Approaches to Overcome Nsaid Induced Ulceration In

Home , Enteric coating, Prostaglandin analogue

Baldi et al Journal of Drug Delivery & Therapeutics. 2015; 5(2):9-16 9

Available online on 15.03.2015 at http://jddtonline.info Journal of Drug Delivery and Therapeutics Open access to Pharmaceutical and Medical research © 2015, publisher and licensee JDDT, This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited

REVIEW ARTICLE

APPROACHES TO OVERCOME NSAID INDUCED ULCERATION IN ARTHRITIC PAIN MANAGEMENT: PERSPECTIVES AND PROSPECTS Ganeshanand, Kamal Jeet, Baldi Ashish* Department of Quality Assurance, I.S.F. College of Pharmacy, Moga, Punjab, 142001 Received 21 Jan 2015; Review Completed 19 Feb 2015; Accepted 10 March 2015, Available online 15 march 2015

ABSTRACT

Rheumatoid arthritis is an auto-immune joint disorder involving pain and inflammation. Various approaches are used for pain management and relief from arthritis with single and multiple dose therapy. In single dose therapy, use of non-steroidal anti- inflammatory drugs like diclofenac aceclofenac, celicoxib etc. reported many side effects mainly leading to decrease in production of prostaglandin and holding the ulcer. High dosing frequency of these drugs is also a major factor of risk. Recently developed novel formulations are especially suitable for achieving controlled and delayed release profile with low risk of dose dumping. These systems have received great attention of pharmaceutical industry as they deliver accurate amount of drug at the right time and location thus increasing patient compliance and economic feasibility and avoiding drug associated side effects. Present review mainly deals with the problem of ulceration in pain management, various approaches to overcome this and specifically explore the possibilities to apply novel drug delivery systems for this purpose.

Keywords: Arthritis, Drug delivery systems, Gastroretentive, NSAIDs, Pain, Rheumatoid arthritis, Rheumatic pain

management.

INTRODUCTION Arthritis is a form of joint disorder that involves pain, maintaining or improving mobility and chronic inflammation of one or more joints1. There are minimizing disability. It may induce medication, over 100 different forms of arthritis. The commonest physical therapy, and patient education3. form is osteoarthritis, which is the result of trauma to ANTI-INFLAMMATORY DRUGS USED FOR the joint, infection of the joint, or age. Other arthritis PAIN MANGEMENT IN ARTHIRITIS forms are rheumatoid arthritis, septic arthritis, psoriatic arthritis, and related autoimmune diseases. Rheumatoid Patients with rheumatic diseases, including RA and arthritis (RA) is a potentially destructive disease with osteoarthritis, almost universally describe pain and profound impact on joint pain and may be localized to stiffness as important contributors to reduced health- the affected joint. The pain associated with arthritis is related quality of life. The treatment options available, due to inflammation that occurs around the joint, non-steroidal anti-inflammatory drugs (NSAIDs) are the damage to the joint from disease, daily wear and tear of most widely used agents for symptomatic treatment4. joint, muscle strains caused by forceful movements Most frequently used NSAIDs in arthritic pain against stiff painful joints and fatigue. Arthritis in children is common, and a major cause of potential management are enlisted below: morbidity with significant long-term consequences,  Aspirin, Celecoxib, Diclofenac, Indomethacin 2 joint damage and disability if left untreated .  Diflunisal, Fenoprofen, Flurbiprofen, Ibuprofen, RA is the most common cause of disability in the USA. Ketoprofen, Naproxen More than 20 million individuals with arthritis have  Ketorolac, Meloxicam, Nabumetone, Oxaprozin, severe limitations in function on a daily basis3. Each Piroxicam year, arthritis results in nearly 1 million hospitalizations  Salsalate, Sulindac, Tolmetin etc. and close to 45 million outpatient visits to health care centres. *For Correspondence Arthritis can make it very difficult for an individual to Dr. Ashish Baldi Professor and Principal, remain physically active, contributing to an increased I.S.F. College of Pharmacy, risk of obesity, high cholesterol or vulnerability to heart G.T. Road, N.H. 95, Moga, disease. Individuals with arthritis are also at increased Punjab, India- 142001. risk of depression, which may be related to fear of Tel: +91-8968423848; worsening symptoms. Therapy is aimed at relieving E-mail: [email protected] © 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO Baldi et al Journal of Drug Delivery & Therapeutics. 2015; 5(2):9-16 10

Role of NSAIDs in arthritic pain management inflammatory, antipyretic and analgesic activity in laboratory animals. It has been shown to be well NSAIDs are used as effective therapy for pain tolerated and effective in short term therapy of management to relieve pain, swelling (inflammation), degenerative joint disorders and RA. In long term, and joint stiffness caused by arthritis. These drugs may frequent dosing show side effect in the patient8. also be used to treat other painful conditions such as dental pain, muscle aches, pain after surgery or NSAIDs associated side effect parturition, but are not appropriate for long-term disease NSAIDs are reasonably safe medications, when low control5. The safety of NSAIDs has been closely doses are taken for brief period. Side effects most monitored by regulatory authorities across the globe. commonly occur with large doses over a prolonged time These are used for the treatment of mild to moderate (months or years). Some side effects are mild and go pain, fever and inflammation. NSAIDs mainly work by away on their own or after reducing the dose. Others blocking the effect of chemicals called cyclo-oxygenase may be more serious and need medical attention9. (COX) enzymes thereby decreasing prostaglandins Common side effects of NSAIDs include: synthesis. Some prostaglandins are produced at sites of injury or damage, and cause pain and inflammation. By  GI gastropathy, abdominal cramps, stomach pain, blocking the effect of COX enzymes, fewer stomach ulcers and heartburn. prostaglandins are produced, leading to pain and inflammation cessation6.  Headaches, ringing in the ears and dizziness. Topical form of NSAIDs produces a higher local  Allergic reactions such as rashes, wheezing, and concentration of the drug, and target the inflammation throat swelling and site and pain, where it preferentially distributes.  Liver or kidney problems, high blood pressure and Achieving sufficiently high concentration to exert local increased bleeding tendency (especially with therapeutic activity, for the effective distribution, skin aspirin). absorption is most critical factor of the drug to the site of inflammation and thus it can affect the efficacy of Many of the adverse effects of NSAIDs are also related topical formulation7. to inhibition of prostaglandin production, making their use problematic in some patient populations. The PROBLEMS ASSOCIATED WITH USE OF biology of prostaglandin as it relates to gastrointestinal, NSAIDs IN ARTHRITIS renal, and cardiovascular physiology and the Symptomatic relief but not cure pharmacologic properties of specific NSAIDs is a key to using these drugs safely5. The most obvious symptoms indicating arthritic state and its severity are inflammation and pain in and around NSAIDs induced ulceration: A cause of worry in the affected joint. Anti-inflammatory drugs used for arthritis pain management in arthritic individuals provide Being acidic in nature, most of the NSAIDs (diclofenac, relieves from pain for a certain time and reduce ibuprofen) are known to damage stomach lining and inflammation but no existing treatment modality may also cause ulceration and perforation in extreme ensures cure of arthritis. Hence, all NSAIDs offers only 10 5 cases . The lifetime risk of developing peptic ulcer is symptomatic relieve in RA . approximately 10%. However this situation becomes High dose frequencies alarming in patients, who are receiving for long term in situations like RA for months and years. Development The recommended dose of NSAIDs for treating RA is and peptic ulcers and associated pain is one of the major generally given 3-4 times daily for e.g. diclofenac is causes of withdrawal of NSAIDs and non compliance in given daily thrice at a dose of 50 mg. Rheumatoid rheumatic pain management. NSAIDs damage arthritic treatment modulates the involvement of long gastrointestinal mucosa by causing both local injuries term use of anti-inflammatory drugs for years. and by systemically inhibiting prostaglandin Furthermore due to increase in pain with severity of production. However, current consensus on the disease and age, patient start more frequent self pathogenesis of symptomatic peptic ulcer disease medication of higher dosages. Furthermore resulting from exposure to NSAID is mainly a simultaneous application of different dosages forms like consequence of systemic (post-absorptive) inhibition of tablets, gels, etc. also results in higher concentrations of GI mucosal COX activity rather than a local effect; drug in the body. Due to these reasons, NSAIDs NSAIDs are valuable agents in the treatment of arthritis induced toxicities and related complications arise in and many other musculoskeletal disorders and as many patients. Frequent administration of these drugs at analgesics in a wide variety of clinical scenarios. higher dose also results in decreased therapeutic However, as stated above, their use has been limited effectiveness. Both toxicities and lack of efficacy result mainly by their association with mucosal injury to the in high withdrawal rate, which question impact of these upper gastrointestinal tract, including the development drugs on the underlining disease mechanistically. of peptic ulcer disease11. Conventional NSAIDs based treatment therapies have much well recognised toxicity and is incompletely effective with few patients. Diclofenac sodium, the most preferred NSAID in arthritic pain management is a non-steroidal, non-pyrazole compound with anti- © 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO Baldi et al Journal of Drug Delivery & Therapeutics. 2015; 5(2):9-16 11

APPROACHES TO OVERCOME NSAIDs combination with misoprostol drug are available in INDUCED ULCERATION market. Despite of several technological advancement in novel drug delivery system, only tablet and enteric Combination with other drugs coated tablets available in the market for oral Antacid administration of these drugs. By keeping in view above mentioned problems associated with use of NSAIDs in Antacids were usually co-prescribed with NSAIDs arthritic pain management, more specifically high although no broad evidences were available as to the frequency of dosing and ulceration, application of novel effects of antacids in preventing NSAID associated drug delivery systems may offer suitable, safe, gastropathy12. A represent active survey of an outpatient therapeutically effective, more acceptable and cost prescription database was performed to measure the efficient alternative. extent of such a combination and to explore its associated factors13. However, erratic absorption pattern Controlled/sustained release formulations of some NSAIDs upon co-administration with antacid Sustained release systems include any system that should also be taken into consideration14,15. NSAID can achieves slow release of drug over an extended period also increase gastric acid secretion, although it is not of time or if the system is successful at maintaining clear whether such acts have any impact on ulcer constant drug levels in the target tissue or cells, it is formation or healing. Prostaglandins exert inhibitory considered a controlled-release system. acts on parietal cells, so the inhibition of their synthesis by NSAIDs can result in an increase in gastric acid The basic rationale behind sustained/controlled release secretion16. drug delivery is altering the pharmacokinetics and pharmacodynamics of drugs by using customized novel Cytoprotectant drug delivery pattern and modification of molecular Cytoprotectant are said to enhance endogenous mucosal structure or physiological parameters inherent in a protection mechanism and provide a physical barrier selected route of administration18. Thus, optimal design over the surface of ulcer. These drugs are now day most of a sustained/controlled release system necessitates a frequently co-administrated with NSAIDs to prevent thorough understanding of the pharmacokinetics and ulcer formation. Prostaglandin of E and I series have a pharmacodynamics of the drug. When the drug is generally protective action in the GI track and a administered in a conventional dosage form, it results in deficiency in endogenous prostaglandin production may a fluctuation of drug concentration at the site of action contribute to ulcer formation. (peak and valley pattern) and therefore in systemic circulation and tissue compartment. Improved Misoprostal, a synthetic prostaglandin E1 (PGE1) efficiency in treatment, optimized therapy and more methyl ester analogue has potent anti-secretory and uniform blood concentration is the benefits of this drug cytoprotective effects on the gastric and duodenal administration method. Advantages of mucus17. Misoprostal is a stable prostaglandin analogue, controlled/sustained release formulation include: has been shown in large studies to significantly reduce serious gastrointestinal side-effects due to the  Reduction in fluctuation in drug level and hence concurrent administration of NSAIDs and appears to be more uniform pharmacological response with superior to ranitidine and sucralfate in preventing reduced frequent dosing and cure of control of NSAID-induced gastric and dudenol ulcers. condition more promptly with diminish the chances of ulcer induction. Misoprostal is absorbed rapidly when administered  Improved patient compliance. It has been found orally, vaginally, rectally or intracervically. The vaginal that there is an inverse relationship between the route is advantageous because peak levels are reached number of dosages per day and the compliance slowly and sustained for long time and this is associated rate. with fewer side effects. It exerts a direct action on the parietal cell inhibiting the basal secretion of gastric acid  Although the initial unit cost of sustained release as well as stimulation of production seen in response to products is usually greater than that of conventional food, histamine, pentagastrin and caffeine. It also dosage forms because of the special nature of these increases mucosal blood flow and augments the products, the average cost of treatment over an secretion of mucus and bicarbonate12 extended time period may be less. Economy may . also result from a decrease in nursing time and Drug delivery approaches for prevention of NSAIDs hospitalization time19. induced ulceration Gastroretentive/floating formulation Current status Gastroretentive drug delivery is an approach to prolong Presently most preferred treatment approaches for pain gastric residence time. Over the last few decades, management in arthritis consists of diclofenac (NSAID) several gastroretentive drug delivery approaches being and misoprostol (a cytoprotectent) as mono- or designed and developed, including high density combination therapy, with recommended dose of 50 mg (sinking) systems that is retained in the bottom of the and 200 µg respectively given 3-4 time daily. If this stomach low density (floating) systems that causes regiment is not tolerated, diclofenac may be given 50 buoyancy in gastric fluid20. Two type of floating mg or 75 mg twice a day. Currently tablet and enteric system, single unit and multiple unit dosage form are coated tablet forms of diclofenac alone or in available21 thereby targeting site-specific drug release in

© 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO Baldi et al Journal of Drug Delivery & Therapeutics. 2015; 5(2):9-16 12 the upper gastrointestinal tract (GIT) for local or  To deliver drugs that are optimally absorbed in the systemic effects. Gastroretentive dosage forms can small intestine to their primary absorption site in remain in the gastric region for long periods and hence their most concentrated form. significantly prolong the gastric retention time (GRT) of  To deliver drugs intended for the local action in 22 drugs . The gastro retentive systems are advantageous intestines. E.g. intestinal antiseptics could be for drugs absorbed through the stomach, e.g. ferrous delivered to their site of action in a concentrated 23 salts, antacids . form and bypass systemic absorption in the Floating drug delivery system is also called the stomach. hydrodynamically balanced system (HBS)24. This type  To provide a delayed release component to repeat of drug delivery system is specifically beneficial to action tablets. reduce NSAIDs induced peptic ulcers due to avoidance Hence this strategy avoids contact of NSAIDs to 25 of direct contact of NSAIDs to stomach lining , no mucosal lining of stomach result in prevention from dose dumping, decreased frequency of dosing, associated irritation and erosion and may offer a possibility of co-administration with suitable alternative to avoid NSAIDs induced 26 antacids/cytoprotectent and better bioavailability . The ulceration32. associated advantages with floating drug delivery systems are as follows: Novel/Multiple unit dosage forms formulation (MUDF)  Administration of floating dosage forms, tablet or capsules, will result in dissolution of the drug in the Oral modified drug delivery systems can be classified in gastric fluid27. Drug dissolved in the gastric fluid to two broad groups: single unit dosage forms (SUDFs) would be available for absorption in the small and multiple unit dosage forms (MUDFs). Several mini- intestine after emptying of the stomach contents. It tablets can be either filled into hard capsules or is therefore expected that a drug will be fully compacted into bigger tablets that, after disintegration, absorbed from floating dosage forms if it remains release these subunits as multiple dosage forms. The in the solution form even at the alkaline pH of the concept of MUDFs was initially introduced in 1950s. intestine28. The production of MUDFs is a common strategy to  Improves patient compliance by decreasing dosing control the release of drug as shown by the frequency. reproducibility of the release profiles when compared to the ones obtained with SUDFs33.  Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration MUDFs have an enough surface area-to-volume ratio are avoided; a desirable plasma drug concentration and provide an ideal shape for the application of film is maintained by continuous drug release29. coatings. The preparation process necessitates extra care  Better therapeutic effect of short half-life drugs can and fine adjustments of various equipment’s like be achieved. tableting machines for the preparation of minitablets,  Superior to single unit dosage forms due to uniform the volume per dose is usually higher than for tablets drug release and no risk of dose dumping. because of the lower bulk densities of pellets compared  Avoidance of gastric irritation, because of to compressed tablets, compared to larger single unit sustained release effect, floatability and uniform dosage forms, the specific surface area per dose of 34 release of drug through multi particulate system. multiple units is higher and more . These systems consist of pellets, granules, beads, microspheres, mini Enteric coated drug delivery system or micro tablets filled in to sachets, capsules or Enteric refers to the small intestine; therefore enteric compressed into tablets. coating on the dosage form prevents the release of drug 30 Mechanism of drug release from MUDFs: Mainly before it reaches the small intestine . Most enteric three mechanisms are applied for the drug release coatings work by presenting a surface that is stable to MUDFs i.e. diffusion, osmosis, erosion. In diffusion it highly acidic pH of stomach, but breaks down rapidly at occurs through a membrane that controls the movement a less acidic (relatively more basic) pH. Enteric coating of the drug or solvent between two sides. Both the is suitable for drugs that have irritant effect in stomach membrane permeability of the drug and the solvent as (like NSAIDs) and drugs which are unstable in acidic well as the geometry of the device determines the pH of stomach. Thus, enteric coating is aimed to diffusion rate of molecules through the membrane. prevent the formulations from gastric fluid in the Modeling the release characteristics of reservoir devices stomach and release the drug component in the as well as monolithic devices, in which the transport of intestinal region or once it has passed into the the drug is by a solution diffusion mechanism, involves duodenum. The enteric coated tablet is the most 31 a solution to Flick’s second law for the valid boundary common example of a delayed-action tablet product . conditions35. Osmotic pressure is used as the driving Advantages offered by enteric coated drug delivery force for these systems to release the drug in a system include: controlled manner. Osmotic pump tablet (OPT)  Prevention from gastric distress or nausea due to generally consists of a core including the drug, an irritation caused by certain drugs e.g. NSAIDs. osmotic agent, other excipients and semi permeable 36  Protection of acid-labile drugs from the acidic pH membrane coat . In some cases coatings can be of gastric fluid e.g. enzymes and certain antibiotics. designed to wear away gradually with time, thus

delivering the drug contained within the particle by utilized for the purpose of prolonged release with erosion. desired pattern and reducing the risk of NSAID induced ulceration are given in Table 1. Diagrammatic Various novel drug delivery technologies and dosage representations of the same are depicted in Fig. 1. forms holding promising potential to be effectively

Table 1: Novel technologies/dosage forms that can be explored to overcome NSAIDs induced ulceration in arthritic pain management Type Characteristics Function Ref Tab-in-a-Cap Multiple release profiles are easily achieved Provides both controlled and multi-phase 37 by filling immediate release formulation release for single and combination (prostaglandin analogue) in outer larger prescription. Patient convenience and capsule and sustained or controlled release compliance and cost effective therapy. formulation (NSAID) in inner smaller tablet. Sustained, pulsed or delayed release profiles achievable. ACCU- ACCU-BREAK tablet technology use an Permits reduction in cost to patients. 38, 39 BREAK inactive layer (segment) as the break region. May also promote adherence to therapy by The layer containing drug can be scored into reducing the need of frequent administration. 2, 3 or 4 equal segments, all adjacent to an Dose adjustment as per requirement is inactive breakable support segment. Thus, a possible. tablet could be broken easily into the specific dose desired. Spheroids/ Controlled-release beads/granules in the Both NSAID and prostaglandin analogue, 40, 41 Pallets/ range from 1 to 2 mm containing drugs may may be simultaneously administered as beads Bead be formulated. Each bead begins as an inert in single dosage form with desired release core onto which the drug is applied. Drug profile and drug loading. release from these beads occurs by a Possibility of aqueous or solvent-based diffusion process in a controlled, granulation. High-speed process is well predetermined manner. These dosage form suited for sensitive molecules like proteins enable high drug loading and granules and enzymes. produces beads that are of controlled size and Suitable for high drug loading as required in density with a defined-based granulation arthritic pain management. extrusion and spheronisation techniques. Multilayer Customizable multilayered oral drug delivery Use of highly swellable hydrophilic 42 dosage forms platform technology may also be explored. It polymers (e.g. HPMC). uses well-established ingredients and is Dynamic control of the surface of the layer easily manufactured using conventional containing the drug that is exposed to production equipment. The combination of surrounding fluids. layers, each with different rates of swelling, May allow efficient administration of gelling and erosion, controls the drug release NSAID and prostaglandin analogue with rate within the body required release profile and high dose delivery in pain management. Delayed It is used to release the drug from the tablet NSAID and prostaglandin analogue may be 43 release (Lag) after a pre-determined lag-time that is simultaneously administered on possible based independent of food or pH. It can release pattern to avoid dose dumping and technology additionally be used for multiple pulse associated side effects. delivery of one or more drugs with predetermined time intervals between the pulses. OROS OROS delivery systems consist of the push- This technique may be adopted for co- 44 (Osmotic and pull system is comprised of a bilayer or administration of two drugs for example Chronset) trilayer tablet core consisting of one push NSAID and prostaglandin analogue. layer and one or more drugs layers. The drug A delivery orifice is laser drilled at the layer and the osmotic engine are encased in opposite end of the osmotic engine providing hard capsule which is surrounded by the rate an outlet for the drug. controlling semi permeable membrane. A Contact of NSAID with gastric mucosa may barrier layer composed of an inert substance be avoided to reduce the possibility of separates the drug layer from osmotic engine. ulceration. Using this technology, the drug formulation is completely protected from chemical and enzymatic degradation in the GIT before release, and the timing of release is unaffected by GIT contents.

One Step OSDrC technology allows placement of any This is ideal for manufacturing a variety of 45 Dry Coating number of cores of any shape into the tablet high-quality drug products at low cost. Technology just where they need to be positioned for This innovative technology can also replace (OSDrC) optimum delivery of active pharmaceutical conventional sugar- and film-coated tablets. ingredients. This technology opens the door Multiple drugs e.g. NSAID and to new world of pharmaceutical tablet prostaglandin analogue may also be manufacturing with advantages like administered in different cores. uniqueness, high quality, low cost and innovativeness. Diffucaps/ In this technology, a unit dosage form, such Diffutabs are particularly useful for high- 46 Diffutabs as a capsule for delivering drugs into the dose products and drugs that require body in a circadian release fashion, is sustained release and once-a-day dosing. comprised of one or more populations of Different formulations containing NSAID drug-containing particles (beads, pellets, and prostaglandin analogue may be granules, etc.). Drug profiles are created by developed and then mixed as a unit dosage layering an active drug onto a neutral core form for simultaneous administration of such as cellulose spheres and then one or these drugs with different pattern of release. more rate-controlling, functional membranes are applied.

Figure 1: A: TAB IN CAP; B: ACCU BREAK; C: Spheroids; D: Bead; E: Multilayer dosage forms; F: Delayed release (Lag) based technology; G: OROS; H: OSDrC; I: Diffucaps/Diffutabs © 2011-14, JDDT. All Rights Reserved ISSN: 2250-1177 CODEN (USA): JDDTAO Baldi et al Journal of Drug Delivery & Therapeutics. 2015; 5(2):9-16 15

CONCLUSION AND FUTURE PROSPECTS ailments without the problem of NSAID-induced ulceration. These drug delivery systems may be Undoubtedly use of NSAIDs for management of explored in future to find out better strategies for arthritic pain is essential to increase the quality of life in effective management of rheumatic disorders. patients suffering from rheumatic disorders. However side effect associated with these drugs are major cause ACKNOWLEDGEMENT of worry for physicians for successive therapeutic The authors would like to grateful of Shri. Praveen management of rheumatic inflammation and pain. Multi Garg, Chairman, I.S.F. College of Pharmacy, Moga, drug based therapy approach especially NSAIDs along Punjab for providing necessary facilities to carry out the with prostaglandin analogue is one of the most proposed review work. promising approach to overcome ulceration induced by high dose and frequency of anti-inflammatory drugs. CONFLICT OF INTEREST Various novel drug delivery based technologies, as discussed in the article, also hold promising potential The authors declare no conflicts of interest. for pain management and patient compliance in these

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