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The current interest shown in novel drug delivery systems (NDDS) by both national and international pharmaceutical firms, pioneering research to devise new strategies for effective delivery of drugs is tremendous. The current global market for NDDS1 is more than €80 billion. The 1950s were the initial stages where the focus was on microencapsulated drug particles. These drug particles were packaged in tiny shells or capsules of dimensions measurable in micrometers and delivered into the body.
A major facelift was brought about with the use of polymers for the manufacture of the capsules or cages in the 1960s. Besides adding to the flexibility and versatility of the process of drug delivery, a few concerns regarding the pulsatile nature of drug delivery were also mitigated. The delivery of drugs to a specific site can be either sustained or pulsatile. The pulsatile mode is however preferred as it closely mimics the in vivo mechanism of release of triggering of repairing agents, as exemplified by the release of hormones. The advent of transepithelial and transdermal delivery strategies in the 1990s has added to the multi dimension nature of the NDDS. The subsequent addition of liposomes at the commencement of this decade has added to the repertoire of existing drug delivery systems. Several strategies are being tried out currently to discover novel carriers for the drugs to be delivered specifically and effectively. Some of the interesting candidates with potential to be deemed as suitable carriers for the novel drugs include Human Serum Albumin (HSA), Silica Gel, Antisense RNA, recombinant DNA and synthetic peptides among others.
Novel drug delivery system2 refers to the use of a delivery device with the objective of releasing the drug into the patient body at a predetermined rate, or at specific time or with a specific release profile, at a desired area of effect.
The NDDS essentially consists of the drug against the causative agent of the disease being treated and a carrier system into which the drug is loaded and transported to site of action. Efforts are now being made to devise carriers that can transport multiple drugs and release them on command.
1.2 TARGETED DRUG DELIVERY SYSTEM:
The aim of drug targeting is to achieve a desired pharmacological response at a selected site without undesirable interactions at other sites.
At present drug targeting is achieved by two approaches.3,5
The first approach involves chemical modification of the parent compound to a derivative which is activated only at target site.
The second approach utilises carriers such as liposomes, microspheres, nanoparticles, monoclonal antibodies and macro molecules to direct the drug to its site of action.
There are variety of statergies to modify the chemical structure of drug molecules, the most common being the prodrug and most sophisticated being the chemical delivery system approach. A prodrug is an inactive drug that is activated predictably in vivo to the active drug, but with few exceptions it cannot achieve site specific delivery. In contrast, a chemical delivery system involves transformation of the active drug by synthetic means into an inactive derivative which, when placed in the body, will undergo several predictable enzymatic transformations principally at the site of action. This is successful in targeting drug.
Obstacles of target drug delivery4 are because of impermeability of the GI tract to most macromolecules and instability of the drug carrier complex in the hostile environment of the GI tract, administration of large drug carrier complexes is restricted to intravenous or intra arterial injections or to the direct injection into the target site such as tumor. Major obstacle of drug targeting using macromolecules and particulate carriers(Liposomes,Nanoparticles) is rapid sequestering of intravascularly administered drug carrier by mononuclear phagocytes of reticuloendothelial system(RES).So first involves blocking of RES prior to administering the drug carrier, shows some undesirable effects in cancer patients. In recent research nanoparticles for reducing RES uptake is by covalent attachment of PEG uptake is by covalent attachment of PEG to surface of particles and shows increasing circulation time.
A second approach is to impart specificity to the drug carrier by coupling specific ligands onto its external surface. These include monoclonal antibodies, erythrocyte membrane glycoprotein, heated aggregated immunoglobulins. So far, none of these stratergies has proven to be successful due to difficulties in preserving the recognition ability in vivo and avoiding triggering any immunological response.
1.3 COLON SPECIFIC DRUG DELIVERY SYSTEM
The oral route is most popular route of drug administration6,7. For sustained release as well as controlled release systems, the oral route of administration has received the most attention. Patient acceptance of oral administration of drugs is quite high. It is a relatively safe route of drug administration compared with most parentral forms, and the constraints of sterility and potential damage at the site of administration are minimal. Colon-specific drug-delivery systems3 offer several potential therapeutic advantages. In a number of colonic diseases such as colorectal cancer, Crohn's disease, and spastic colon, it has been shown that local is more effective than systemic delivery. Colonic drug delivery can be achieved by oral or by rectal administration. Rectal delivery forms (suppositories and enemas) are not always effective because a high variability is observed in the distribution of drugs administered by this route. Therefore, the oral route is preferred. Absorption and degradation of the active ingredient in the upper part of the gastrointestinal tract is the major obstacle with the delivery of drugs by the oral route and must be overcome for successful colonic drug delivery. Drugs for which the colon is a potential absorption site (for example, peptides and proteins) can be delivered to this region for subsequent systemic absorption. The digestive enzymes of the gastrointestinal tract generally degrade these agents. However, these enzymes are present in significantly lower amounts in the colon compared with the upper portion of the gastrointestinal tract. Colon-specific drug delivery has been attempted in a number of ways that primarily seek to exploit the changes in the physiological parameters along the gastrointestinal tract. These approaches include the use of prodrugs, pH-sensitive polymers, bacterial degradable polymers, hydrogels and matrices, and multicoating time-dependent delivery systems.
Advantages of Colon Targeted Drug Delivery System
Time dependent system: small intestine transit time fairly consistent.
pH dependent system : formulation8 is well protected in the stomach.
It has minimum side effect.
Unnecessary systemic absorption does not occur.
Colonic drug delivery can be achieved by oral and rectal administration.
Colon specific formulation can be used to prolong drug delivery.
It enhances the absorption of poorly absorbed drug.
It helps in efficient vaccine delivery.
Reduces the adverse effects in the treatment of colonic diseases (ulcerative colitis, colorectal cancer, crohn's disease etc.)
Produces a 'friendlier' environment for peptides and proteins when compared to upper gastrointestinal tract.
Minimizes extensive first pass metabolism of steroids.
Prevents the gastric irritation produced by oral administration of NSAIDS.
Disadvantages of Colon Targeted Drug Delivery System
1. Time dependent system:
a) Substantial variation in gastric retention times
b) Transit through the colon more rapid than normal in patients with colon
2. pH-dependent system:
pH level in the small intestine and colon vary between and within individuals.
pH level in the end of small intestine and caecum are similar.
Poor site specificity.
3. Microflora activated Systems:
Diet and disease can affect colonic microflora.
Enzymatic degradation may be excessively slow.
Few have been accepted for use in relation to medicines.
1.4 ANATOMY AND PHYSIOLOGY OF COLON
The adult colon is about 5 feet long. It connects to the small bowel, which is also known as the small intestine. The major functions of the colon are to absorb water and salts from partially digested food that enters from the small bowel and then send waste out of the body through the anus. What remains after absorption is stool, which passes from the colon into the rectum and out through the anus when a person has a bowel movement.9
The colon comprises several segments:
the ascending colon
the transverse colon
the descending colon
the sigmoid colon
The colon is formed during the first 3 months of embryonic development. As the foetus grows and the abdominal cavity enlarges, the bowel returns to the abdomen and turns, or rotates, counter clockwise to its final position. The small bowel and colon are held in position by tissue known as the mesentery. The ascending colon and descending colon are fixed in place in the abdominal cavity. The cecum, transverse colon, and sigmoid colon are suspended from the back of the abdominal wall by the mesentery.
Fig 1.1 Large intestine representing parts of colon
This is the first part of the colon. It is a dilated region which has a blind end inferiorly and is continuous with the ascending colon superiorly. Just below the junction of the two the ileo caecal valve opens from the ileum. The vermiform appendix is a fine tube, closed at one end, which leads from the cecum. It is usually about 8 to 9 cm long and has the same structure as the walls of the colon but contains more lymphoid tissue.
This passes upwards from the cecum to the level of the liver when it curves actually to the left at the hepatic flexure to become the transverse colon. The nerve supply is by parasympathetic fibers of the vagus nerve.
This is a loop of colon that extends across the abdominal cavity in front of the duodenum and the stomach to the area of the spleen where it forms the splenic flexure and curves acutely downwards to become the descending colon.
This passes down the left side of the abdominal cavity then curves towards the midline. After it enters the true pelvis it is known as the sigmoid colon.
This part describes an S-shaped curve in the pelvis that continues downwards to become the rectum.
This is a slightly dilated section 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 large intestine absorption ban of water, by osmosis, continues until the familiar semisolid consistency of faeces is achieved. Mineral salts, vitamins and some drugs are also absorbed into the blood capillaries from the large intestine. It is colonized by certain types of bacteria, which synthesize vitamin K and folic acid.They include E.coli, E.aerogenes, S.faecalis and C.perfringens. Hydrogen, carbon dioxide and methane are produced by bacterial fermentation of unabsorbed nutrients, especially carbohydrate. Large number of microbes are present in faeces. In large intestine no peristaltic movement was seen like other parts of digestive tract. Only long intervals a wave of strong peristalsis sweep along the colon transverse colon forcing its contents into descending and sigmoid colons. This is known as mass movement. This combination of stimulus and response is called the gastrocolic reflex.
Usually rectum is empty, but when a mass movement forces the contents of the sigmoid colon into rectum the nerve endings in its walls are stimulated by stretch and assist the process of defaecation.10
Rationale for Colon Specific Drug Delivery
Targeting of drugs to colon is done for various reasons11.
Local treatment of inflammatory diseases e.g. crohn's disease.
Colonic diseases can be treated e.g. colorectal cancer and amoebiasis.
Oral delivery of peptide and protein drugs, which normally become inactivated in upper, parts the gastrointestinal tract.
Oral delivery of drugs/therapeutic substances that have undesirable side effects in the stomach and small intestine.
For the treatment of the diseases in which the diurnal rhythm is evident, e.g. asthma, rheumatic disease and ischemic heart disease.
Delivery of the drugs to the colon via, the oral route is valuable in treating diseases related to colon (Crohn's disease, ulcerative colitis, irritable bowel disease, carcinomas and infections) whereby high local concentration can be achieved while minimizing side effects that occurs because of release higher up in the gastrointestinal tract or because of release higher up in the gastrointestinal tract.
1.5 APPROACHES OF COLON TARGETED DRUG DELIVERY SYSTEM
Most of the conventional drug delivery system for treating colon disorders such as inflammatory bowel syndrome (ulcerative colitis, Crohn's disease etc.), infectious diseases (e.g. amoebiasis) and colon cancer are failing as the drug do not reach the site of action at appropriate concentrations. In light of the above-mentioned potential difficulties, different approaches have been studied for the purpose of achieving colonic targeting and are summarized below.
1.5.1 Prodrug Approach
A prodrug12 is an inactive chemical derivative of a parent compound that is activated predictably in vivo to active drug species at the target site. In this there is a covalent link between parent molecule and carrier molecule. Depending upon the linkage the triggering mechanism for the release of the drug in the colon was decided.
Breakage of linkage in colon is by different enzymes like azoreductase, ß-galactosidase, ß-xylosidase, nitroreductase, glycosidase deaminase, etc.
Examples of prodrugs delivery are:
1. Dexamethasone-2-ß-glucoside and Prednisolone-2-ß-glucoside for delivery of these steroids to the colon.
2. Non-essential amino acids such as glycine, tyrosine, methionine, and glutamic acid were conjugated to salicylic acid. The conjugate showed minimal absorption and degradation in the upper GI tract and showed more enzymatic specificity for hydrolysis by colonic enzymes.
3. Sulphasalazine, which was used for the treatment of rheumatoid arthritis, having an azo bond between 5-ASA and sulpha pyridine.
1.5.2 Time-Dependent Approach
They are developed to deliver drugs after a lag of five to six hours. The lag time13 is dependent on size of dosage form and gastric motility associated with the pathological condition of the individual.
An example of such a dosage form would be an impermeable capsule body containing the drug, fitted with a hydrogel plug that is used to deliver the drug after a predetermined time. This dosage form, for example Pulsincap®, releases the drug once the hydrogel plug hydrates and swells in aqueous media and is ejected from the device, thereby allowing the release of the drug from the capsule. Another example describes use of a hydrophobic material and surfactant in the tablet coating. The release of drug from the Time Clock® depends mainly on the thickness of the hydrophobic layer and is not dependent on the pH of the GI environment. The rationale behind all time-release delivery systems is valid provided that small intestine transit times remain constant. Changes in GI tract motility can significantly affect time-release drug delivery systems targeting the release of drugs to the colon.
1.5.3 pH-Dependent Approach
This approach is based on the pH-dependent14 release of the drug from the system. In this case the pH differential between the upper and terminal parts of GI tract is exploited to effectively deliver drugs to the colon. The pH of the intestine and colon depends on many factors such as diet, food intake, intestinal motility and disease states. By combining knowledge of polymers and their solubility at different pH environments, delivery systems have been designed to deliver the drug at the target site. Commonly used co-polymers of methacrylic acid and methyl methacrylate have been extensively investigated for colonic drug delivery systems. In vitro evaluation of Eudragit® S and Eudragit® FS was performed and it was found that the latter would be more appropriate for drug delivery to the ileocolonic region.