Colon targeted drug delivery system - an overview

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Abstract

By definition, colonic delivery refers to targeted delivery of drugs into the lower GI tract, which occurs primarily in the large intestine (i.e. colon). Targeted drug delivery to the colon would therefore ensure direct treatment at the disease site, lower dosing and fewer systemic side effects. In addition to local therapy, the colon can also be utilized as a portal for the entry of drugs into the systemic circulation.

Colon-targeted delivery of drugs has recently gained importance in addressing specific needs in the therapy of colon based diseases. Many techniques have been tried for the development of colon targeted drug delivery systems, with not much success in the past. Present research into the utilization of the metabolic activity and the colonic environment in the lower gastrointestinal tract has attained immense value in the design of novel colon targeted drug delivery systems by the utilization of natural biodegradable polymers. Successful delivery through this colon also requires the drug to be in solution form before it reaches in to the colon or alternatively, it should dissolve in the luminal fluids of the colon, but this can be a limiting factor for poorly water soluble drugs as the fluid volume in the colon is much lower and more viscous than in the upper part of the gastrointestinal tract. In such instances, the drug may need to be delivered in a pre-solubilized form, or delivery should be directed to the proximal colon, as a fluid gradient exists in the colon with more free water present in the proximal colon than in the distal colon. Aside from drug solubility, the stability of the drug in the colonic environment is a further factor that warrants attention. In order to formulate a suitable dosage form, the mechanisms and effective parameters need to be tacit and clarified. Therefore, we review the importance and rationale of pharmaceutical development and production, possible formulation variables and aids during the formulation, technologies involved in the fabrication, various mechanisms, characterization and application of colon targeted drug delivery system and also discussed the inclusion of organic acid in the formulation which would enhance the drug solubility in the luminal fluids of the colon and the results of recent researches on the colon targeted drug delivery system.

Key words: Colon delivery, natural polymers, organic acid, release mechanism, colonic microflora.

1.1 Introduction

Oral controlled - release formulations for the small intestine and colon have received considerable attention in the past 25 years for a variety of reasons including pharmaceutical superiority and clinical benefits derived from the drug - release pattern that are not achieved with traditional immediate (or) sustained - release products1.

By definition, colonic delivery refers to targeted delivery of drugs into the lower GI tract, which occurs primarily in the large intestine (i.e. colon). The site-specific delivery of drugs to lower parts of the GI tract is advantageous for localized treatment of several colonic diseases, mainly inflammatory bowel disease (Crohn’s disease and ulcerative colitis), irritable bowel syndrome, and colon cancer. Other potential applications of colonic delivery include chronotherapy, prophylaxis of colon cancer and treatment of nicotine addiction2.3. It has also gained increased importance not just for the delivery of drugs for the treatment of local diseases4, but also potential site for the systemic delivery of therapeutic proteins and peptides which are being delivered by injections. These delivery systems when taken orally, allow drugs to release the drug from the delivery system once the delivery system arrives into the colon.

These delayed mechanisms are designed to improve the efficacy of the drug by concentrating the drug molecules where they are need most, and also minimize the potential side effects and drug instability issues associated with premature release of drug in the upper parts of the GIT, namely stomach and small intestine4.

Colon targeted drug delivery would ensures direct treatment at the disease site, lower dosing and less systemic side effects. In addition to restricted therapy, the colon can also be utilized as a portal for the entry of drugs into the systemic circulation. For example, molecules that are degraded/poorly absorbed in the upper gut, such as peptides and proteins, may be better absorbed from the more benign environment of the colon. . Overall, there is less free fluid in the colon than in the small intestine and hence, dissolution could be problematic for poorly water-soluble drugs. In such instances, the drug may need to be delivered in a pre-solubilized form, or delivery should be directed to the proximal colon, as a fluid gradient exists in the colon with more free water present in the proximal colon than in the distal colon. Aside from drug solubility, the stability of the drug in the colonic environment is a further factor that warrants attention. The drug could bind in a nonspecific manner to dietary residues, intestinal secretions, mucus or general faecal matter, thereby reducing the concentration of free drug. Moreover, the resident micro-flora could also affect colonic performance via degradation of the drug5,6.

1.2 Why is colon targeted drug delivery needed?

  • Targeted drug delivery to the colon would ensure direct treatment at the disease site, lower dosing and fewer systemic side effects.
  • Site-specific or targeted drug delivery system would allow oral administration of peptide and protein drugs, colon-specific formulation could also be used to prolong the drug delivery.
  • Colon-specific drug delivery system is considered to be beneficial 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 Crohn’s disease. Such inflammatory conditions are usually treated with glucocorticoids and sulphasalazine (targeted).
  • A number of others serious diseases of the colon, e.g. colorectal cancer, might 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 hepatic metabolism, in particular, therapeutic proteins and peptides.

1.3 Colon anatomy5

The GI tract is divided into stomach, small intestine and large intestine. The large intestine extending from the ileocecal junction to the anus is divided in to three main parts. These are the colon, the rectum and anal canal.

The entire colon is about 5 feet (150 cm) long, and is divided in to five major segments. Peritoneal folds called as mesentery which is supported by ascending and descending colon. The right colon consists of the cecum, ascending colon, hepatic flexure and the right half of the transverse colon and the values were shown in Table 1. The left colon contain the left half of the transverse colon, descending colon, splenic flexure and sigmoid. The rectum is the last anatomic segment before the anus7. The human intestine and colon were shown in Figure1 and Figure 2 respectively.

The major function of the colon is the creation of suitable environment for the growth of colonic microorganisms, storage reservoir of faecal contents, expulsion of the contents of the colon at an appropriate time and absorption of potassium and water from the lumen3. The absorptive capacity is very high, each about 2000ml of fluid enters the colon through the ileocecal valve from which more than 90% of the fluid is absorbed. On average, it has been estimated that colon contains only about 220 gm of wet material equivalent to just 35 gm of dry matter. The majority of this dry matter is bacteria. The colon tissue containing the villi, lymph, muscle, nerves, and vessels.

 Structure of human intestine

Figure 1: Structure of human intestine

Structure of colon

Figure 2: Structure of colon

Table 1: Measures of different parts of colon

S.NO

Large Intestine

Length(cm)

1

2

3

4

5

6

7

Cecum

Ascending colon

Descending colon

Transverse colon

Sigmoid colon

Rectum

Anal canal

6-9

20-25

10-15

40-45

35- 40

12

3

1.4 Colonic microflora

A large number of anaerobic and aerobic bacteria are present the entire length of the human GI tract. Over 400 distinct bacterial species have been found, 20- 30% of which are of the genus bacteroids7. The upper region of the GIT has a very small number of bacteria and predominantly consists of gram positive facultative bacteria. The rate of microbial growth is greatest in the proximal areas because of high concentration of energy source.

The metabolic activity of microflora can be modified by various factors such as age, GI disease, and intake of drug and fermentation of dietary residues.

1.5 pH differences in the colon

On entry in to the colon, the pH dropped to 6.4 ± 0.5. The pH in the mid colon was found to be 6.6 ± 1 and in the left colon, 7.0 ± 1 and the values are shown in Table 2.

1.6 Gastrointestinal transit

Gastric emptying of dosage form is highly variable and depends primarily on whether the subject is fed or fasted and on the properties of the dosage form such as size and density. The transit times of dosage forms in tract are shown in Table 3.

Table 2: Average pH of the GI Tract

Location

pH

1. Stomach

Fasted condition

Fed condition

2. Small intestine

Jejunum

Ileum

3. Large intestine

Right colon

Mid colon and

Left colon

1.5 – 2.0

3.0 – 5.0

5.0 – 6.5

6.0 – 7.5

6.4

6.7 – 7.3

Table 3: Gastrointestinal Transit time of contents

Organ

Transit Time (hr)

Stomach

Small intestine

Large intestine

<1(fasting)

>3(fed)

3-4

20-30

Diseases affecting colonic transit have important implications for drug delivery, diarrhea increases colonic transit and constipation decreases it. The digestive motility pattern takes place when food is present in the stomach. It is said by regular, frequent contractions (about 4-5/min.) which effect the mixing intestinal contents and moving them towards the colon in short segments and lasts as long as food remains present in the stomach. The most frequent movements seen in the colon are very slow segmenting movements that typically occurs every 30 minutes8.

1.7 Drug absorption in the colon

Drugs are absorbed passively by either paracellular or transcellular route. Transcellular absorption involves the passage of drugs through cells and this is the route most lipophilic drugs takes, where paracellular absorption involves the transport of drug through the tight junction between cells and is the route most hydrophilic drug takes7.

The colon may not be the best site for drug absorption since the colonic mucosa lacks well defined villi as found in the small intestine. The slower rate if transit in colon lets the drug stay in contact mucosa for a longer period than in small intestine which compensates much lower surface area.

The colon contents become more viscous with progressive absorption of water as one travels further through the colon. This causes a reduced dissolution rate, slow diffusion of drug through the mucosa.

Theoretically, drug absorption can occur along the entire GI tract, while in actuality, most drugs are absorbed in the duodenum and proximal jejunum. Recent studies have shown that some drugs (e.g. Theophyline and Metoprolol) continue to be absorbed in the colon.

1.8 Oral preparations9-11

Solid formulations intended for targeted drug release into the lower gastrointestinal (GI) tract are beneficial for the localized treatment of several diseases and conditions, mainly inflammatory bowel diseases, irritable bowel syndrome and colon cancer. Also, because of their natural potential to delay or avoid systemic absorption of drug from the small intestine, colonic formulations can be utilized for chronotherapy of diseases which are affected by circadian biorhythms (e.g., asthma, hypertension and arthritis), and to achieve clinically significant bioavailability of drugs that are poorly absorbed from the upper parts of the gastrointestinal tract because of their polar nature and/or vulnerability to chemical and enzymatic degradation in the small intestine (e.g., peptides and proteins). The recent patent literature pertaining to various modified release (MR) formulation methods that are claimed to provide colonic delivery for a wide range of therapeutic agents. These technologies either utilize a single or a combination of two or more physiological characteristics of the colon, which includes pH, microflora (enterobacteria), transit time, and luminal pressure. Accordingly, these technologies may be grouped under four distinct classes;

1. pH-controlled (or delayed-release) system

2. Time-controlled (or time-dependent) system

3. Microbially-controlled system

4. Pressure-controlled system.

Among these, formulations that release drugs in response to colonic pH, entero-bacteria, or both are most common and promising.

1.9 Topical preparations

Topical Preparations (foams, suppositories or enemas) plays major role in ulcerative colities, either alone or in combination with oral steroids. They should generally not be used once a patient requires high-dose oral or intravenous steroid therapy.

1.10 Old systemic and topical steroids

Synthetic glucocorticoids such as prednisone, prednisolone, methyl-prednisolone, hydrocortisone, and ACTH are the most commonly used traditional corticosteroids in the treatment of ulcerative colitis.

1.11 Colonic diseases

  • Crohn’s Diseses
  • Ulcerative Colitis
  • Diversional Colitis
  • Ischemic Colitis
  • Diverticular Inflammatory Bowel Disease
  • Colon Cancer
  • Lymphoma of the Colon

1.12a Inflammatory Bowel Disease

The cause of inflammatory bowel disease is multi-factoral and it is due to the inflammatory responses, genetic factors such as multiple genetic factors, candidate genes, chromosome location, etc., infectious agents like Escherichia coli, Measles virus, Cytomegalovirus, etc., dietary factors such as saturated fats, milk products, allergic foods etc. It is a general term that has the following two diseases,

  1. Ulcerative colitis

  2. Crohn’s disease

Ulcerative colitis occurs only in the large intestine. Ulcers form in the inner lining of the intestine, or mucosa, of the colon or rectum, often resulting in diarrhea, blood, and pus. The inflammation is usually very rigorous in the sigmoid and rectum and usually reduces in the colon.

Crohn's disease: Crohn's disease, also called regional enteritis, is a chronic inflammation of the intestines which is usually confined to the terminal portion of the small intestine, the ileum. Ulcerative colitis is a common inflammation of the colon, or large intestine. These diseases and other inflammatory bowel disease have been linked with an increased risk of colorectal cancer.

1.12b Diagnosis of inflammatory bowel disease

Blood tests: An increased number of white blood cells may indicate the presence of inflammation. New blood tests that measure certain antibodies may make it easier to differentiate Crohn's disease from ulcerative colitis. Feces sample is also taken and examined for blood, infectious agents, or both.

Endoscopic technique: Flexible sigmoidoscopy and colonoscopy are endoscopic techniques. They are important in the diagnosis of both ulcerative colitis and Crohn's disease and both techniques involve snaking a fiber optic tube called an endoscope through the rectum to view the lining of the colon. The tissue sample may also be collected for a biopsy.

The other diagnostic techniques of this disease are constellation of positive endoscopic, ratiographic, and histological findings with negative stool cultures. The differential diagnosis of IBS includes infectious colitis, celiac sprue, intestinal lymphoma, radiation enteropathy, NSAIDs use, and ischemic colitis.

1.13 Approaches to colon-specific drug delivery 12-14

Colon-specific drug delivery is considered beneficial in the treatment of colon-related diseases and the oral delivery of protein and peptide drugs. Generally, each colon-specific drug delivery system has been designed based on one of the following mechanisms with varying degrees of success;

  1. Coating with pH dependent polymers
  2. Coating with pH independent biodegradable polymers
  3. Delivery systems based on the metabolic activity of colonic bacteria

Prodrugs

Hydrogels

Polysaccharides

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, in particular, therapeutic proteins and peptides. Proteins and peptides such as insulin, calcitonin and vasopressin may be delivered systemically via colonic absorption. Other examples include novel peptides such as cytokine inhibitors and antibiotics, which are useful in the treatment of inflammatory bowel diseases and GI infections, respectively. Apart from protecting these labile molecules, colon also offers an opportunistic site for oral delivery of vaccines because it is rich in lymphoid tissue. Therefore, the uptake of antigens through the colonic mucosa may lead to rapid and local production of antibodies. There is also an increasing interest in the colonic delivery for improving the oral bioavailability of drugs that are substrates of metabolizing enzymes is comparatively lower in the colonic mucosa than in the small intestine. Increasing bioavailability via a colonic formulation approach has also been found to be effective in minimizing unwanted side-effects. Drug release from this system is triggered by colonic microflora coupled with pH sensitive polymer coatings14.

1.13a Coating with pH dependent polymers

In these systems drugs can be formulated as solid dosage forms such as tablets, capsules and pellets and coated with pH sensitive polymers as an enteric coating. Widely used polymers are methacrylic resins (Eudragits) which are available in water soluble and insoluble forms. Eudragit L and S are copolymers of methacrylic acid and methacrylate. 5-aminosalicylic acid is commercially available as an oral dosage form coated with Eudragit L and S. Other colon-specific delivery systems based on methacrylic resins are described for prednisolone, insulin and quinolones8,15.

The pH-dependent systems exploit the generally accepted view that pH of the human GIT increases progressively from the stomach (pH 1-2 which increase to 4 during digestion), small intestine (pH 6 - 7) at the site of digestion and it increases to 7-8 in the distal ileum. The gamma scintigraphy technique becomes most popular technique to investigate the gastrointestinal performance of pharmaceutical formulations.

Mostly used polymer most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit S more specifically Eudragit L and S. Eudragit L100 and S100 are the copolymers of methacrylic acid and methyl methacrylate. Carboxyl polymer form salts and dissolve above pH 5.5 and disperse in water to form latex and thus avoid the use of organic solvents is the coating process. Eudragit L100-55 polymers with ionizable phthalic acid groups dissolve much faster and at a lower pH than those with acrylic or methacrylic acid groups16.

Colon targeted drug delivery systems based on methycrylic resins has described for insulin, prednisolone, quinolones, salsalazine, cyclosporine, beclomethasone dipropionate and naproxane, Khan et al. prepared lactose-based placebo tablets and coated using various combinations of two methacrylic acid polymers, Eudragit L100-55 and Eudragit 100 by spraying from aqueous systems. The same coating formulations are then applied on tablets and evaluated for in vitro dissolution rates under various conditions. Dissolution studies performed on the mesalazine tablets further confirmed that the release profiles of the drug could be manipulated by changing the Eudragit L100-55 and Eudragit S100 ratios within the pH range of 5.5 to 7.0 in which the individual polymers are soluble respectively, and a coating formulation consisting of a combination of the two copolymers can overcome the issue of high GI pH variability among individuals. Enteric polymers used for such modified release dosage form is summarized in Table 4.

1.13b Coating with pH independent biodegradable polymers

Drugs that are coated with the polymers, which are showing degradability due to the influence of colonic microorganisms, can be exploited in designing drugs for colon targeting in order to release an orally administered drug in the colon.

The intestinal microflora has a large metabolic capacity and it appears that reduction of azo bonds is a general reaction of colonic bacteria. The azo polymers having a high degree of hydrophilicity were degraded by colonic bacteria15,16.

The copolymers of styrene and 2-hydroxy mehyl methacrylate which were cross linked with divinyl azo benzene and N.N¹ bis (β-styrene sulphonyl) - 4, 4¹-diamino azo- benzene to coat oral dosage forms of insulin and vasopressin. On arrival at the colon the coating is degraded by bacterial azo reductases there by releasing the drug.

1.13c Delivery systems based on the metabolic activity of colonic bacteria

i. Prodrugs

Prodrugs8 of steroids having a hydroxyl group at C-21 position were prepared using poly-l-aspartic acid carrier. The ester prodrug of dexamethasone with poly-l-aspartic acid when subjected to in vitro drug release studies in gastro intestinal tract homgenates released dexamethasone because of the cleavage of the ester bond by bacterial enzymes.

The polymeric prodrugs of sulfasaslazine, is used in the treatment of ulcerative colitis and crohn’s disease. Chemically sulfasaslazine is 5- aminosalicylic acid (5-ASA) coupled with sulphapyridine by azo bonding. On arrival at the colon the azo bond is reduced by colonic azo reductases to 5-ASA and sulphapyridne17,18.

Bacteria in Colon

Hydrolysis of sulfasalazine (i) into 5-aminosalicylic acid (ii) and sulfapyridine

Classical prodrug design often represents a nonspecific chemical approach to mask unwanted drug properties such as low bioavailability, less site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, prodrugs targeting to a specific enzyme or a specific membrane transporter, or both, have potential drug delivery system especially for cancer chemotherapy. Site specific targeting with prodrugs can be further improved by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody directed enzyme prodrug therapy, gene directed enzyme prodrug therapy, and peptide transporter-associated prodrug therapy19.

ii. Strategy for pro-drug site-specific drug delivery

The use of prodrugs has been actively pursued to achieve very precise and direct effects at the "site of action," with minimal effect on the rest of the body. There are at least three factors should be optimized for the site specific delivery of drugs by using the prodrug approach12,13.

1. The prodrug must to reach the target for the site of action as early as possible, and uptake from the site must be fast and essentially perfusion rate limited.

2. Once the drug reached to the site, prodrug must be selectively liberated to the active drug relative to its conversion at other sites.

3. Once selectively liberated at the site of action, the active drug must be somewhat retained by the tissue.

iii. Targeted Prodrug Design

Prodrugs can be designed to target specific enzymes or carriers by considering enzyme substrate specificity or carrier substrate specificity in order to overcome various unwanted drug properties. This type of targeted prodrug design requires considerable knowledge related to a particular enzymes or carrier systems including their molecular and functional characteristics. Targeted prodrug design discussed in 2 categories:

1. Targeting specific enzymes and

2. Targeting specific membrane transporters.

iv. Prodrug Design Targeting Enzymes

In prodrug design, enzymes can be recognized as pre-systemic metabolic sites and an irreversible chemical modification technique is more successfully achieved to reduce the pre-systemic metabolism by targeting enzymes rather than by a prodrug approach. The enzyme targeted prodrug approach can be widely used to improve oral drug absorption, as well as site specific drug delivery. In the case of enhancing oral drug absorption, GI enzymes may be the main targets for prodrug design, and the use of a nutrient moiety as a derivatizing group permits more specific targeting for gastro-intestinal enzymes to improve oral drug absorption20. These prodrugs have the further advantage of producing nontoxic nutrient byproducts when they regenerate the active drugs in-vivo. Extensive studies on gastrointestinal enzymes, which provide necessary information (e.g., enzyme distribution, activity, and specificity) for prodrug design20-23.

In the prodrug approach, site specific delivery can be obtained from tissue specific activation of a prodrug, which is the result of metabolism by an enzyme that is either exceptional for the tissue or present at a higher amount (compared with other tissues); thus, it activates the prodrug more competently. For example, glycosidase activity of the colonic microflora offers an opportunity to design a colon specific drug delivery system. Glycoside derivatives are hydrophilic and are poorly absorbed from the small intestine, but once they reach the colon, they can be effectively liberated by bacterial glycosidases to release the free drug and facilitates the absorption by the colonic mucosa. These glycosidic prodrugs, the dexamethasone glucoside appeared to be the better candidate, with nearly 60% of the orally administered prodrugs reaching the caecum as a free steroid, while orally administered parent steroids were absorbed almost from the small intestine. L-dopa was decarboxylated to dopamine by aromatic L-amino acid decarboxylase, which is highly concentrated in the kidney. The concentration of dopamine in the kidney after administration of L-- glutamyl dopa was almost 5 times higher than that after an equivalent dose of L-dopa. Appropriately designed prodrugs have been found to be effective in the treatment of animal tumors possessing high levels of an activating enzyme. However, clinical results were unsatisfactory when it was found that the human tumors containing appropriately high levels of the activating enzymes were rare and that the high levels of activating enzymes were not associated with any particular type of tumor. Recently, new therapies have been proposed to overcome this limitation of prodrug therapy9-11.

These new approaches are referred to as;

  • ADEPT (antibody-directed enzyme prodrug therapy - shown in Figure 3) , and
  • GDEPT (gene-directed enzyme prodrug therapy - shown in Figure 4), which attempt the localization of prodrug activation enzymes into specific cancer cells prior to prodrug administration.

Schematic representation of ADEPT

Figure 3. Schematic representation of ADEPT.

Schematic representation of GDEPT

Figure 4. Schematic representation of GDEPT.

1.14 Hhydrogels8,24-27

The hydrogels contain acidic co-monomers and enzymatically degradable azoaromatic cross-links. In the acidic pH of stomach, the gels have a low degree of swelling, which protect the drug against degradation by digestive enzymes. As the gels pass down the GI tract, the degree of swelling increases. On entering the colon, the gels reach a degree of swelling making the cross-links accessible to enzymes (azoreductases) or mediators (electron carriers).

A number of drug delivery devices have been pro posed to deliver the drug for efficient therapy. Among them, hydrogels, specially based on polysaccharides, have attracted considerable attention as an excellent candidates for controlled release devices or targetable devices of the therapeutic agents. The release rate of drugs from hydrogels was primarily determined by the swelling extent, which further enhanced by addition of enzyme in the buffer solutions whereas swelling of polymeric networks was depended on composition of copolymer and pH of the surrounding medium. The controlled release of active anti-microbial agents- amoxicillin, metronidazole, oxytetracycline and tetracycline-HCl from the polymeric matrix have been well reported.

Diffusion mechanism of the drugs from the polymeric matrix can be calculated from the equation;

Equations

Where;

Mt / M∞ is the fractional release of drug in time t, ‘k’ is the constant characteristic of the drug-polymer system, and ‘n’ is the diffusion exponent ‘D’ is the diffusion coefficient and ‘λ’ is the thickness of the sample.

The release of water-soluble drugs, entrapped in a hydrogels, occur only after water penetrates the polymeric networks to swell and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. The release of drug is closely related to the swelling characteristics of the hydrogels, which in turn, is a, key function of chemical architecture of the hydrogels. In the present study the effect of pH on the release pattern of tetracycline have been studied by varying the pH of the release medium. The amount of drug release in pH7.4 buffer was higher than the release medium of pH2.2 buffer and distilled water. The swelling of hydrogels [psy-clpoly(AAm)], increased when the pH of the medium changed from acidic to basic. At lower pH values the -CONH2 groups does not ionized and keep the polymeric networks at its collapsed state. At high pH values, it is partially ionize d, and the charged –COO groups repel each other, leading to the higher swelling of the polymer and resultant to more drug release. The release of drug was observed to be faster in pH 7.4 (Equation 1). From the percent cumulative release studies of tetracycline it was observed that first 50% of the total release occurred in 90min., 120min. and 135min. in releasing medium of pH7.4 buffer, pH2.2 buffer and distilled water respectively. The diffusion exponent ‘n’ have 0.74, 0.60 and 0.56 values and gel characteristic constant ‘k’ have 1.272×10-2, 2.754×10-2 and 3.639×10-2 values in distilled water, pH2.2 buffer and pH7.4 buffer respectively for the tetracycline release from the hydrogels and these values were obtained from the slope and intercept of the plot between ln Mt/M∞ versus ln t (Equation 2). It means Non-Fickian or Anomalous diffusion occurs for the tetracycline release from the hydrogels It is also observed that in each release medium the Initial diffusion coefficient was observed to more than late time diffusion coefficient.

1.15 Polysaccharides as carriers28

Natural polysaccharides such as pectin and xylan are not digested in human stomach or small intestine, but are degraded in the colon by resident bacteria. Pectin in the form of compression coat was evaluated for targeting to colon. The coat was susceptible to enzymatic attack in the colon there by releasing the drug.

A novel tablet formulation for oral administration using guar gum as a carrier and indomethacin, metronidazole, albendazole, mebendazole as a model drug. Drug release studies under conditions mimicking mouth to colon transit have shown the guar gum protects the drug from being released completely in the physiological environment of stomach and small intestine29-32.

Inulin28 is the other natural polysaccharide found in many plants such as onion, garlic. Inulin HP (High degree of polymerization) incorporated in Eudragit RS film was evaluated as a possible biodegradable coating for colonic drug delivery. Polymers that under go microbially degradation and used for colonic drug delivery are summarized in Table 5.

1.16 General considerations for design of colonic formulations

Formulations for colonic delivery are, in general, delayed-released dosage forms which maybe designed either to provide a ‘burst release’ or a sustained / prolonged / targeted.

a. Pathology and of disease, especially the affected parts of the lower GIT.

b. Physicochemical and biopharmaceutical properties of the drug such as solubility, stability and permeability at the intended site of delivery.

c. The preferred release data of the drug.

Very common physiological factor which is considered in the design of delayed release colonic formulations is pH gradient of the GI tract. In normal healthy subjects, there is a progressive increase in luminal pH from the duodenum (pH is 6.6±0.5) to the end of the ileum (pH is 7.5 ± 0.4), a decrease in the cecum (pH is 6.4 ± 0.4), and then a slow rise from the right to the left colon with a final value of 7.0 ± 0.7. Some reports suggested that alterations in gastrointestinal pH profiles may occur in patients with inflammatory bowel disease, which should be considered in the development of delayed release formulations.

1.17 Types or modified release formulations for colon targeted drug delivery systems33,34

These are of two types:

  • Single unit colon targeted drug delivery system: It may suffer from the disadvantage of unintentional disintegration of the formulation due to manufacturing deficiency or unusual gastric physiology that may lead to drastically compromised systemic drug bioavailability or loss of local therapeutic action in the colon.
  • Multiparticulate dosage form systems: These are developed in comparison to single unit systems because of their potential benefits like increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying. Multiparticulate approaches tried for colonic delivery includes formulations in the form of pellets, granules, microparticles and nanoparticles. The use of multiparticulate formulations in preference to single unit dosage forms for colon targeting purposes. Showed that multiparticulate formulations enabled the drug to reach the colon quickly and were retained in the ascending colon for a relatively long period of time. Because of their smaller particle size as compared to single unit dosage forms these systems tend to be more uniformly dispersed in the GI tract and also ensure more uniform drug absorption. Most commonly investigated multiparticulate formulations for colon specific drug delivery include pellets, granular matrices, beads, microspheres, and nanoparticles. Examples of colon targeted formulations are summarized in Table 6.

1.18 Evaluation of colon- specific drug delivery systems35-39:

Different in vitro and in vivo methods are used to evaluate different carrier systems for their ability to deliver drugs specifically to the colon. The ability of the coats or carriers to remain intact in stomach and small intestine is generally assessed by conducting drug release studies in 0.1N hydrochloric acid for 2 hours followed by phosphate buffer (pH -7.4) for 3 h by using dissolution apparatus. The drug release studies may also be performed by using rat cecal contents.

Another in-vitro method involves incubation of the drug delivery system in a fermentor with commonly found colonic bacteria. In vivo methods offer various animal models. Guinea pigs were used to evaluate colon- specific drug delivery from a glucoside prodrug of dexamethasone. In vivo gamma scintigraphic studies were carried out on the guar gum matrix tablets, using technetium 99 m- DTPA as a tracer. Scintigraphs taken at regular intervals have shown that some amount of tracer present on the surface of the tablets was released in stomach and small intestine. Radiotelemetry, Roentenograpgy are the other in vivo evaluation methods for colon-specific drug delivery systems40.

1.19 Limitations and challenges in colon targeted drug delivery

  • 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. This is due to the rationale after a colon specific drug delivery system is quite diverse.
  • As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time and increased responsiveness 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 colon is particularly difficult to access. In addition to that the wide range of pH values and different enzymes present throughout the gastrointestinal tract, through which the dosage form has to travel before reaching the target site, further complicate the reliability and delivery efficiency.
  • Successful delivery through this site also requires the drug to be in solution form before it arrives in the colon or, alternatively, it should dissolve in the luminal fluids 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.
  • In addition, the stability of the drug is also a concern and must be taken into consideration while designing the delivery system. The drug may potentially bind in a nonspecific way to dietary residues, intestinal secretions, mucus or faecal matter.
  • The resident microflora could also affect colonic performance via metabolic degradation of the drug. 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.

The literature also suggested that the cytochrome P-450(3A) class of drug metabolizing enzymes have lower activity in the colonic mucosa. A longer residence time of 3 to 5 days results in elevated plasma levels of the drugs and therefore higher bioavailability in general, but especially for drugs that are substrates for this class of enzyme.

1.20 Current and future developments

Currently, there are several modified release solid formulation technologies available for colonic delivery. These technologies rely on GI pH, transit times, enterobacteria and luminal pressure for site-specific delivery. Each of these technologies represents a unique system in terms of design but has certain shortcomings, which are often related to degree of site-specificity, toxicity, cost and ease of scale up/manufacturing. It appears that microbially-controlled systems based on natural polymers have the greatest potential for colonic delivery, particularly in terms of site-specificity and safety. In this regard, formulations that employ a film coating system based on the combination of a polysaccharide and a suitable film forming polymer represents a significant technological advancement. Further developments in this area require means to improve the co-processing of the polymeric blend of a polysaccharide(s) and a film forming material while maintaining the propensity of the composition to microbial degradation in the colon42,43.

1.21 Opportunities in colon targeted drug delivery

  • In the area of targeted delivery, the colonic region of the GI tract is the one that has been embraced by scientists and is being extensively investigated over the past two decades.
  • Targeted delivery to the colon is being explored not only for local colonic pathologies, thus avoiding systemic effects of drugs or inconvenient and painful trans-colonic administration of drugs, but also for systemic delivery of drugs like proteins and peptides, which are other wise degraded and/or poorly absorbed in the stomach and small intestine but may be better absorbed from the more benign environment of the colon.
  • This is also a potential site for the treatment of diseases sensitive to circadian rhythms such as asthma, angina and arthritis. Moreover, there is an urgent need for delivery of drugs to the colon that reported to be absorbable in the colon, such as steroids, which would increase efficiency and enable reduction of the required effective dose.
  • The treatment of disorders of the large intestine, such as irritable bowel syndrome (IBS), colitis, Crohn’s disease and other colon diseases, where it is necessary to attain a high concentration of the active agent, may be efficiently achieved by colon-specific delivery.
  • The development of a dosage form that improves the oral absorption of peptide and protein drugs whose bioavailability is very low because of instability in the GI tract is one of the greatest challenges for oral peptide delivery.
  • The bioavailability of protein drugs delivered at the colon site needs to be addressed.
  • More research is focused on the specificity of drug uptake at the colon site is necessary. Such studies would significant in advancing the cause of colon targeted drug delivery in future.

Table 4: Enteric Polymers used in the development of Modified-Release Formulations for Colonic drug Delivery systems

Enteric Polymers

Optimum pH for dissolution

Polyvinyl acetate phthalate (PVAP)

5.0

Cellulose acetate trimelitate (CAT)

5.5

Hydroxypropyl methylcellulose phthalate (HPMCP)

> 5.5

Hydroxypropylmethylcellulose acetate succinate (HPMCAS)

> 6.0

Methacrylie acid copolymer, Type C (Eudragit L100-55)

> 6.0

Methacrylic acid copolymer dispersion (Eudragit L30D-55)

> 5

Methacrylic acid copolymer, Tyep A

> 6.0

(Eudragit®L-100 and Eudragist L12,5)

_

Cellulose acetate phthalate (CAP) (Aquateric)

6.0

Methacrylic acid copolymer, Type B

> 7.0

(Eudragist S-100 and Eudragit S12,5)

_

Eudragit FS30D

> 7.0

Shellac (MarCoat 125 &125N)

7.0

Table 5: Microbially degradable polymers used for Colonic drug delivery system.

Class

Examples

Disacharides

Lactose

Maltose

Oligosaccharides

Cellobiose

Cyclodextrins

Lectulose

Raffinose

Stachyose

Polysaccharides

Alginates

Amylose

Arabinogalactan

Arabinoxylan

Cellulose

Chitosan

Chondroitin sulfate

Xextran

Galactomnam (guar gum, locust bean gun)

Inulin

Karaya gum (kadaya gum)

Laminarin

Pectins and pectates

Starch

Tragacanth gum

Xanthan gum

Xylan

Table 6: Examples of colon targeted formulations based on conventional techniques.

Technique employed

Polymer (s) used

Drug used

Reference

pH dependent

Eudragit L100 and S100

Mesalzine

44

DudragitL100 and S100

NS

45

Eudragit L 100 andS100

Diclofenac sodium and 5-ASA

46

Eudragit S, Eudragit FS, Eudragit P4135F

Prednisolone

47

Eudragit L 30 D-55 and Eudragit FS 30D

Paracetamol

48

Time dependent

Hydroxy propyl methyl cellulose

Pseudo ephedrine HCl

49

Hydroxyethyl cellulose, ethyl

Theophyline

50

Cellulose, microcrystalline cellulose Lactose/behinic acid

Indomethacin

51

Hydroxy propyl methyl cellulose

NS

52

Hydroxy propyl methyl cellulose acetate succinate

Diltiazem HCl

53

Bacteria dependent/ Polysaccharide based

Chitosan

Declofenac sodium

54

Pectin

Indomethacin

55

Guar gum

Dexamethasone

56

Chondroitin sulphate

Indomethacin

57

Amylose

5-Acetyl salicylic acid

References:

  1. Glibert S Banker (ed.), Modern Pharmaceutics (4th edn), Marcel Dekker, New York, 2002, 527-584.

  2. Abdul B, John B. Perspectives on Colonic Drug Delivery, Business Briefing, Pharmatech, 2003, 185–190.

  3. Bajpai S K, Bajpai M, Dengree R. Chemically treated gelatin capsules for colon-targeted drug delivery: a novel approach, J. Appl. Polym.Sci., 2003, 89, 2277–2282.

  4. Edith mathiowitz (ed.). Encyclopedia of controlled drug delivery, John wiley and sons, Inc. Newyork, 2003, 698-726.

  5. Sarasija S, Hota A. Colon-specific drug delivery systems, Indian journal of pharmaceutical sciences, 62(1), 2000, 1-8.

  6. Chourasia M K, Jain S K. Pharmaceutical Approaches to Colon Targeted Drug Delivery, Journal of pharmaceutical sciences, 6(1), 2003, 33-66.

  7. Colonic Delivery Formulations, Recent Patents on Drug Delivery and Formulation, 1(1), 2007, 55.

  8. Hamman et al, Drug Target Insights, 2, 2007, 80.

  9. Basit A W, Podczeck F, Newton J M. The use of formulation technology to assess regional gastrointestinal drug absorption in humans, Eur. J. Pharm. Sci., 21, 2004, 179–89.

  10. Stella V J, Charman W N, Naringrekar V H. Prodrugs, Inc: Do they have advantages in clinical practice? Drugs, 29, 1985, 455-473.

  11. Higuchi T, Stella V (ed.). Prodrugs: an overview and definition. Inc: Prodrugs as Novel Drug Delivery Systems, ACS Symposium Series, Washington, DC: American Chemical Society, 1975, 1-115.

  12. D’Acquisto F, May M J, Ghosh S. An emerging theme in anti-inflammatory therapies, Mol. Intervent., 2, 2002, 22–35.

  13. Cawley D B, Simpson D L, Hershman H R. Biochimie, 68, 1981, 375–81.

  14. Kopeck J, Kopeckova P, Brondsted H, Rath R, Lkesue K. Polymers for colon-specific drug delivery, Journal of controlled release, 19, 1992, 121-130.

  15. Schacht E, Gevaert A, kenawy ER, Molly K Gelan J. Polymers for colon-specific drug delivery, Journal of controlled release, 39, 1996, 327-338.

  16. Ramprasad Y V, Krishnaiah Y S, Satyanarayana S. Studies of guar gum compression-coated 5-aminosalicylic acid tablets for colon-specific drug delivery, Drug development and industrial pharmacy, 25(5), 1999, 651-657.

  17. Sinha V R, Kumria R. Colonic drug delivery: prodrug approach, Pharmaceutical research, 224(1-2), 2001, 19-38.

  18. Sinkula A A, Yalkowsky S H. Rationale for design of biologically reversible drug derivatives: prodrugs, J Pharm Sci., 64, 1975, 181-210.

  19. Ardizzone S, Bollani S, Manzionna G, Bianchi Porro G. Inflammatory bowel disease approaching the 3rd millennium: pathogenesis and therapeutic implications. Eur J Gastroenterol Hepatol., 11(1), 1999, 27-32.

  20. Ardizzone S, Porro G B. Comparative tolerability of therapies for ulcerative colitis, Drug Saf., 25(8), 2002, 561-82.

  21. Ardizzone S, Porro G B. Inflammatory bowel disease: new insights into pathogenesis and treatment, J Intern Med., 252(6), 2002, 475-96.

  22. Clemett D, Markham A. Colitis Foundation of America, Prolonged-release mesalazine: ulcerative colitis and Crohn’s disease, Drugs, 59, 2000, 929–956.

  23. Mahkam M, Doosite L. The relation between swelling properties and cross linking of hydrogels designed for colon- specific drug delivery, Drug delivery, 12(6), 2005, 343-347.

  24. Orienti L, Trere R, Zecchi V. Hydrogels formed by crosslinked polyvinylalcohol as colon-specific drug delivery systems, Drug development and industrial pharmacy, 27(8), 2001, 877-884.

  25. Kinget R, Van-Den-Mooter G, Samyn C. Azopolymers for colon-specific drug delivery, Part 2. Influence of the type of azopolymer on degradation by intestinal microflora, International journal of Pharmaceutics, 93, 1993, 133-139.

  26. Bronsted H, Hovgaard L, Simonsen L. Dextran hydrogels for colon-specific drug delivery, Part 3. In vitro and in vivo degradation, STP-Pharm-Sciences, 5(1), 1995, 60-64.

  27. Krishnaiah.Y S, Satyanarayana S. Inc: Advances in controlled and novel drug delivery: Colon-specific drug delivery systems, CBS Publishers and Distributors, New Delhi: India, 2001, 89-119.

  28. Ramprasad Y V, Krishnaiah Y S, Satyanarayana S. In vitro evaluation of guar gum as a carrier for colon-specific drug delivery. Journal of controlled release, 59, 1998, 281-287.

  29. Ramprasad Y V, Krishnaiah Y S, Satyanarayana S. Studies of guar gum compression-coated 5-aminosalicylic acid tablets for colon-specific drug delivery, Drug development and industrial pharmacy, 25(5), 1999, 651-657.

  30. Gliko Kabir L, Yagen B, Baluom M, Rubinstein A. Phosphated crosslinked guar gum for colon-specific drug delivery, Part 1. Preparation and physiological characterization, Journal of controlled release, 63, 2000, 121-127.

  31. Gliko Kabir L, Yagen B, Baluom M, Rubinstein A. Phosphated crosslinked guar gum for colon-specific drug delivery, Part 2. In vitro and in vivo evaluation in the rat, Journal of controlled release, 63, 2000, 63:129-134.

  32. Dautry-Varsat A. Biochimie, 68, 1986, 375–81.

  33. Thacharodi D, Rap K P. Development and in vitro evaluation of chitosan- based drug delivery system, Biomaterials, 45, 1995, 145-8.

  34. Nykänen P, Krogars K, Säkkinen M, Heinämäki J, JFrjenson H,Veski P, Marvola M. Organic acids as excipients in matrix granules for colon-specific drug delivery, Int. J. Pharm., 184, 1999, 251–261.

  35. Krishnaiah Y S, Ramprasad Y V, Satyanarayana S, Seethadevi A, Nageswar Rao L Bhaskar P, Karthikeyan R R S. Guar gum as a carrier for colon specific delivery; Influence of metronidazole and tinidazole on in vitro release of albendazole from guar gum matrix tablets, Journal of pharmaceutical sciences, 4(3), 2001, 235-243.

  36. Krishnaiah Y S, Kumar B D, Satyanarayana S, Karthikeyan R S. Studies on the development of oral colon targeted drug delivery systems for celecoxib in the prevention of colorectal cancer. Journal of drug targeting. 2002; 10(3):247-254.

  37. Krishnaiah Y S, Bhaskar Reddy P R, Satyanarayana S, Karthikeyan R S. Studies on the development of oral colon targeted drug delivery systems for metronidazole in the treatment of amoebiasis, International journal of pharmaceutics, 236(1-2), 2002, 43-55.

  38. Sinha V R, Kumria R. Microbially triggered drug delivery to the colon, European journal of pharmaceutical sciences, 18(1), 2003, 3-18.

  39. Bankar J A. Matrix tablets, Inc: The theory and practice of industrial pharmacy (3rd edn), Verghese publishing House, Bombay, 1987, 453-455.

  40. Breimer D D. Future challenges for drug delivery, J Control Rel 62, 1999, 3–6.

  41. Basit A, Bloor J. Perspectives on colonic drug delivery, Business Briefing, Pharmatech., 2003, 185-190.

  42. Langer R. Drug delivery and targeting, Nature, 392, 1998, 5–10.

  43. Kost J, Langer R. Responsive polymeric delivery systems, Adv Drug Deliv Rev., 46, 2001, 125–148.

  44. Colonic Delivery Formulations, Recent Patents on Drug Delivery and Formulation, 1(1), 2007, 57.

  45. Nykänen P, Lempää S, Aaltonen M L, JFrjenson H, Veski P, Marvola M. Citric acid as excipient in multiple-unit entericcoated tablets for targeting drugs on the colon. Int. J. Pharm., 229, 2001, 155–162.

  46. Colonic Delivery Formulations, Recent Patents on Drug Delivery and Formulation, 1(1), 2007, 59.

  47. Basit A, Bloor J. Perspectives on colonic drug delivery, Business Briefing, Pharmatech., 2003, 185-190.

  48. Davis S S, Robertson C, Wilding IR. Gastrointestinal transit of a multiparticulate tablet formulation in patients with active ulcerative colitis, Int J Pharm., 68, 1991, 199-204.

  49. Panchagnula R. Transdermal delivery of drugs, Indian J Pharmacol., 29, 1997, 140-56.

  50. Rao P R, Diwan P V. Formulation and in vitro evaluation of polymeric films of diltiazem hydrochloride and indomethacin for transdermal administration, Drug Dev Indian Pharmac., 24, 1998, 327-36.

  51. Nykänen P, Krogars K, Säkkinen M, Heinämäki J, JFrjenson H, Veski P, Marvola M. Organic acids as excipients in matrix granules for colon-specific drug delivery. Int. J. Pharm., 184, 1999, 251–261.

  52. Rao P R, Diwan P V. Formulation and in vitro evaluation of polymeric films, Drug Dev Indian Pharmac., 24, 1998, 327-36.

  53. Thacharodi D, Rap K P. Development and in vitro evaluation of chitosan- based drug delivery system, Biomaterials, 16, 1995, 145-8.

  54. Ariese F, Ernst WHO, Sijm DTHM. Natural and synthetic organic compounds in the environment—a symposium report, Environ Toxicol Pharmacol., 10, 2001, 65–80.

  55. Aura A M, O’Leary K A, Williamson G, Ojala M, Bailey M, Puupponen Pimia R. Quercetin derivatives are deconjugated and converted to hydroxyphenylacetic acids but not methylated by human fecal flora in vitro, J Agr Food Chem., 50, 2002, 1725–1730.

  56. Breimer DD. Future challenges for drug delivery, J Control Rel., 62, 1999, 3–6.

  57. J M Hebden, C G Wilson, R C Spiller, P J Gilchrist, E Blackshaw. Colon assessed time release delivery system”, Pharmaceutical Research, 16, 1999, 1,087–1,092.

About Authors:

Prushothaman. M

Prushothaman. M

Vasavi Institute of Pharmaceutical Sciences, Vasavi Nagar, Kadappa, Andra Pradesh, India.

Vijaya Ratna. J

Vijaya Ratna. J

Dept. of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andra Pradesh, India.

Prabakaran. L

Prabakaran. L

Department of Pharmaceutics, Karpagam University, Pollachi Main Road, Coimbatore, India.

Address for correspondence: Email: vedpurushoth@yahoo.co.in, Ph.: +91 9160199622.

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Comments

Sudha Thamarapalli's picture

hello sir, hope you remember me. i was your student at SPSP. right now iam doing my m.pharma II year in pharmaceutical technology. your review is very nice and informative. hope to see more reviews from you sir. regards, Sudha. T

Regards,

Sudha.T

Devang Patel's picture

How dissolution medium containing rat cecal contents are prepared ?