically and efficaciously. Some of the interesting campaigners with possible to be deemed as suited bearers for the fresh drugs include Human Serum Albumin ( HSA ) , Silica Gel, Antisense RNA, recombinant DNA and man-made peptides among others.
Novel drug bringing system2 refers to the usage of a bringing device with the aim of let go ofing the drug into the patient organic structure at a preset rate, or at specific clip or with a specific release profile, at a coveted country of consequence.
The NDDS basically consists of the drug against the causative agent of the disease being treated and a bearer system into which the drug is loaded and transported to site of action. Attempts are now being made to invent bearers that can transport multiple drugs and let go of them on bid.
1.2 TARGETED DRUG DELIVERY SYSTEM:
The purpose of drug targeting is to accomplish a coveted pharmacological response at a selected site without unwanted interactions at other sites.
At present drug targeting is achieved by two approaches.3,5
The first attack involves chemical alteration of the parent compound to a derivative which is activated merely at mark site.
The 2nd attack utilises bearers such as liposomes, microspheres, nanoparticles, monoclonal antibodies and macro molecules to direct the drug to its site of action.
There are assortment of statergies to modify the chemical construction of drug molecules, the most common being the prodrug and most sophisticated being the chemical bringing system attack. A prodrug is an inactive drug that is activated predictably in vivo to the active drug, but with few exclusions it can non accomplish site specific bringing. In contrast, a chemical bringing system involves transmutation of the active drug by man-made agencies into an inactive derived function which, when placed in the organic structure, will undergo several predictable enzymatic transmutations chiefly at the site of action. This is successful in aiming drug.
Obstacles of mark drug delivery4 are because of impermeableness of the GI piece of land to most supermolecules and instability of the drug bearer composite in the hostile environment of the GI piece of land, disposal of big drug bearer composites is restricted to endovenous or intra arterial injections or to the direct injection into the mark site such as tumour. Major obstruction of drug aiming utilizing supermolecules and particulate bearers ( Liposomes, Nanoparticles ) is rapid sequestering of intravascularly administered drug bearer by mononucleate scavenger cells of reticuloendothelial system ( RES ) .So first involves barricading of RES prior to administrating the drug bearer, shows some unwanted effects in malignant neoplastic disease patients. In recent research nanoparticles for cut downing RES consumption is by covalent fond regard of PEG consumption is by covalent fond regard of PEG to surface of atoms and shows increasing circulation clip.
A 2nd attack is to leave specificity to the drug bearer by matching specific ligands onto its external surface. These include monoclonal antibodies, erythrocyte membrane glycoprotein, heated aggregative Igs. So far, none of these stratergies has proven to be successful due to troubles in continuing the acknowledgment ability in vivo and avoiding triping any immunological response.
1.3 COLON SPECIFIC DRUG DELIVERY SYSTEM
The unwritten path is most popular path of drug administration6,7. For sustained release every bit good as controlled release systems, the unwritten path of disposal has received the most attending. Patient credence of unwritten disposal of drugs is rather high. It is a comparatively safe path of drug disposal compared with most parentral signifiers, and the restraints of asepsis and possible harm at the site of disposal are minimum. Colon-specific drug-delivery systems3 offer several possible curative advantages. In a figure of colonic diseases such as colorectal malignant neoplastic disease, Crohn ‘s disease, and spastic colon, it has been shown that local is more effectual than systemic bringing. Colonic drug bringing can be achieved by unwritten or by rectal disposal. Rectal bringing signifiers ( suppositories and clyster ) are non ever effectual because a high variableness is observed in the distribution of drugs administered by this path. Therefore, the unwritten path is preferred. Absorption and debasement of the active ingredient in the upper portion of the GI piece of land is the major obstruction with the bringing of drugs by the unwritten path and must be overcome for successful colonic drug bringing. Drugs for which the colon is a possible soaking up site ( for illustration, peptides and proteins ) can be delivered to this part for subsequent systemic soaking up. The digestive enzymes of the GI piece of land by and large degrade these agents. However, these enzymes are present in significantly lower sums in the colon compared with the upper part of the GI piece of land. Colon-specific drug bringing has been attempted in a figure of ways that chiefly seek to work the alterations in the physiological parametric quantities along the GI piece of land. These attacks include the usage of prodrugs, pH-sensitive polymers, bacterial degradable polymers, hydrogels and matrices, and multicoating time-dependent bringing systems.
Advantages of Colon Targeted Drug Delivery System
Time dependent system: little intestine theodolite clip reasonably consistent.
pH dependent system: formulation8 is good protected in the tummy.
It has minimal side consequence.
Unnecessary systemic soaking up does non happen.
Colonic drug bringing can be achieved by unwritten and rectal disposal.
Colon specific preparation can be used to protract drug bringing.
It enhances the soaking up of ailing absorbed drug.
It helps in efficient vaccinum bringing.
Reduces the inauspicious effects in the intervention of colonic diseases ( ulcerative inflammatory bowel disease, colorectal malignant neoplastic disease, Crohn ‘s disease etc. )
Produces a ‘friendlier ‘ environment for peptides and proteins when compared to upper GI piece of land.
Minimizes extensive first base on balls metamorphosis of steroids.
Prevents the stomachic annoyance produced by unwritten disposal of NSAIDS.
Disadvantages of Colon Targeted Drug Delivery System
1. Time dependent system:
a ) Significant fluctuation in stomachic keeping times
B ) Transit through the colon more rapid than normal in patients with colon
2. pH-dependent system:
pH degree in the little bowel and colon vary between and within persons.
pH degree in the terminal of little bowel and cecum are similar.
Poor site specificity.
3. Microflora activated Systems:
Diet and disease can impact colonic microflora.
Enzymatic debasement may be overly slow.
Few have been accepted for usage in relation to medical specialties.
1.4 ANATOMY AND PHYSIOLOGY OF COLON
The grownup colon is about 5 pess long. It connects to the little intestine, which is besides known as the little bowel. The major maps of the colon are to absorb H2O and salts from partly digested nutrient that enters from the little intestine and so direct waste out of the organic structure through the anus. What remains after soaking up is stool, which passes from the colon into the rectum and out through the anus when a individual has a intestine movement.9
The colon comprises several sections:
the rise colon
the transverse colon
the descending colon
the sigmoid colon
The colon is formed during the first 3 months of embryologic development. As the fetus grows and the abdominal pit enlarges, the intestine returns to the venters and bends, or rotates, counter clockwise to its concluding place. The little intestine and colon are held in place by tissue known as the mesentery. The go uping colon and descending colon are fixed in topographic point in the abdominal pit. The caecum, transverse colon, and sigmoid colon are suspended from the dorsum of the abdominal wall by the mesentery.
Fig 1.1 Large bowel stand foring parts of colon
This is the first portion of the colon. It is a dilated part which has a unsighted terminal inferiorly and is uninterrupted with the go uping colon superiorly. Just below the junction of the two the ileo cecal valve opens from the ileum. The vermiform appendix is a all right tubing, closed at one terminal, which leads from the caecum. It is normally approximately 8 to 9 centimeters long and has the same construction as the walls of the colon but contains more lymphoid tissue.
This passes upwards from the caecum to the degree of the liver when it curves really to the left at the hepatic flection to go the cross colon. The nervus supply is by parasympathetic fibres of the pneumogastric nervus.
This is a cringle of colon that extends across the abdominal pit in forepart of the duodenum and the tummy to the country of the lien where it forms the splenetic flection and curves acutely downwards to go the descending colon.
This passes down the left side of the abdominal pit so curves towards the midplane. After it enters the true pelvic girdle it is known as the sigmoid colon.
This portion describes an S-shaped curve in the pelvic girdle that continues downwards to go the rectum.
This is a somewhat dilated subdivision of the colon about 13cm long. It leads from the sigmoid colon and terminates in the anal canal.
1.4.1 Functions of colon:
In the big intestine soaking up prohibition of H2O, by osmosis, continues until the familiar semisolid consistence of fecal matters is achieved. Mineral salts, vitamins and some drugs are besides absorbed into the blood capillaries from the big bowel. It is colonized by certain types of bacteriums, which synthesize vitamin K and folic acid.They include E.coli, E.aerogenes, S.faecalis and C.perfringens. Hydrogen, C dioxide and methane are produced by bacterial agitation of unabsorbed foods, particularly saccharide. Large figure of bugs are present in fecal matters. In big bowel no peristaltic motion was seen like other parts of digestive piece of land. Merely long intervals a moving ridge of strong vermiculation expanse along the colon transverse colon coercing its contents into falling and sigmoid colons. This is known as mass motion. This combination of stimulation and response is called the gastrocolic physiological reaction.
Normally rectum is empty, but when a mass motion forces the contents of the sigmoid colon into rectum the nervus terminations in its walls are stimulated by stretch and help the procedure of defaecation.10
Rationale for Colon Specific Drug Delivery
Targeting of drugs to colon is done for assorted reasons11.
Local intervention of inflammatory diseases e.g. Crohn ‘s disease.
Colonic diseases can be treated e.g. colorectal malignant neoplastic disease and amebiasis.
Oral bringing of peptide and protein drugs, which usually become inactivated in upper, parts the GI piece of land.
Oral bringing of drugs/therapeutic substances that have unwanted side effects in the tummy and little bowel.
For the intervention of the diseases in which the diurnal beat is apparent, e.g. asthma, arthritic disease and ischaemic bosom disease.
Delivery of the drugs to the colon via, the unwritten path is valuable in handling diseases related to colon ( Crohn ‘s disease, ulcerative inflammatory bowel disease, cranky intestine disease, carcinomas and infections ) whereby high local concentration can be achieved while minimising side effects that occurs because of release higher up in the GI piece of land or because of release higher up in the GI piece of land.
1.5 APPROACHES OF COLON TARGETED DRUG DELIVERY SYSTEM
Most of the conventional drug bringing system for handling colon upsets such as inflammatory intestine syndrome ( ulcerative inflammatory bowel disease, Crohn ‘s disease etc. ) , infective diseases ( e.g. amebiasis ) and colon malignant neoplastic disease are neglecting as the drug do non make the site of action at appropriate concentrations. In visible radiation of the above-named possible troubles, different attacks have been studied for the intent of accomplishing colonic targeting and are summarized below.
1.5.1 Prodrug Approach
A prodrug12 is an inactive chemical derived function of a parent compound that is activated predictably in vivo to active drug species at the mark site. In this there is a covalent nexus between parent molecule and bearer molecule. Depending upon the linkage the triping mechanism for the release of the drug in the colon was decided.
Breakage of linkage in colon is by different enzymes like azoreductase, & A ; szlig ; -galactosidase, & A ; szlig ; -xylosidase, nitroreductase, glycosidase deaminase, etc.
Examples of prodrugs bringing are:
1. Dexamethasone-2- & A ; szlig ; -glucoside and Prednisolone-2- & A ; szlig ; -glucoside for bringing of these steroids to the colon.
2. Non-essential aminic acids such as glycine, tyrosine, methionine, and glutamic acid were conjugated to salicylic acid. The conjugate showed minimum soaking up and debasement in the upper GI piece of land and showed more enzymatic specificity for hydrolysis by colonic enzymes.
3. Sulphasalazine, which was used for the intervention of rheumatoid arthritis, holding an azo bond between 5-ASA and sulpha pyridine.
1.5.2 Time-Dependent Approach
They are developed to present drugs after a slowdown of five to six hours. The slowdown time13 is dependent on size of dose signifier and stomachic motility associated with the pathological status of the person.
An illustration of such a dose signifier would be an impermeable capsule organic structure incorporating the drug, fitted with a hydrogel stopper that is used to present the drug after a preset clip. This dose signifier, for illustration Pulsincap® , releases the drug once the hydrogel stopper hydrates and crestless waves in aqueous media and is ejected from the device, thereby leting the release of the drug from the capsule. Another illustration describes usage of a hydrophobic stuff and wetting agent in the tablet coating. The release of drug from the Time Clock® depends chiefly on the thickness of the hydrophobic bed and is non dependent on the pH of the GI environment. The principle behind all time-release bringing systems is valid provided that little bowel theodolite times remain changeless. Changes in GI tract motility can significantly impact time-release drug bringing systems aiming the release of drugs to the colon.
1.5.3 pH-Dependent Approach
This attack is based on the pH-dependent14 release of the drug from the system. In this instance the pH derived function between the upper and terminal parts of GI piece of land is exploited to efficaciously present drugs to the colon. The pH of the bowel and colon depends on many factors such as diet, nutrient consumption, enteric motility and disease provinces. By uniting cognition of polymers and their solubility at different pH environments, bringing systems have been designed to present the drug at the mark site. Normally used co-polymers of methacrylic acid and methyl methacrylate have been extensively investigated for colonic drug bringing systems. In vitro rating of Eudragit® S and Eudragit® FS was performed and it was found that the latter would be more appropriate for drug bringing to the ileocolonic part.