S. Shweta et al., J. Sci. Res. Phar. 2012, 1(3), 23-25

Journal of Scientific Research in Pharmacy 2012, 1(3) 23-25

Journal of Scientific Research in Pharmacy Review Article Available online through ISSN: 2277-9469

www.jsrponline.com

Recent Advancement in the Development of Colon Drug Delivery System: A Review

S. Shweta*1, P. Ashish

1, S. Dharmendra

1, J.K. Surendra

2

1Charak Institute of Pharmacy, Mandleshwar.,

2Sagar Institute of Research and Technology, Bhopal, M.P., India.

Received on: 25-08-2012; Revised on: 25-08-2012; Accepted on: 28-08-2012

ABSTRACT

The development of new delivery systems for the controlled release of drugs is one of the most interesting fields of research in pharmaceutical

sciences. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of l ocal diseases associated with the

colon like Crohn’s disease, ulcerative colitis, etc. but also for the systemic delivery of proteins, therapeutic peptides, anti-asthmatic drugs, antihypertensive

drugs and anti-diabetic agents. In oral colon-specific drug delivery system, colon has a large amount of lymphoma tissue (facilitates direct absorption in to

the blood), negligible brush boarder membrane activity, and much less pancreatic enzymatic activity as compared with the smal l intestine. The efficiency of

drug delivery system is evaluated using different in vitro and in vivo release studies. The focus of this review is to provide detailed insight into the

conventional as well as recent approaches used to target the therapeutic agents specifically to the colon.

Keywords: Colon drug delivery, Crohn’s disease, inflammatory Bowel disease, Approaches, CODESTM.

INTRODUCTION

The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. The delivery of drugs to the colon for local action is highly desirable in a variety of conditions like inflammatory bowel diseases (IBD), infectious diseases and colon cancer. Many protein and peptide drugs like insulin cannot be administered through the oral route because of their degradation by the digestive enzymes of the stomach and the small intestine. Delivery of drugs to the systemic circulation through colonic absorption represents a novel mode of introducing peptides and protein drug molecules and drugs that absorb poorly from the upper gastrointestinal tract (GIT) as the colon lacks various digestive enzymes present in the upper GIT [1]. It has been reported that at least 1 million Americans are believed to have IBD with 15 000–30 000 new cases diagnosed annually. Therefore, it appears that targeted drug delivery with an appropriate release pattern could be crucial in providing effective therapy for this chronic disease. The colon is also viewed as the preferred absorption site for oral administration of protein and peptide drugs, because of the relatively low proteolytic enzyme activities in the colon. The colon in attraction interest as a site where poorly absorbed drug molecule may have an improved bioavailability. This reason of colon is acolonized as having a somewhat less hostile environment with less diversity and intensity of activity then the stomach and small intestine. Additionally, the colon has a longer retention time and appears highly responsive to agents that enhance the absorption of poorly absorbed drug apart from retardin g of targeting dosage forms, a reliable colonic drug delivery could also be important starting position for the colonic a bsorption of per orally applied, undigested, unchanged and fully active peptide drugs [2, 3].

Advantages:

Colon is an ideal site for the delivery of agents to cure the local diseases of the colon.

Local treatment has the advantage of requiring smaller drug quantities.

Reduces dosage frequency. Hence, lower cost of expensive drugs. Possibly leading to a reduced incidence of side effects and drug

interactions. The colon is an attractive site where poorly absorbed drug molecules

may have an improved bioavailability. Reduce gastric irritation caused by many drugs (e.g. NSAIDS).

Bye pass initial first pass meta bolism. Extended daytime or nighttime activity.

*Corresponding author: S. Shweta Charak Institute of Pharmacy, Mandleshwar, M.P., India. *E-Mail: ashish03pharma@gmail.com

Improve patient compliance. Targeted drug delivery system. It has a longer retention time and appears highly responsive to agents

that enhance the absorption of poorly absorbed drugs.

It has low hostile environment, less peptidase activity so peptides, oral vaccines, insulin, growth hormones, can be given through this

route [4, 5].

Why Colon Targeted Drug Delivery is needed: Targeted drug delivery to the colon would ensure direct treatment at

the disease site, lower dosing and fewer systemic side effects. To delay the drug absorption. 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 and systemic drug delivery could be achieved, topical treatment of inflammatory bowel disease, for example Ulcerative Colitis or Cohn’s disease. Such inflammatory conditions are usually treated with glucocorticoids and sulphasalazine.

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 gastrointestinal tract, highly affected by hepatic metabolism, in particular, therapeutic proteins and peptides.

A number of others serious diseases of the colon, e.g. colorectal cancer, might also be capable of being treated more effe ctively if drugs

were targeted to the colon [6, 7].

Approaches used for site Specific Drug Delivery to Colon (CDDS): By definition, an oral colonic delivery system should retard

drug release in the stomach and small intestine but allow complete release in the colon. The fact that such a system will be exposed to a diverse range of gastrointestinal conditions on passage through the gut makes col onic delivery via the oral route a challenging proposition. Nevertheless, a variety of approaches have been used and systems have been developed for the purpose of achieving colonic targeting. These approaches are either drug-specific (prodrugs) or formulation-specific (coated or matrix preparations). The most commonly used targeting mechanisms are: [8, 9]

• pH-dependent delivery; • Time-dependent delivery; • Pressure-dependent delivery; and

• Bacteria-dependent delivery.

pH-dependent Delivery: pH-sensitive enteric coatings have been used routinely to

deliver drugs to the small intestine. These polymer coatings are

S. Shweta et al., J. Sci. Res. Phar. 2012, 1(3), 23-25

Journal of Scientific Research in Pharmacy 2012, 1(3) 23-25

insensitive to the acidic conditions of the stomach yet dissolve at the higher pH environment of the small intestine. This pH differential principle has also been attempted for colonic delivery purposes, although the polymers used for colonic targe ting tend to have a threshold pH for dissolution that is higher than for those used in conventional enteric coating applications. Most commonly, copolymers of methacrylic acid and methyl methacrylate that dissolve at pH6 (Eudragit® L) and pH7 (Eudragit® S) have been investigated. This approach is based on the assumption that gastrointestinal pH increases progressively from the small intestine to colon. In fact, the pH in the distal small intestine is usually around 7.5, while the pH in the proximal colon is closer to 6.These delivery systems therefore have a tendency to release their drug load prior to reaching the colon. To overcome the problem of premature drug release, a copolymer of methacrylic a cid, methyl methacrylate and ethyl acrylate (Eudragit® FS), which dissolves at a slower rate and at a higher threshold pH (7–7.5), has been developed recently. A series of in vitro dissolution studies with this polymer have highlighted clear benefits over the Eudragit® S polymer for colonic

targeting [10, 11].

Time-dependent Delivery: Time-dependent delivery has also been proposed as a means

of targeting the colon. Time-dependent systems release their drug load after a preprogrammed time delay. To attain colonic release, the lag time should equate to the time taken for the system to reach the colon. This time is difficult to predict in advance, although a lag time of five hours is usually considered sufficient, given that small intestinal transit time is reported to be relatively constant at three to four hours. One of the earliest systems to utilise this principle was the Pulsincap™ device. Somewhat complex in design, the system consists of an impermeable capsule filled with drug and stoppered at one end with a hydrogel plug. On contact with gastrointestinal fluids, the plug hydrates and swells and, after a set lag time, ejects from the capsule body, thereby allowing drug release to occur. The lag time is controlled by the size and composition of the plug. Hebden, et al.investigated the behaviour of the Pulsincap™ system, preprogrammed with a five-hour time delay, in fasted human subjects using gamma scintigraphy. While drug was released in all subjects approximately five hours post-administration, the position of the device at the time of release varied considerably, with some still present in the stoma ch. To reduce the influence of gastric e mptying on the performance of the Pulsincap™, the system was modified by application of an outer enteric coat. This double barrier concept forms the basis of most current time release systems. The outer enteric coat dissolves on entering the small intestine to reveal an inner polymeric barrier that delays drug release by either swelling, eroding or dissolving over a period of time equivalent to small intestinal transit. Although the use of an outer enteric coat overcomes,to a certain extent, the variability in gastric emptying,the intrinsic problem with such syste ms is the overall inter and intrasubject variability in transit. More over, gastrointestinal transit is prone to diurnal rhythms, with transit being appreciably slower in the evening as compared with the morning. The basic fact that such systems are unable to sense and adapt to an individual’s transit time and merely release their drug load after a preset lag time, irrespective of whether the formulation is in the colon or not, clearly

limits their utility [11, 12].

Pressure - dependent Delivery: Gastrointestinal pressure has also been utilized to trigger

drug release in the distal gut. This pressure, which is generated via muscular contractions of the gut wall for grinding and propulsion of intestinal contents, varies in intensity and duration throughout the gastrointestinal tra ct, with the colon considered to have a higher luminal pressure due to the processe s that occur during stool formation. Systems have therefore been developed to resist the pressures of the upper gastrointestinal tra ct but rupture in response to the raised pressure of the colon. Capsule shells fabricated from the water-insoluble polymer ethyl cellulose have been used for this purpose. The system can be modified to withstand and rupture at different pressures by changing the size of the capsule and thickness of the capsule shell wall. Proof of concept studies has been conducted in dogs and, to a limited extent, in humans. Although the results appear promising, it has not been proven definitively that rupture occurs in the colon.

One must also question the influence of co-administered food on performance, as fed state contractions may be sufficiently powerful to

disintegrate the capsule in the stomach [12].

Bacteria - dependent Delivery: The resident gastrointestinal bacteria provide a further

means of effecting drug release in the colon. These bacteria predominantly colonise the distal regions of the gastrointestinal tract where the bacterial count in the colon is 1011 per gramme, as compared

with 104 per gramme in the upper small intestine. Moreover, 400 different species are present. Colonic bacteria are predominantly anaerobic in nature and produce enzymes that are capable of metabolizing endogenous and exogenous substrates, such as carbohydrates and proteins that escape digestion in the upper gastrointestinal tract. Therefore, ma terials that are recalcitrant to the conditions of the stomach and small intestine, yet susceptible to degradation by bacterial enzymes within the colon, can be utilized as carriers for drug delivery to the colon.

This principle has been exploited commercially to deliver 5 -aminosalicylic acid to the colon by way of a prodrug carrier. The prodrug sulphasalazine consists of two separate moieties, sulphapyridine and 5 -aminosalicylic acid, linked by an azo-bond. The prodrug passes through the upper gut intact, but, once in the colon, the azo-bond is cleaved by the host bacteria, liberating the carrier molecule sulphapyridine and the pharmacologically active agent 5-aminosalicylic acid.6 This concept has led to the development of novel azo-bond-based polymers (azo-polymers) for the purpose of obtaining universal carrier systems.However, issues with regard to the safety and toxicity of these

synthetic polymers have yet to be addressed [9, 11].

Newly Developed Approaches for CDDS: 1). Pressure Controlled Drug-Delivery Systems:

As a result of peristalsis, higher pressures are encountered in the colon than in the small intestine. Takaya et al. developed pressure controlled colon-delivery capsules prepared using ethyl cellulose, which is insoluble in water [13]. In such systems, drug release occurs following the disintegration of a water-insoluble polymer capsule because of pressure in the lumen of the colon. The thickness of the ethyl cellulose membrane is the most important factor for the disintegration of the formulation [14, 15]. The system also appeared to depend on capsule size and density. Because of reabsorption of water from the colon, the viscosity of luminal content is higher in the colon than in the small intestine. It has therefore been concluded that drug dissolution in the colon could present a problem in relation to colon-specific oral drug delivery systems. In pressure controlled ethyl cellulose single unit capsules the drug is in a liquid Lag times of three to five hours in relation to drug absorption were noted when pressure-controlled capsules were

administered to humans [16].

2). Novel Colon Targeted Delivery System (CODESTM): CODESTM is an unique CDDS technology that was designed to

avoid the inherent problems associated with pH or time dependent systems. CODESTM is a combined approach of pH dependent and microbially triggered CDDS. It has been developed by utilizing a unique mechanism involving lactulose, which acts as a trigger for site specific drug release in the colon, (Fig.1). The system consists of a traditional tablet core containing lactulose, which is over coated with and acid soluble material, Eudragit-E, and then subsequently over coated with an enteric material, Eudragit-L. The premise of the technology is that the enteric coating protects the tablet while it is located in the stomach and then dissolves quickly following gastric emptying. The acid soluble material coating then protects the preparation as it passes through the alkaline pH of the small intestine. Once the tablet arrives in the colon, the bacteria enzymetically degrade the polysaccharide (lactulose) into organic acid. This lowers the pH surrounding the system sufficient to effect the dissolution of the acid soluble coating and subsequent drug release [17-19].

Fig. 1: Schematics of the conceptual design of CODES™

S. Shweta et al., J. Sci. Res. Phar. 2012, 1(3), 23-25

Journal of Scientific Research in Pharmacy 2012, 1(3) 23-25

3). Osmotic Controlled Drug Delivery (ORDS-CT): The OROS-CT (Alza corporation) can be used to target the

drug locally to the colon for the treatment of disease or to achieve systemic a bsorption that is otherwise unattainable. The ORO SCT system can be a single osmotic unit or may incorporate a s many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatin capsule. Each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by a semipermeable membrane. An orifice is drilled through the membrane next to the drug layer. Immediately after the OROSCT is swallowed, the gelatin capsule containing the push -pull units dissolves. Because of its drug-impermeable enteric coating, each push-pull unit is prevented from absorbing water in the acidic aqueous environment of the stomach, and hence no drug is delivered. As the unit enters the small intestine, the coating dissolves in this higher pH environment (pH >7), water enters the unit, causing the osmotic push compartment to swell, and concomitantly creates a flowable gel in the drug compartment. Swelling of the osmotic push compartment forces drug gel out of the orifice at a rate precisely controlled by the rate of water transport through the semipermeable membrane. For treating ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to prevent drug delivery in the small intestine. Drug release begins when the unit reaches the colon. OROS-CT units can maintain a constant release rate for up to 24 hours in the colon or can deliver drug over a period as short as four hours. Recently, new phase transited systems have come which promise to be a good tool for targeting drugs to the colon. Various in vitro / in vivo evaluation techniques have been developed and proposed to test the performance and stability of CDDS [20-22].

CONCLUSION The colonic region of the GIT has become an increasingly

important site for drug delivery and absorption. CDDS offers considerable therapeutic benefits to patients in terms of both local and systemic treatment. Colon specificity is more likely to be achieved with systems that utilize natural materials that are degraded by colonic bacterial enzymes. Considering the sophistication of colon-specific drug delivery systems, and the uncertainty of current dissolution methods in establishing possible in-vitro/in-vivo correlation, challenges remain for pharmaceutical scientists to develop and validate a dissolution method that incorporates the physiological features of the colon, and yet can be

used routinely in an industry setting for the evaluation of CDDS.

REFERENCES: 1. Yang L, James S.C., Joseph A. colon-specific drug delivery: new

approaches and in-vitro/in-vivo evolution, Int. J. pharm., 2002: 1-15.

2. Schacht E. et al., polymers for colon specific drug delivery, J. control release, 1996: 327-328.

3. Wilding R et al., Enteric coated timed released systems for colonic targeting, Int. J. pharm., 1994: 99-102.

4. Yang L., Chu J. S., Fix J. A., Colon targeted review, Int. J. Pharm., 2002: 1-15.

5. Evans G., pulsatile-drug-delivery-review, Pharmacol. Rev., 1987: 124-129.

6. Gaurav T. et al., Drug delivery system, Int. J. of Dru. Del., 2010: 1-11.

7. Vyas S.P. and Khar R.K., Controlled drug delivery: concepts and advances, New Delhi: Vallabh Prakashan; 2005; 218-253.

8. Fara J.W., N ovel Drug Delivery and its Therapeutic Application, Colonic drug absorption and metabolism, 1989: 103-120.

9. C Tuleu et al., Colonic delivery of sodium butyrate via oral route: Acrylic coating design of pellets and in vivo evaluation in rats, Methods and Findings in Experi. and Cli. Pharmacol., 2001: 245-253.

10. Dew M. J et al., An oral preparation to release drugs in the human colon, Bri. J. of Cli. Pharmacol., 1982: 405–408.

11. Rudolph M. W. et al., A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis, European J. of Pharma. and Biopharma., 2001: 183-190.

12. Encyclopedia of Pharmaceutical Technology Vol. 2. 13. Takaya T. et al., Importance of dissolution process on systemic

availability of drugs delivered by colon delivery system, J. Control Rel., 1998: 111-122.

14. Muraoka M. et al., Evaluation of intestinal pressure-controlled colon delivery capsule containing caffeine as a model drug in human volunteers, J. Control Rel., 1998: 119-129.

15. Jeong Y. et al., Evaluation of an intestinal pressure-controlled colon delivery capsules prepared by a dipping method, J. Control Rel., 175-182.

16. Hay D. J. et al., Spread of steroid containing foam after intrarectal administration, Brit. Med. J., 1979: 1751-1753.

17. Watanabe S. et al., Colon specific drug release system, U. S. Patent; 1998: 09/183339.

18. Takemura S. et al., Human gastrointestinal treatment study of a novel colon delivery system (CODES) using scintography, Pro. Int. Sym. Control Rel. Bioact. Mat., 2000: 27.

19. Masataka K. et al., Scintigraphic evaluation of a novel colon -targeted delivery system (CODESTM) in healthy volunteers, J. Pharm. Sci., 2004: 1287-1299.

20. Theeuwes F. et al., Delivery of drugs to colon by oral dosage forms, U. S. Patent; 4904474.

21. Philip A.K. and Pathak K. Osmotic flow through asymmetric membrane: A means for controlled delivery of drugs with varying solubility, AAPS Pharm. Sci. Tech., 2006: 1-11

22. Philip A.K. and Pathak K. Wet process induced phase transited drug delivery system: A means for achieving osmotic, controlled, and level a ivivc. for poorly water soluble drug, Drug. Dev. Ind. Pharm., 2008; 735-743.

Source of support: Nil, Conflict of interest: None Declared