Polymeric Micro- Particulate System for Nonsteroidal Anti- inflammatory Drugs : A Review

Dr. (Mrs). Swarnlata Saraf

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed drugs worldwide. These are categorized as  ‘over-the counter’ (OTC) availability, and are also consumed on non-prescription basis as well.

Though reasonably safe in prescribed dosages , these drugs cause gastrointestinal toxicity in a large number of cases for short durations as they can affect all segments of the gastrointestinal tract. The NSAIDs cause oral ulceration and stricture formation in esophagus, stomach and duodenum and may cause severe bleeding, perforation and obstruction.

The most of the cases of NSAID-induced gastrointestinal ulcers can heal spontaneously even the drug is continued. However, in some cases they can cause serious toxicity requiring hospitalization and requires aggressive management. The above consideration, envisaged the need of safest delivery for the management of NSAID induced gastrointestinal toxicity. The micro particulate drug delivery of NSAIDs was suggested to be the best alternatives for the safe and effective delivery of these drugs. The present article deals with different aspects of the micro capsular system of different NSAIDs. 

Introduction

The gastrointestinal tract (GIT) is the main target of NSAID toxicity. It is the most frequent organ affected by adverse drug reactions and unfortunately, it is the most common drug-induced toxicity that can be fatal. World over,  more than 35 million people consume these drugs on a daily basis and about 30% of users may develop GIT toxicity of sufficient degree requiring a physician’s intervention. It has also been estimated that one third of the cost of treating arthritis patients relates to treatment of the side effects of NSAIDs.  The conservative calculations estimate that approximately 1,07,000 patients are hospitalized annually for non-steroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications, and at least 16,500 NSAID-related deaths occur each year by arthritis patients alone. The figures for all NSAID users would be overwhelming. Surprisingly, the management of this problem has undergone little change in the last 50 years, and is not only frequently under-diagnosed but also under-treated. Indian studies have shown that NSAIDs are among the most common drugs responsible for adverse drug reactions seen in clinical practices.¹ In general, at least 10 to 20 percent of patients have dyspepsia while taking a NSAIDs and prevalence may range from 5 to 50 percent. Within a six-month period of treatment, 5 to 15 percent of patients with rheumatoid arthritis can be expected to discontinue NSAID therapy because of dyspepsia. Incidence of new ulcers is range from 10-40% for gastric ulcers and 5-15% for duodenal ulcers. Most patients are, however, asymptomatic. According to prospective data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS); 13 of every 1,000 patients with rheumatoid arthritis who take NSAIDs for one year have a serious gastrointestinal complication and the risk of osteoarthritis is 7.3 per 1,000 patients ^2,3.

Mechanisms of NSAIDs-induced GI ulcerations

What causes ulceration is precisely unknown. It is believed to occur as the result of a complex interplay of aggravating factors and protective factors. Prostaglandins (PGs) have long been known to be mucoprotective and ulcer healing agents. Prostaglandins protect GI mucosa by forming a cytoprotective layer and increasing the secretion of bicarbonate ions that neutralize the gastric acidity. All therapeutically useful NSAIDs act by inhibiting the synthesis of PGs⁴. Gastric damage by these agent can be brought about by at least two  distinct mechanism. Local irritation by orally administered drug, allows back diffusion of acid into the gastric mucosa and induces tissue damage. The parenteral administration also can cause damage and bleeding, correlated with inhibition of the biosynthesis of gastric prostaglandins, especially PGI2 and PGE2, that serve as cytoprotective agents in the gastric mucosa. These eicosanoids, inhibits acid secretion by the secretion of cytoprotective mucus  in the intestine; inhibition of their synthesis may render the stomach more susceptible to damage ^5-26.

Recent studies have shown that use of multiple NSAIDs; non-use of anti-ulcer medication, and NSAID use in patients with previous history of peptic ulcers raises the possibility of developing GI ulcers by 14-17 folds²⁷.

Classification of NSAIDs

A proposed classification based on their chemical class and plasma half-lives^80-81.

1.Carboxylic Acid

· Salicylic acids and esters

Asprin, Diflunisal, Benorylate,   Trisalicylate, Salsalate, Sodium salicylate

· Acetic acid

Phenylacetic acids

          Diclofenac, Aceclofenac,   Fentizac, Fenclofenac                                              

Carbo and hetrocyclic acids

         Etodolac, Indomethacin, Sulindac, Tolmetin, Tenidep, Zomepirac, Clopirac, Ketorolac, Tromethamine

·  Propionic acids

         Carprofen, Fenbufen, Flurbiprofen, Ketoprofen, Oxaprozin,Suprofen, Tiaprofenic acid, Ibuprofen, Naproxen, Fenoprofen, Indoprofen, Benoxaprofen, Pirprofen

·  Fenamic acids

            Flufenamic, Mefenamic, Meclofenamic, Niflumic

2.Inolic acid

· Pyrazolones

            Oxyphenbutazone, Phenylbutazone, Azapropazone, Feprazone

· Oxicams

            Piroxicam, Sudoxicam, Isoxicam, Tenoxicam, Meloxicam

3.Nonacidic compounds

Nabumetone, Proquazone, Fluproquazone,Tiaramide, Befexamac, Flunizole, Epirazole, Tinoridine

4. Diaryl- substituted furanones

Rofecoxib

5. Diaryl-substituted pyrazoles

Celecoxib

6. Sulfonanilides

7. Nimesulide

Microencapsulation

Currently, there is a trend towards a safe delivery of drugs, which includes a growing awareness by patients of what they take and what benefits are associated with certain excipients also. The excipients includes polymer mostly in novel approaches are being used  in maintaining the release profile of drugs which produces the toxicity after oral therapy. In many cases, microencapsulation can be used to overcome these challenges

Microencapsulation is a process by which solids, liquids or even gases may be encapsulated into microscopic size particles through the formation of thin coating of wall material around the substance. The process had its early origin in the late 1930 as a clean substitute for carbon ribbons as sought by the business machines industry.

Micrencapsulation encompasses science and technology and technology involving several varied disciplines, is advancing rapidly, but the application of the principles involved has yet approached its full potential. Many methods for preparing microcapsules have been developed and improved significantly, some are based on exclusively on physical phenomena and some utilize polymerization reactions to produce a capsule shell and others combine physical and chemical phenomena. There is no single process have been developed till today which is able to produce the full range of capsules desired by potential capsule users^28-32.

The technologies available for microencapsulation can be divided into two categories Type A, (chemical processes) includes complex coacervation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in- situ polymerization, in liquid drying, thermal and ionic gelation in liquid media, desolvation in liquid media and Type B, (mechanical processes) includes spray drying, spray chilling, fluidized bed, electro static deposition, centrifugal extrusion, spinning disk or rotational polymerization at liquid – gas or solid gas interface, pressure extrusion or spraying in to solvent extraction bath³³.

Microencapsulation: Application in NSAIDs

The NSAIDs like indomethacin, ibuprofen, fenoprofen with a short half –lives of 6hrs or less in patients and are given three or four times daily. The steady state is reached within 24 to 36 hrs after the drug is initially administered but is characterized by marked fluctuations in plasma between peak post absorption levels and trough levels at the time of next dosage. The development of new functional drug molecule of these drugs requires technologies for incorporating drug into dosage form without reducing their bioavailability or functionality. In many cases, micro encapsulation can provide the necessary protection for these compounds, but in all cases bioavailability should be carefully studied. A wide range of core material have been encapsulated, including adhesives pharmaceuticals, agrochemicals, living cells, active enzymes, flavors, fragrances, and inks for the development of various type of dosage form like sustained release, taste masking of bitter drugs, single layered tablet containing chemically incompatible ingredients, new formulation concepts for creams, ointments, aerosols, protection of degradable drugs in gastro-intestinal tract, increment of shelf life of drugs, alteration of surface properties of drugs and prevention of volatile liquids from evaporation^34-39.The applications of various microencapsulation technologies to pharmaceutically important non steroidal anti- inflammatory drugs are summarized in Table 1.

Table 1: The Micro- particulate delivery of non steroidal anti-inflammatory drugs.

Conclusion

The  review shows the commonly used microencapsulation techniques and their utility in the encapsulation of NSAIDs. The highlights show a road map of achievements of the development of micropariculate delivery for NSAIDs. The literature reveals about microcapsules which shows that micro-particulate delivery reduces  marked fluctuations in plasma between peak and  trough levels at the time of next dosages.  The review also  reveals about  the selection of different  polymers  according to intended use of drugs.

Micro particulate drug delivery technology represents one of the frontier areas of science, which involves multidisciplinary scientific approach, contributing to human health care. The development of appropriate carriers for drug delivery is a challenge for biomedical scientists. Carrier like chitosan is an abundant natural based polymers. The physical and chemical properties of chitosan, such as inter and intermolecular hydrogen bonding and the cationic change in acidic medium makes the polymer attractive for conventional and novel pharmaceutical products. Chitosan can reside longer in the stomch and allow for stomach specific drug delivery. As a result of the physical, chemical and biological properties, chitosan has been used in NSAIDs microcapsules for sustained drug delivery by oral route.

Now a days polymethacrylate polymers are widely used as microcapsules wall materials for NSAIDs in pharmaceutical industry due to biocompatibility. Eudragit L and S types are used as enteric coating, Eudragit RL,RS and NE 30D are widely used to form water insoluble film coats for sustained release. Eudragit L 30D is used as an enteric coating film former and releases the drug by  diffusion.

Microencapsulation  techniques which uses organic solvents is now a days can be replaced by aqueous technology by using sodium alginate.

Cellulosic polymers are continuously using as a wall forming material to form a controlled release characteristics in microcapsules. Ethyl cellulose and cellulose acetate in microcapsules provides a hydrophobic coating and is used to modify the release of NSAIDs and to mask an unpleasant taste or to improve the stability of formulations.

NSAIDs release pattern can be modify by this technique with choice of suitable biodegradable polymer on the basis of its crystallinity, hydrophobicity, copolymer ratio and its molecular weight. Due to biodegradability and reputation as safe materials ,aliphatic polyesters like poly (lactide), poly (glycolide), poly (lactide-co-glycolide), polycaprolactone are used to modify release of NSAIDs.

Thus, the information summarized in the article will be used as a tool for development of microcapsular system for the NSAIDs. The microcapsule of NSAIDs  improves patient compliance  mainly via  control plasma concentration and avoid of frequent dosing.

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About Authors

Kamlesh Dashora, S. Saraf and Swarnlata Saraf*

Corresponding Author*

Dr. (Mrs). Swarnlata Saraf* has nearly 14 years of research and teaching experience. She is a leading scientist and well known in the field of herbal Cosmetics. Dr. (Mrs.) Saraf did her doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. She has over 40 publications to her credit published in international and national journals. She is an active member of IPA, APTI and ISTE. Her research interest extends from Herbal Cosmetics to transdermal drug delivery (Iontophoresis), New Drug Delivery Systems for biological therapeutic agents. Presently She is working as a Reader at Institute of pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.).

*Swarnlata Saraf, Reader, Institute of Pharmacy,Pt. Ravishankar Shukla University,Raipur (C.G) – 492 010, INDIA,e-mail:  swarnlata_saraf@rediffmail.com, Phone: (0771) 2263773

Prof. S. Saraf has nearly 17 years of research and teaching experience at U.G. and P.G. level. He is a leading scientist and well-known academician . Prof. Saraf did his doctoral research at the Dept. of Pharmacy, Dr. H. S. Gour University, SAGAR. He has over 50 research publications to his credit published in international and national journals. He has delivered invited lectures and chaired many sessions in several National Conferences and Symposia in India. His research interest extends from Herbal Cosmetics to Herbal drug standardization Modern analytical techniques, New Drug Delivery Systems with biotechnology bias. He has authored 1 books, in press. Presently, he is Professor and Director Institute of pharmacy and Dean, Faculty of Technology, Pt. Ravishankar Shukla University , Raipur , (C.G.). E-mail: shailendrasaraf@rediffmail.com

Mr. Kamlesh Dashora has nearly 11 years of teaching, research and industrial experience. Mr. Dashora did his masters degree from Department. of Pharmacy, SGSITS, Indore, one of the premier institute of technical education in the central India. He has over 12 publications to his credit published in international and national journals. His research interest extends from Noble topical delivery systems, Delivery Systems for biologicals to regulatory affairs. Presently, he is working at Institute of pharmacy Pt. Ravishankar Shukla University, Raipur, (C.G.) INDIA