A Novel Prodrug Approach in Colonic Drug Delivery System

 

Sharma Pramod*, Raghuvanshi Dhiraj and Chaturvedi Prerna

Department of Pharmaceutical Chemistry, Swami Vivekanand College of Pharmacy, Near Toll Naka, Khandwa Road, Indore-452020

*Corresponding Author E-mail: sharmapramod07@gmail.com

ABSTRACT:

The drug delivery method is chosen based upon the physiological properties of drug, the desired site of action, the biological barrier including drug metabolism that must be overcome to deliver the drug. Prodrugs are continuously being developed as many of the new drugs have low solubility and degradation against enzymatic acid catalyzed breakdown in the human body. Prodrugs are the means of enhancing the therapeutic benefit of drug controlling the pharmacokinetics, pharmacodynamics, non specific toxicity immunogenicity and efficacy. One of the approaches used for colon specific drug delivery is the formation of prodrugs which optimizes drug delivery and improves drug efficacy. Many prodrugs have been evaluated for colon drug delivery. These prodrugs are designed to pass intact and unabsorbed from the upper GIT and undergo biotransformation in the colon releasing the active drug molecule. This biotransformation is carried out by a variety of enzymes, mainly of bacterial origin present in the colon. The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Technical difficulties faced in preparation of other types of colon specific delivery systems, like coated, multiple coated, systems etc., can be avoided. These approaches have also been used to target various other drugs molecules to the colon to improve the absorption characteristics of these drugs. These include coating with biodegradable polymers, coating with pH-sensitive polymers, time dependent formulations, forming biodegradable matrices, and forming a prodrugs. The present review includes various prodrugs approaches investigated for colon drug delivery.

 

KEYWORDS: Colonic Drug Delivery System (CDDS), Prodrugs, Conjugates, Enzymes, Polymers.

 

INTRODUCTION:

For many decades treatment of an acute diseases or illness has been mostly accomplished by delivery of drugs to the patients by various conventional delivery systems which are known to provide a prompt release of drugs, to achieve as well as maintain drug concentration within the therapeutic effective range. A prodrug is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in vivo to release the active drug. It should have improved delivery properties over the parent drug molecule. The drug delivery method is chosen based upon the physiochemical properties of drug, the desired site of action, the biological barrier including drug metabolism that must be overcome to deliver the drug.

 

Recently several technical advancements have been made which resulted in the development of new techniques for drug delivery. These techniques are capable of controlling the rate of drug delivery, and or targeting the delivery of drug to tissues. Alternate drug delivery systems are continuously being developed as many of the new drugs have low solubility and degradation against enzymatic acid catalyzed breakdown in the human body. Improvement in the delivery method for peptides, proteins are necessary as they may continue to be developed as drug^1-3 .

 

Prodrug drug delivery system may have highly desirable attributes and improved utilities like:

• Targeting delivery to specific tissues

• Improved safety and efficacy

• Decreased in frequency of dosing and the amount of drug needed.

• Reduction of toxicity

• Improved patient compliances.

Prodrug as a carrier in CDDS:

These can be described as compounds which undergo chemical as well as biological biotransformation prior to exhibit their pharmacological effect. Prodrug and proprodrugs were found wide application in oral, parental, ocular, topical delivery systems for controlling and targeting the drug molecules. The concept of pro-prodrug is also gaining importance where a pro-prodrug is a prodrug of prodrug. Types of prodrugs used as delivery systems are: bioprecursor prodrug, macromolecular prodrug, drug antibody conjugates, enzymatically activated reduction reaction-reaction prodrug, enzymatically activated hydrolysis reaction prodrug, oxidation activated prodrug, reduction activated prodrug, hydrolysis activated prodrug and gene directed enzyme prodrug therapy (GDEPT) and antibody directed enzyme prodrug therapy (ADEPT) ^4,5 .

 

Limitations of prodrug:

The problem associated with prodrug design is its toxicity which is due to

·        Formation of unexpected metabolite from the total drug conjugates.

·        Toxicity may be due to inert carrier generated by cleavage of promoiety and drug conjugate which is converted into toxic metabolite.

·        The prodrug might consume a vital cell constituent such as glutathione during its activation stage which causes depletion of prodrug.

 

Basic concept of colonic drug delivery:

For the treatment of Inflammatory Bowel disease (IBD), with anti-inflammatory agents, various approaches have been used to target the drug molecules to the colon. These approaches have also been used to target various other drug molecules to the colon to improve the absorption characteristics of these drugs. These include coating with biodegradable polymers, coating with pH-sensitive polymers, time dependent formulations, forming biodegradable matrices, and forming a prodrug. All these approaches attempt to lower the absorption and release of the drug in the stomach and small intestine and thereby facilitate quantitative drug delivery to the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissue, for the prodrug-drug conversion. Medical therapy for IBD is restricted to aminosalicylates, corticosteroids, and immunosuppressant. When synthesizing prodrugs, the choice of carrier depends on the functional group available on the drug molecule for conjugation with the carrier (e.g., the hydroxyl group present on the corticosteroids can enter into a glycosidic linkage⁶ with various sugars, the carboxyl group of biphenyl acetic acid forms an ester/amide conjugate with cyclodextrin.)^7-9; Amino-acid, glycoside, glucuronide, azo, dextran, and cyclodextrin conjugates are some of the conjugates evaluated for colon-specific delivery. Generally, a prodrug is successful as a colon drug carrier if it is hydrophilic and bulky to minimize absorption from the upper GIT, and if once in the colon, it is converted into a more lipophilic drug molecule, which is then available for absorption.

 

Enzymes present in colon:

·        Reducing enzymes

Nitroreductase

Azoreductase

N-oxide reductases

Sulphoxide reductases

Hydrogenase

 

·        Hydrolytic enzymes

Esterase

Amidase

Glycosidase

Glucuronidase

Sulfatase

 

Natural polysaccharides as polymer for colonic drug delivery:

Chitoson

Pectin

Guar gum

Chondroitin sulphate

Dextran

Almond gum

Locust bean gum

Cyclodextrin

Inulin

Boswellia gum

Khaya gum

 

Amino acid conjugates:

Proteins and their basic units (i.e. the amino-acids (AA)) have polar groups like the −NH2− and −COOH−. These polar groups are hydrophilic and reduce the membrane permeability of A.A and proteins, increased the hydrophilicity and length of the carrier amino acid, decreasing the membrane permeability of the conjugate, and prepared salicyclic-glutamic acid conjugates.This conjugate gave good results as a colon-specific carrier for salicylic acid. It showed minimal absorption and degradation in the upper GIT and showed more enzymatic specificity for hydrolysis by colonic enzymes¹⁰ .

 

Fig 1. Structure of Salicyluric acid

The amino acid carriers have been found to increase the bioavailability and efficacy of drugs and at the same time reduces their toxicity. Therefore these agents can be used for drug delivery to the large bowel for IBD and other large bowel disorders.

 

Glycoside conjugates:

The glycosides may be glucoside, galactoside, or cellobioside depending upon whether the sugar moiety is a glucose, galactose, or cellulose respectively. Because they are bulky and hydrophilic, these glycosides do not penetrate the biological membranes upon ingestion¹¹ . They breakdown upon action of glycosidase, releasing the drug part from the sugar¹² . However, the small intestinal transit time, when compared to the large intestinal transit time, is short, and moreover, considering the time required for the hydrolysis of glycosidic bond, these conjugates can be expected to be good colon specific drug carriers¹³ . Comparing the efficacy of different sugar moieties to act as carriers for corticosteroids, prepared glucoside, galactoside, and cellobioside of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone¹⁴ .

 

Fig 2. Structure of 5-aminosalicyl-glycine conjugate

 

Azo conjugates:

The use of these azo compounds for colon-targeting has been in the form of hydrogels as a coating material for coating the drug cores and as prodrugs¹⁵ . In the latter approach the drug is attached via an azo bond to a carrier. This azo bond is stable in the upper GIT and is cleaved in the colon by the azo-reductases produced by the microflora. Sulphasalazine, which was used for the treatment of rheumatoid arthritis, was later known to have potential in the treatment of IBD¹⁶ . This compound has an azo bound between 5-ASA and sulphapyridine (SP). In the colon, the azo reductases cleave the azo bond releasing the drug, 5-ASA and the carrier SP. In another approach two molecules of 5-ASA have been joined together to form an ultimate prodrugs disodium azodisalicylate (olsalazine), in which one molecule of 5-ASA is used as a carrier for the other¹⁷ .

 

Fig 3. Sodium salt of Sulphasalazine

Polymeric prodrugs:

Polymeric prodrugs with drug molecule linked directly to a high molecular weight polymeric backbone have also been investigated for colon-drug delivery. The linkage between the drug and the polymer is susceptible to enzymatic attack in the large intestine and the drug is released at this site. Polymeric systems that swell minimally under acidic conditions in the stomach, but swell extensively under basic conditions in the large intestine, were also thought to be possible drug carriers for colon drug delivery¹⁸ . Swelling under basic conditions of the large intestine would make these polymers prone to enzymatic and hydrolytic degradation. Therefore, polymeric prodrugs of 5-ASA, namely methacryloyloxyethyl 5-aminosalicylate (MOES) and N-methacryloylamido ethyl-5-amino salicylamide (MAES) , were prepared as monomers and polymerized. Due to low swelling in acidic media, these polymers could shield the drug in the stomach. As the pH increased in the GIT, these polymers swelled and became susceptible to hydrolysis. These were also found to be suitable drug carriers for colon delivery¹⁹ .

 

Fig 4. Structure of polyneric prodrug of 5-ASA (Poly-ASA)

 

Cyclodextrin conjugates:

Cyclodextrin conjugates were prepared by substituting one primary hydroxyl group of the cyclodextrin with biphenylylacetic acid forming amide/ester conjugate. Amide conjugate showed no hydrolysis in contents of stomach, small intestine, cecum, and colon of rats. The ester conjugate showed less than 10% of drug release in the contents of stomach, small intestine and their tissue homogenates, but a significant hydrolysis in contents of cecum and colon. Increasing the percentage of cecal contents from 1% to 6.7% in the dissolution medium increased the hydrolysis of the conjugate from about 20% to 46% in 48 h. This study indicates that cyclodextrin prodrugs have a great potential as colonic drug carriers due to their stability and site-specificity²⁰ .

 

Fig 5. Cyclodextrin-Biphenylacetic acid conjugate

Table1. Criteria for selection of drugs for cdds:

Criteria	Pharmacological class	Non-peptide drug	Peptide drug
Drugs used for local effects in colon against GIT diseases	Anti-inflammatory drugs	Oxyprenolol, Metoprolol, Nifedipine	Amylin, Antisense oligonucleotide
Drugs poorly absorbed from upper GIT	Antihypertensive and Antianginal drugs	Ibuprofen, Isosorbides, Theophylline	Cyclosporine, Desmopressin
Drugs for colon cancer	Antineoplastic drugs	Pseudoephedrine	Epoetin, Glucagon
Drugs that degrade in stomach and small intestine	Peptides and Proteins	Bromophenaramine, 5-Flourouracil, Doxrubicin,	Gonadoreline, Insulin, Interferons
Drugs that undergo extensive first pass metabolism	Nitroglycerin and Corticosteroids	Bleomycin, Nicotine	Protirelin, Sermorelin, Saloatonin
Drugs for targeting	Antiarthritic and Antiasthamatic drugs	Prednisolone, Hydrocortisone, 5-Amino-salicylic acid	Somatropin, Urotoilitin

 

Fig 6. Structure of Dexamethasone-Dextran conjugates with succiniate spacer

 

 

Dextrin conjugates:

More recently, Dextran-5ASA ester conjugates were also found to be stable in the upper GIT of rat. Liberation of 5-ASA was observed in the cecal contents suggesting the respective protective and selective action of dextran for colon-specific drug delivery²¹ .

 

Future prospective:

1) Development of drug delivery system which can be capable of delivering of drug at a therapeutically effective rate to a

desired site for duration required for optimal treatment.

2) Modulation of gastrointestinal transit time.

3) Minimization of hepatic first pass elimination.

 

CONCLUSION:

Such systems can be formulated in a much easier manner and many technical difficulties faced in preparation of other types of colon specific delivery systems, like coated, multiple coated, systems etc., can be avoided. These agents, however, are new chemical entities and require more detailed toxicologic studies before they can be used as colon carriers. The use of natural polysaccharide carriers, like dextrans and cyclodextrin, seems to be a better alternative than the synthetic polymers because of their in vivo biodegradation to simple saccharides/sugars at this time. Prodrugs seem to be promising therapeutic agents for the management of diseases of the lower bowel due to their ability to show the required action with lower doses as they release the entire dose at the site of action. Additionally, they reduce the side effects compared to the parent drug.

ACKNOWLEDGEMENT:

Authors are thankful to Principal, Swami Vivekanand College of Pharmacy, Dr. P. K. Dubey sir for constant encouragement and providing necessary facilities.

 

REFERENCES:

1.       Sinha V. R.,   Kumria R. Colonic drug delivery: prodrug approach. Pharmaceutical Research. 18(5): 2001.

2.       Kamlesh Wadher,  Kalsait Ravi and Umekar  Milind. Alternate drug delivery system: recent advancement and future challenges. Arch. Pharm. Sci. and Res. 1(2): 2009: 97-105.

3.       Jain SK, Vyas SP. Magnetically responsive diclofenac sodium-loaded erythrocytes: preparation and in vitro characterization. J. Microencap. 11: 1994:141-151.

4.       Jithan AV. Oral drug delivery technology. Pharma Book Syndicate. Hyderabad. 2007. pp. 188.

5.       Mengi SA, Deshpande SG, Occular drug delivery,controlled and novel drug delivery system. CBS Publishers and Distributors. 1^st ed: pp. 2043

6.       Jain SK, Agrawal GP, Jain NK. Prodrugs to enzymes and membrane transporters, controlled and novel drug delivery system. CBS Publishers and Distributors. 2004.

7.       Sinha V. R.,   Kumria R. Colonic drug delivery: prodrug approach. Pharmaceutical Research. 18(5): 2001.

8.       Friend DR, Chang GW.  A colon-specific drug deliverysystem based on drug glycosides and the glycosidases of colonic bacteria. J. Med. Chem. 27:1984: 261-266.

9.       Uekama K, Minami K and Hirayama F. 6A-O [(4-biphenylyl)acetyl)]-a-,-b-, and -g-cyclodextrins and 6A-deoxy-6A-[[(4-biphenylyl)acetyl] amino]-a-,-b- and -g-cyclodextrins: Potentialprodrugs for colon specific delivery. J. Med. Chem. 40: 1997: 2755–2761.

10.     K. Minami, F. Hirayama, and K. Uekama., Colon specific drugdelivery based on cyclodextrin prodrug: Release behaviour ofbiphenylyl acetic acid from its cyclodextrin conjugates in rat intestinaltract after oral administration. J. Pharm. Sci. 87: 1998: 715–720.

11.     Nakamura J et al. Effect of oral pretreatment with antibiotics on the hydrolysis of salicylic acidtyrosine and salicylic acid methionine prodrugs in rabbit intestinal microorganisms. Chem. Pharm. Bull. 40:1992: 2572–2576.

12.     Pownall HJ, Hickson DL and Smith LC. Transport of biological lipophills: Effect of lipophilic structure. J. Am. Chem.Soc. 105: 1983: 2440–2445.

13.     Rubinstein et al. Approaches and opportunities in colon-specific drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 12:1995: 101–149.

14.     Friend DR, Chang GW. Drug glycosides: Potential prodrugs for colon-specific drug delivery. J. Med. Chem. 28: 1985: 51–57.

15.     Mooter GVD et al. Use of azo polymers for colon-specific drug delivery. J.Pharm. Sci. 86: 1997: 1321–1327.

16.     U. Klotz. Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-Aminosalicylic acid. Clin. Pharmacokinet.10: 1985: 285–302.

17.     Travis SP et al. Optimum dose of olsalazine for maintainingremission in ulcerative colitis. Gut 35: 1994: 1282–1286.

18.     Mooter GV, Samjn C and Kinget R. The relation between swelling properties and enzymatic degradation of azo-polymers. Pharm. Res. 11: 1994: 1737–1741.

19.     Davaran S, Hanaee J  and Khosravi A. Release of 5-aminosalicylic acid from acrylic type polymeric prodrugs designed for colon specific drug delivery. J. Control. Release 58:1999: 279–287.

20.     Hirayama F, Minami K and Uekama K.  In vitro evaluation of Biphenylyl acetic acid-b-cyclodextrin conjugates as colon targeting prodrugs: Drug release behaviour in rat biological media. J. Pharm. Pharmacol. 48:1996: 27–31.

21.     Jung YJ. Synthesis and properties of dextran-5-aminosalicyclic acid ester as a potential colon-specific prodrug of 5-aminosalicyclic acid. Arch.Pharmacal. Res. 21: 1998: 179–186.