WO1991016896A1

WO1991016896A1 - Pharmaceutical composition for use in treating pain

Info

Publication number: WO1991016896A1
Application number: PCT/US1991/002985
Authority: WO
Inventors: Michael F. Rafferty; Awilda Stapelfeld
Original assignee: G.D. Searle & Co.
Priority date: 1990-05-03
Filing date: 1991-05-01
Publication date: 1991-11-14
Also published as: IE911487A1; AU7793791A; PT97563A; IE62051B1

Abstract

A pharmaceutical composition and a method for treating mild to moderate pain in a subject in need of such treatment is performed by administering an analgesic agent selected from diclofenac, ibuprofen, piroxicam and their pharmaceutically acceptable salts in a dosage which by itself would provide less than the therapeutic effect, and administering misoprostol in a dosage which is sufficient to potentiate the analgesic effect of the analgesic agent to the therapeutic effect.

Description

PHARMACEUTICAL COMPOSITION FOR USE IN TREATING PAIN

BACKGROUND OF THE INVENTION

The invention herein is directed to a new pharmaceutical composition useful in the treatment of pain which comprises two active ingredients, namely a nonsteroidal anti-inflammatory agent and a prostaglandin, which prostaglandin exhibits analgesic activity. The nonsteroidal anti-inflammatory agent can be selected from diclofenac, ibuprofen and piroxicam. The prostaglandin is misoprostol, (+) methyl 11a, 16-dihydroxy-16-methyl-9-oxoprost-l3E-en-l-oate. The invention herein is also directed to a new method for treating mild to moderate pain by administering one of the above-mentioned nonsteroidal anti-inflammatory agents in an amount which by itself would provide less than a therapeutic analgesic effect and misoprostol in an amount sufficient to potentiate the analgesic effect of the nonsteroidal anti-inflammatory agent to the desired therapeutic analgesic effect.

Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a class of drugs which have long been recognized as having high therapeutic value especially for the treatment of inflammatory conditions such as experienced in inflammatory diseases like osteoarthritis (OA) and rheumatoid arthritis (RA) . NSAIDs are also widely regarded as having high therapeutic value in the treatment of mild to moderate pain. While the NSAIDs present a beneficial therapeutic value they also have been known to exhibit undesirable side effects. An especially undesirable side effect of the administration of NSAIDs is the ulcerogenic effects generally associated with chronic use. In chronic use of NSAIDs, use of high dosages of NSAIDs and especially the use of NSAIDs by the elderly can lead to NSAID induced ulcers. NSAID induced ulcers in the stomach can be dangerous. Such ulcers generally exhibit little or few symptoms and can cause dangerous

S bleeding when undetected. The United States Food and Drug Administration requires a class warning for all NSAIDs, which states: Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy.

Certain prostaglandins have been shown to prevent NSAID induced ulcers. The prostaglandin compound commercially available under the USAN (United States Adopted Name) name misoprostol is a pharmaceutically acceptable prostaglandin which has been accepted for use in the prevention of NSAID induced ulcers in many countries, including the United States. Misoprostol is commercially available by prescription in such countries.

E-type prostaglandins are recognized as modulators of pain sensitivity. However, the extent and nature of the modulation is not well understood nor predictable. A review of the scientific literature reveals that the nature and direction of this modulatory effect can differ depending upon experimental design and investigator. Both PGE_j^ and PGE₂ have been reported to potentiate the behavioral response (writhing) to intraperitoneal phenylbenzoguinone injection in mice

(G.W.L. James & M. K. Church, Arzneimittelforschung 28, 804-7 (1978)) and to intracarotid injection of bradykinin in rats (T. Mikami and K. Miyasaka, J. Pharm. Pharmacol. 3JL_. 856-7 (1979)) after systemic administration. PGE₂ has also been shown to potentiate bradykinin-induced writhing in mice (T. Walter, T. T. Chau, and B. M. Weichman, Agents and Actions 27., 375-7 (1979) ) and to increase sensitivity to noxious thermal and mechanical stimuli after administration to the spinal cord in rats (Y. Taiwo and J. D. Levine,

J. Neurosci 8., 1346-9 (1988)). Subder al injection of PGE_! has been found to increase the sensitivity of pain

_SUBSTITUTE SHEET sensory fibers (nociceptors) which respond to a variety of sensory stimuli (S. Pateromichelakis, J. R. Rood, Brain Research 232, 89-96 (1982)). However, Sanyal et al. reported that PGE can induce an analgesic effect in the rat after peripheral (A. K. Sanyal, S. K.

Bhattacharya, P. R. Keshary, D. N. Srivastava, P. K. Debnath, Clin. Exp. Pharmacol. Physiol. 4., 247-255 (1977)) and intracerebroventricular administration (A. K. Sanyal, D. N. Srivastava, S. K. Bhattacharya, P.K.S.P. Reddy, P. K. Debnath, A. K. Sanyal, Clin. Exp. Pharmacol. Physiol. 2 , 353-357 (1975)). However, these results conflict with an earlier report that PGE_X antagonizes the analgesic effect of morphine. (S. Ferri, A. Santagostino, P. C. Boraga, I. Galatulas, Psvchopharmacolo ia 34. 231-5 (1974)).

A review of these references shows that the effects of Ε>GE₁ on pain sensitivity have been reported to be either facilitory (hyperalgesic) or analgesic. It is therefore impossible to predict the nature of the effects of a PGE-^ analogue, such as misoprostol, on pain responsivity. In view of the unpredictability of any analgesic effect of a PGE-L analogue, it is further unpredictable to assess the analgesic effect of a combination of a PGE_α prostaglandin and a nonsteroidal anti-inflammatory agent (NSAID) and especially the effect of the PGE_χ analogue on the analgesic activity of the NSAID. The literature reports that NSAIDs and E-Type prostaglandins have opposite effects on pain sensitivity (G.W.L. James and M. K. Church, Arznei ittel-Forschung .28., 804-7 (1978) ; Y. O. Taiwo and J. D. Levine, J. Neurosci 8., 1346-9 (1988)).

It would be desirable to provide a pharmaceutical composition which would exhibit the beneficial properties of an NSAID and which composition would exhibit the beneficial properties of a prostaglandin for countering (by inhibiting, reducing or preventing) the undesirable side effect of ulcerogenesis induced by

HEET NSAID administration and which composition would exhibit enhanced analgesic activity. Such a composition could thereby provide the same or greater analgesic therapeutic benefit using less NSAID and thereby further decrease the likelihood of the undesirable NSAID ulcerogenic side effect due to the decreased amount of NSAID and the cytoprotective activity of the prostaglandin. Such a combination would provide an improved NSAID with respect to both efficacy and safety.

SUMMARY OF THE INVENTION

The present invention is directed to a method for imparting analgesia, relief from mild to moderate pain, to a patient in need thereof by administering, concomitantly or simultaneously, a nonsteroidal anti-inflammatory agent and the prostaglandin, misoprostol in an effective dose to potentiate the analgesic effect of the NSAID. In particular, the present invention is directed to a method for treating mild to moderate pain in a subject in need of such therapy, which method provides a desired therapeutic analgesic effect sufficient to relieve the mild to moderate pain. The method is performed by administering an analgesic agent, selected from the nonsteroidal anti-inflammatory agents (NSAIDs) diclofenac, ibuprofen and piroxicam, or their pharmaceutically acceptable salts, in a dosage which by itself would provide less than the desired therapeutic analgesic effect and administering misoprostol in an effective dosage which is sufficient to potentiate the analgesic effect of the selected dosage of the analgesic agent to the desired therapeutic analgesic effect. The invention herein is also directed to a pharmaceutical composition useful for achieving a desired therapeutic analgesic effect in the treatment of mild to moderate pain in a subject in need of such treatment. The composition includes an analgesic agent selected from diclofenac, ibuprofen, piroxicam and their pharmaceutically acceptable salts in an amount of the analgesic agent which by itself would provide less than the desired therapeutic analgesic effect. The composition also includes the prostaglandin, misoprostol, in an amount which is sufficient to potentiate the analgesic effect of the analgesic agent to the desired therapeutic analgesic effect.

SUBSTITUTE SHEET BRIEF DESCRIPTION OF THE DRAWINGS

The method and composition that are the subject of the invention herein will be better understood with reference to the accompanying drawings wherein: Figure 1 is an isobolographic analysis of coadministered misoprostol and diclofenac calculated ED₅₀ values;

Figure 2 is an isobolographic analysis of coadministered misoprostol and ibuprofen calculated ED₅₀ values;

Figure 3 is an isobolographic analysis of coadministered misoprostol and piroxicam calculated ED₅₀ values;

Figure 4 is a graphic analysis of coadministered misoprostol and diclofenac showing a comparison of actual versus predicted responses;

Figure 5 is a graphic analysis of coadministered misoprostol and ibuprofen showing a comparison of actual versus predicted responses; Figure 6 is a graphic analysis of coadministered misoprostol and piroxicam showing a comparison of actual versus predicted responses; and

Figure 7 is a graphic representation illustrating the possible dose ranges for misoprostol and an analgesic agent.

DETAILED DESCRIPTION OF THE INVENTION

The invention herein is directed to a composition and a method for treating mild to moderate pain in a subject (either human or animal, i.e., mammal) in need of such treatment by administering, concomitantly or simultaneously, misoprostol and a nonsteroidal anti-inflammatory agent selected from diclofenac, ibuprofen, piroxicam and their pharmaceutically acceptable salts. For ease of description herein these agents will be referred to as analgesic agents. One benefit derived from the method herein is that the

EET - 1 -

administration of the misoprostol potentiates the analgesic activity of the analgesic agent such that the analgesic agent can be used in a dosage less than the dosage which would be used if the analgesic agent were used by itself. The administration of the misoprostol enhances the analgesic activity of the analgesic agent by potentiation such that the amount of analgesic agent administered to obtain a desired therapeutic analgesic effect can be reduced but the desired therapeutic analgesic effect can be achieved. The opportunity to use less NSAID especially in combination with a cytoprotective prostaglandin, reduces the likelihood of occurrence of the undesirable side effect of the NSAID inducing an ulcer. In view of the known deleterious side effect of ulcerogenesis incumbant with the use of NSAIDs, the practice of the method and use of the composition herein can diminish the likelihood and/or occurrence of such a deleterious side effect. It is further possible that other benefits can be derived from the composition and method herein. For example, prostaglandins, including misoprostol, have shown anti- inflammatory activity. Therefore, the combination of the prostglandin with the NSAID can beneficiate or increase the anti-inflammatory activity of the combination or coadministration regimen. That is, the composition or coadministration regimen can exhibit a greater anti-inflammatory activity than the administration of the NSAID alone.

It has been found herein that the prostaglandin misoprostol exhibits a potentiating effect on the analgesic activity exhibited by the above-described analgesic agents. Misoprostol is shown by the following formula: With regard to the illustrated structure, the dashed line indicates the group extends behind the plane of the paper and the solid, blackened triangular shape indicates that the group projects from the plane of the paper.

The prostaglandin, misoprostol, can be prepared by known reaction schemes such as by the methods taught in U. S. Patents 3,965,143, 4,452,994, 4,529,811 and 4,777,275. The individual isomers can be obtained by chromatographic separation such as taught in U.S. Patent 4,060,691.

An effective but non-toxic quantity of the prostaglandin is employed in the treatment. The dosage regimen for the method of this invention is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the patient, the route of administration, the extent of the mild to moderate pain of the patient and the particular nonsteroidal anti-inflammatory agent employed. Dosages of misoprostol useful in the method herein are in the range up to 1600 μg per day. A preferred range is up to 800 μg per day. Greater or lesser dosages can be used, depending upon the above-noted factors. It is preferred to use as low a dose of misoprostol as possible to obtain the desired potentiation of the therapeutic analgesic benefit of the analgesic agent. The lowest dose of misoprostol is dependent upon the analgesic agent with which it is to be administered and is balanced against the desire to use a low dosage of the selected analgesic agent. Based upon the studies described hereinafter, misoprostol can be used in an amount from about 5 μg to about 200 μg per tablet and in a dosage from about 25 μg to about 1600 μg per day. The term "nonsteroidal anti-inflammatory agent" and "analgesic agent" as used herein, include diclofenac,

SU piroxicam, ibuprofen and their pharmaceutically acceptable salts.

The term "desired therapeutic analgesic effective dosage" as used herein means, with respect to the nonsteroidal anti-inflammatory agent, the dose sufficient for imparting the requisite suppression/alleviation of mild to moderate pain in a patient in need of such therapy. The specific dose is dependent upon the same factors noted above with respect to the dosage of prostaglandin. The determination of the specific dosage for a subject is well within the skill of the prescribing physician. The Physician's Desk Reference, 44th Edition (1990) lists the daily single dosages for various nonsteroidal anti-inflammatory agents.

The term "mild to moderate pain" is a term accepted and understood by those skilled in the medicinal arts and especially, trained medical doctors. Generally, such a term as a mild pain means a pain which does not cause the subject to modify a behavior and a moderate pain means a pain which would cause a subject to modify a behavior. Further, such a term as mild to moderate pain refers to a pain for which a physician would prescribe the general class of NSAID's as an analgesic agent for relieving the pain. While pain is a subjective condition, physicians are trained to evaluate a patient's overall condition, history and description of the level of discomfort so as to assess and thereby diagnose the extent of pain. Following such observation and evaluation the physician can prescribe the desired therapeutic analgesic dosage and dosing regimen.

The analgesic agent can be present in any dosage which would be below the therapeutically acceptable amount if such analgesic agent at such dosage were administered alone. The Physicians' Desk Reference, 44th Edition, states that the recommended dosage of

SHEET diclofenac for treating osteoarthritis is 100 to 150 mg per day in divided doses. For treating rheumatoid arthritis the recommended dosage is 150 to 200 mg per day in divided doses. For treating ankylosing spondylitis the recommended dosage is 100 to 125 mg per day in divided doses. Diclofenac is currently, commercially available by prescription in tablets containing 25, 50 and 75 mg and is administered in prescribed dosing ranges utilizing these 25 mg, 50 mg and 75 mg tablets.

The pharmaceutical composition herein can include an amount up to about 75 mg of diclofenac. Such an amount as up to 75 mg can provide an analgesic effect up to or greater than the current largest commercially available amount of 75 mg. In a preferred practice of the invention herein, the composition can contain up to but less than 25 mg of diclofenac and exhibit the same or better therapeutic analgesic effect as the 25 mg current commercially available tablet. The composition can contain up to but less than 50 mg, or greater than 25 mg but less than 50 mg, of diclofenac and exhibit the same or better therapeutic analgesic effect as the 50 mg current commercially available tablet. The composition can contain up to but less than 75 mg, or greater than 50 mg but less than 75 mg, of diclofenac and exhibit the same or better therapeutic analgesic effect as the 75 mg current commercially available tablet. Preferably the pharmaceutical composition includes a dosage of up to about 25mg. An amount up to 25 mg is desirable as it is less than the current commercially available lowest dosage but is an amount which can provide the same or better analgesic therapeutic effect than the commercially available 25 mg tablet. Such a dosage provides an advantage in that it can provide a therapeutic benefit using a relatively low dosage of the NSAID. Various excipients can be combined with the diclofenac as is well known in the

TE SHEET pharmaceutical art provided such excipients do not exhibit a destabilizing effect on the prostaglandin. For the practice of the method herein, the diclofenac can be administered in an amount up to about 200 mg per day and preferably in an amount up to about 100 mg per day in divided doses or in a single dose. For the practice of the method herein the current commercially available diclofenac tablets can be administered.

The NSAID can be piroxicam. Currently commercially available piroxicam capsules contain either 10 mg or 20 mg of piroxicam. The PDR, 44th Edition, recommends that piroxicam be administered in a single daily dose of 20 mg for rheumatoid arthritis and osteoarthritis. The pharmaceutical composition herein can contain up to 20 mg and preferably contains less than 10 mg of piroxicam. The use of an amount up to 20 mg can provide an analgesic therapeutic benefit equivalent or greater than a 20 mg dosage of piroxicam by itself. Similarly, the use of an amount up to 10 mg can provide a therapeutic analgesic benefit equivalent or greater than the use of 10 mg of piroxicam by itself, which 10 mg is the lowest dosage now currently available. In a preferred practice of the invention herein, the composition can contain up to but less than 10 mg of piroxicam and exhibit the same or better therapeutic analgesic effect as the 10 mg current commercially available tablet. The composition can contain up to but less than 20 mg, or greater than 10 mg but less than 20 mg, of piroxicam and exhibit the same or better therapeutic analgesic effect as the 20 mg current commercially available tablet. Various excipients can be present, provided such excipients do not exhibit a destabilizing effect on either the piroxicam or the prostaglandin. For the practice of the method herein, the piroxicam can be administered in an amount up to about 20 mg per day and preferably in an amount up to about 10 mg per day in either divided doses or in a single dose. For the practice of the method herein the current commercially available piroxicam tablets can be administered.

The NSAID can be ibuprofen. Ibuprofen is available as an over-the-counter analgesic agent in tablets containing 200 mg. Ibuprofen is available by prescription in tablets containing 300, 400, 600 and 800 mg of ibuprofen. The PDR, 44th Edition, recommends that ibuprofen be administered in dosages of 1200 mg to 3200 mg daily for rheumatoid and osteoarthritis; in dosages of 400 mg every 4 to 6 hours as necessary for relief of mild to moderate pain; and in dosages of 400 mg every 4 hours for dysmenorrhea. The PDR states: "In controlled analgesic clinical trials, doses of MOTRIN (Upjoh 's brand of ibuprofen) greater than 400 mg were no more effective than the 400 mg dose." The pharmaceutical composition herein can include up to about 800 mg of ibuprofen and preferably up to about 200 mg of ibuprofen. An amount up to 800 mg can provide the equivalent or greater analgesic therapeutic benefit than the use of 800 mg of ibuprofen by itself. The use of up to 200 mg can provide an analgesic therapeutic benefit equivalent or greater than the current commercially available lowest dosage tablet of 200 mg. In a preferred practice of the invention herein, the composition can contain up to but less than 200 mg of ibuprofen and exhibit the same or better therapeutic analgesic effect as the 200 mg current commercially available tablet. The composition can contain up to but less than 300 mg, or greater than 200 mg but less than 300 mg, of ibuprofen and exhibit the same or better therapeutic analgesic effect as the 300 mg current commercially available tablet. The composition can contain up to but less than 400 mg, or greater than 300 mg but less than 400 mg, of ibuprofen and exhibit the same or better therapeutic analgesic effect as the 400 mg current commercially available

TUTE SHEET tablet. The composition can contain up to but less than 600 mg, or greater than 400 mg but less than 600 mg, of ibuprofen and exhibit the same or better therapeutic analgesic effect as the 600 mg current commercially available tablet. The composition can contain up to but less than 800 mg, or greater than 600 mg but less than 800 mg, of ibuprofen and exhibit the same or better therapeutic analgesic effect as the 800 mg current commercially available tablet. Various excipients can be present, provided such excipients do not exhibit a destabilizing effect on either the ibuprofen or the prostaglandin. For the practice of the method herein, the ibuprofen can be administered in an amount up to about 3200 mg per day and preferably in an amount up to about 1200 mg per day in either divided doses or in a single dose. For the practice of the method herein the current commercially available ibuprofen tablets can be administered.

Regardless of the route of administration selected, the misoprostol, NSAID or composition herein, can be formulated into pharmaceutically acceptable dosage forms by conventional methods known to the pharmaceutical art. For purposes of the practice of the method herein the commercially available forms, formulations and compositions of the NSAIDs and misoprostol can be used. Similar formulations but with lower amounts of the NSAIDs can be used in the practice of the invention herein. A particularly preferred formulation for misoprostol is taught in U.S. Patent 4,301,146.

The misoprostol, NSAID or composition herein can be administered in such oral unit dosage forms as tablets, capsules, pills, powders, or granules. They can be administered intraperitoneally, subcutaneously, or intramuscularly, using forms known in the pharmaceutical art. In general, the preferred form of administration is oral. An advantage of the present

E SHEET method and composition is that the misoprostol is an orally available prostaglandin and can be formulated into orally available dosage forms. An advantage of oral availability is that the methodology of administration is easy to follow and does not require an attending, skilled medical professional. Oral availability is also an accepted and expected method of treatment for mild to moderate pain relief.

The method herein is performed by administering the nonsteroidal anti-inflammatory agent and misoprostol to the patient in need of such therapy in the dosage forms and the dosages set forth herein. The two components can be administered simultaneously or concomitantly. The order of administration of the two active ingredients is not critical, although it can be beneficial to administer the misoprostol first to benefit from the cytoprotective properties in preventing NSAID induced ulcers. A particularly preferred manner of treatment is the co-administering of the two active ingredients in a single dosage form such as a tablet or capsule. The sequencing and timing of the performance of the steps of the method herein are well within the skill of a physician prescribing an analgesic regimen. The selection of the dose of NSAID and misoprostol can be further understood by considering the graph shown in Figure 7. Figure 7 illustrates a plot of the dosage of NSAID versus the dosage of misoprostol. The dosage for the NSAID is represented along the y axis and the dosage for misoprostol is represented along the x axis. The point represented by A along the x axis is the minimum effective amount of misoprostol which potentiates the analgesic activity of an NSAID, which amount is about 25 micrograms (meg or μg) per day or about 5 meg per tablet. The point represented by B along the x axis is the maximum tolerable daily dosage for misoprostol, which has been found to be as high as

SUBSTITUTE SHEET about 1600 meg per day. The PDR, 44th Edition states that cumulative daily doses of 1600 meg have been tolerated by humans with only symptoms of gastrointestinal discomfort being reported. Therefore, it is preferable to use an amount of misoprostol up to about 1600 meg per day and preferably as low a dosage as possible when balanced against the dosage of NSAID administered. The PDR also states that the recommended adult oral dose for Cytotec (G.D.Searle and Co's brand of misoprostol) for the prevention of NSAID induced gastric ulcers is 200 meg four times daily with food, thereby providing a recommended daily dosage of 800 meg.

The points along the y axis will be described in general terms as the specifics of the locations of such points depend upon the NSAID selected. The point represented by C along the y axis is the minimum dosage of an NSAID which would provide a therapeutic benefit in alleviating mild to moderate pain. The point represented as D on the graph is the maximum daily dosage for an NSAID. The point represented by E is the combined dosage for the NSAID and misoprostol and represents the activity for the minimum dosage of NSAID and minimum dosage of misoprostol. The point identified as F is the intersection of the lines extended from the maximum dosages for both the misoprostol and NSAID. The line EF represents the line which would be formed interconnecting the minimum dosages for the misoprostol and NSAID in combination for the ED values, e.g., ED₁₀, ED₂₀, ED₃₀, etc. The area bounded by the lines A B F D C A represent acceptable pharmaceutical dosages for the combination of misoprostol with an NSAID. The area bounded by the lines E F D C E represents the preferred dosages for the combination of NSAID and misoprostol as such an area represents the greatest analgesic activity with the minimum acceptable dose of misoprostol. For each of the NSAIDs herein, such an area is reflected in a range of NSAID to misoprostol of 3:1 for diclofenac, 5:1 for ibuprofen and 1:1 for piroxicam.

The efficacy of the method herein has been demonstrated through animal models. The animal model studies are well accepted for evaluating analgesic activity of chemical compounds as shown in Pong et al. , Prediction of Human Analgesic Dosages of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) from Analgesic ED₅₀ Values in Mice," Arch. int. Pharmacodyn. 273, 212-220 (1985); Otterness et al., Journal of Pharmaceutical Sciences, Vol. 77, No. 9, September 1988, pp 790-795; and Dubinsky et al. , Agents and Actions, Vol. 20, 1/2 (1987) pp 50-60. The efficacy of the composition herein for use in treating mild to moderate pain was shown in the phenyl-benzoquinone-induced writhing test in the mouse. This model is widely used as a primary in vivo efficacy screen for the detection of a wide variety of analgesic agents. Diclofenac (sodium-[o-[2,6-dichlorophenyl]- amino]phenyl]-acetate) is an NSAID that exhibits an ED₅₀ value in this mouse writhing assay of 2.0 mg/kg. The following example illustrates the effect of misoprostol and the NSAIDs herein in pain relief in the mouse writhing assay.

Example 1 Method for Mouse Writhing Assay. This experiment is recognized for the screening of compounds for use as analgesic agents. Diclofenac has been reported in the literature to be active in this assay following oral administration, with an ED₅₀ value of 4.3 mg/kg i.g., Menasse et al, "Pharmacological Properties of Diclofenac Sodium and its Metabolites," Scand. J. Rheumatology 22(suppl.): 5-16; 1978. In this experiment the ability of misoprostol, certain NSAIDs and combinations of misoprostol with such NSAIDs to suppress the chemically induced writhing response in mice was determined.

Male albino mice (Charles River Laboratory; CD-I, 20-30 grams were randomly divided into groups of ten and weighed. Twenty-five minutes after intragastric (i.g.) administration of the test compound, 0.025% w/v phenylbenzoquinone (PBQ) was injected intraperitoneally (i.p.; 0.1 ml/10 grams of body weight). Five minutes after i.p. injection of PBQ, each animal was placed into a large glass beaker and the number of writhes that occurred in the subsequent ten minutes was counted. A writhe consisted of a dorsoflexion of the back, extension of the hindlimbs, and strong contraction of the abdominal musculature. Test compounds were considered to have significantly inhibited the writhing response if the number of writhes observed was less than or equal to one half of the median number of writhes recorded for the control group of mice on the same day (Taber, R.I., "Predictive Value of Analgesic Assays in Mice and Rats," Advances in Biochemical Psychopharmacology, vol. 8, p 191, (1974)). The number of writhes for each animal was converted to the square root function. The effective dose (ED₅₀) that inhibited writhing 50% compared to control values was determined by a regression analysis of the least squared means. Based on these results, an estimation of the number of writhes could be determined for each drug at various dose levels and a statistical prediction could be made as to the additive effects of various combinations of misoprostol and NSAID. The differences between the predicted and actual number of writhes was calculated. These differences were analyzed for significance using a T-test. Isobolographic analysis was used to determine whether the actual effect of the combinations of the two drugs were additive, synergistic or antagonistic ("Criteria For Analyzing Interactions Between Biologically Active Agents," M.C. Berenbaum; Advances in Cancer Research, vol. 25, pp269-335, (1981)). Simplistically, this procedure of analysis is performed by first determining the ED₅₀ values for the two agents separately and plotting these values on separate axes. A line is drawn between the two values which line represents the theoretical dose-additivity line. If the pharmacological effects of the two drugs when coadministered add together, then any dose combination represented by a point on the line will produce an ED₅₀ efficacy. The next step in the analysis was the evaluation of a series of dose combinations and identification of combinations which would generate an ED₅₀ response. These values are plotted on the graph. If the values fall on the line, then the drugs are additive. If the values are inside the line (toward the origin) then the effects are supraadditive, that is they synergize with one another to produce a much greater effect than predicted. If the values are outside of the line, then the two drugs are infraadditive, that is the effect of the combination is less than expected. As can be seen from the drawings of the isobolographs in Figures 1 through 3 which depict the results of the experiments herein, the combinations herein studied and comprising the invention herein fall inside the lines. The

SHEET isobolographs for the combination of misoprostol with diclofenac, piroxicam and ibuprofen all show the empirically determined values to be inside the line of additivity and, therefore, synergistic. In regard to Figure 1 there is shown the isobolographic analysis of coadministered misoprostol and diclofenac. The ED₅₀ for diclofenac alone was 1.8 mg/kg. The ED₅₀ for misoprostol alone was 0.6 mg/kg. The isobolographic analysis shows that an ED₅₀ for the coadministered misoprostol and diclofenac could be obtained using 0.05 mg/kg of diclofenac with a 0.02 mg/kg of misoprostol. This represents a 36 fold decrease in the ED₅₀ value.

With regard to Figure 2 an isobolographic analysis is illustrated for the coadministered misoprostol with ibuprofen. The graph is based upon results from the mouse writhing assay. As can be seen from the graph the ED₅₀ for misoprostol 0.6 mg/kg and for ibuprofen is 3 mg/kg. When the ibuprofen was coadministered with misoprostol wherein misoprostol was present in amount of 0.01 mg/kg. The ibuprofen was present in amount of about 0.08 mg/kg. The ibuprofen exhibited about a 38 fold decrease in dose. That is 1/38 the amount of ibuprofen can be used when coadministered with misoprostol to thereby obtain the same analgesic activity as would be predicted for a dose 38 times as great.

Figure 3 represents the isobolographic analysis of coadministered misoprostol and piroxicam. The misoprostol is plotted along the x axis and piroxicam is plotted along the y axis. As can be seen from Figure 3 and the results of the mouse writhing assay performed using coadministered misoprostol and piroxicam there was about a 67 fold decrease in the amount of piroxicam required when combined with 0.009 mg/kg of misoprostol.

SUBSTITUTE SHEET The graphs shown in Figures 1-3 also show that there was about a 30 fold increase in the analgesic effect of misoprostol when combined with any of the NSAIDs. Regardless of the NSAID selected, such a thirty fold increase in effect was observed. The amount of misoprostol selected to be used in the composition or method herein can be 1/30 of the amount which would normally be prescribed if it were prescribed alone without the presence of an NSAID. The results were further statistically analyzed and the results of this further analysis are shown in Figures 4 through 6. The dose response data for misoprostol alone and the dose response data for the respective NSAID alone were used to calculate a predicted level of response for each of the various dose combinations studied. A determination was made of the difference between the actual and the predicted response levels. The difference showed that the actual values were statistically clearly different from the predicted. Figures 4 through 6 show the plot of the difference in predicted response versus the observed response for the combined dosages of misoprostol and NSAID. The results of the mouse writhing assay that were performed for misoprostol, the various NSAIDs and the combinations of misoprostol with the selected NSAIDs are reported in Table 1.

TABLE 1

These studies show that there was clear evidence of enhancement of analgesic activity between misoprostol and the nonsteroidal anti-inflammatory agents.

The use of the method herein can enhance the analgesic effect of a mild to moderate pain relief therapeutic regimen which includes the administration of a nonsteroidal anti-inflammatory agent. The method can thus provide the desired extent of pain relief by using a lower dose of the nonsteroidal anti-inflammatory

SUBSTITUTE SHEET agent. The method can, therefore, reduce the incidence of gastrointestinal side effects of the nonsteroidal anti-inflammatory agent. The use of an amount of NSAID which is less than the normal amount which would be prescribed, i.e., the normal therapeutic amount, is a significant improvement over the current NSAID therapeutic regimen. Heretofore, prostaglandins have been disclosed as being useful in adjunctive therapy with normal therapeutic dosages of NSAIDs in order to diminish the ulcerogenic side effects of the NSAID administration. The improved method and composition herein is beneficial in that it provides the opportunity to use less NSAID (lower dosage) than heretofore was believed to be therapeutic. The combination of an NSAID with misoprostol creates an attractive therapy for mild to moderate pain relief. The invention herein of employing a prostaglandin which potentiates the analgesic effect of a particular NSAID (one which is capable of interacting with a potentiating prostaglandin to produce an analgesic- potentiated effect) in an effective amount to potentiate such effect is especially beneficial in that it reduces the amount of NSAID administered, it reduces the liklihood of ulcer formation, it aids in the healing of ulcers (if formed) , and it alleviates the mild to moderate pain for which it was administered.

In the formulation of the composition herein, the formulation can be formed in an admixture as disclosed in copending patent application ser. no. , titled "Stabilized Pharmaceutical Admixture Composition," of Franz et. al. (docket no. 2609) or in a tablet such as disclosed in copending patent application ser. no. , titled "Pharmaceutical Composition

Containing Ibuprofen and A Prostaglandin," of Chemburkar et. al. (docket no. 2610) and copending patent application ser. no. , titled

"Pharmaceutical Composition," of Gimet et. al. (docket

SUBSTITUTE SHEET no. 2611) , the entire disclosures of which are hereby incorporated herein by this reference.

SHEET

Claims

What is claimed is:

1. A method for treating mild to moderate pain in a subject in need of such treatment, which method provides a desired therapeutic analgesic effect, the method comprising the step of administering to the subject: an analgesic agent selected from diclofenac, ibuprofen, piroxicam and their pharmaceutically acceptable salts, in a dosage of the analgesic agent which dosage by itself would provide less than the desired therapeutic analgesic effect; and misoprostol in a dosage which is sufficient to potentiate the analgesic effect of the analgesic agent to the desired therapeutic analgesic effect.

2. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent is selected from diclofenac in a dosage up to about 200 mg per day, ibuprofen in a dosage up to about 3200 mg per day, and piroxicam in a dosage up to about 20 mg per day; and the prostaglandin misoprostol is present in an analgesic-agent-potentiating effective dose up to about 1600 meg per day.

3. A method for treating mild to moderate pain as recited in claim 2 wherein the analgesic agent is selected from diclofenac in a dosage up to about 100 mg per day, ibuprofen in a dosage up to about 1200 mg per day, and piroxicam in a dosage up to about 20 mg per day; and the prostaglandin misoprostol is present in an analgesic-agent-potentiating effective dose up to about 800 meg per day.

SUBSTITUTE SHEET

4. A method for treating mild to moderate pain as recited in claim 1 wherein the prostaglandin misoprostol is administered in an analgesic- agent-potentiating effective dose from about 25 meg to about 1600 meg per day.

5. A method for treating mild to moderate pain as recited in claim 1 wherein the prostaglandin misoprostol is administered in an analgesic- agent-potentiating effective dose up to about

1600 meg per day and wherein the weight ratio of diclofenac to misoprostol is at least 3:1, the weight ratio of ibuprofen to misoprostol is at least 5:1, and the weight ratio of piroxicam to misoprostol is at least 1:1.

6. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent comprises diclofenac administered in an amount up to about 200 mg per day; and wherein the prostaglandin misoprostol is administered in an analgesic-agent-potentiating effective dose up to about 1600 meg per day and the weight ratio of diclofenac to misoprostol is at least 3:1.

7. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent comprises ibuprofen administered in an amount up to about 3200 mg per day; and wherein the prostaglandin misoprostol is administered in an analgesic-agent-potentiating effective dose up to about 1600 meg per day and the weight ratio of ibuprofen to misoprostol is at least 5:1.

8. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent comprises piroxicam administered in an amount up

SUBSTITUTE SHEET to about 20 mg per day; and wherein the prostaglandin misoprostol is administered in an analgesic-agent-potentiating effective dose up to about 1600 meg per day and the weight ratio of piroxicam to misoprostol is at least 1:1.

9. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent and the misoprostol are administered simultaneously.

10. A method for treating mild to moderate pain as recited in claim 1 wherein the analgesic agent and the misoprostol are administered concomitantly.

11. A method for treating mild to moderate pain as recited in claim 1 wherein the administration is performed by oral administration.

12. A pharmaceutical composition useful for achieving a therapeutic analgesic effect in the treatment of mild to moderate pain in a subject in need of such treatment, the composition comprising: an analgesic agent selected from diclofenac, ibuprofen and piroxicam in a dosage of the analgesic agent which dosage by itself would provide less than the therapeutic analgesic effect; and misoprostol in a dosage which is sufficient to potentiate the analgesic effect of the analgesic agent to the therapeutic analgesic effect.

13. A pharmaceutical composition as recited in claim 12, wherein the analgesic agent is selected from diclofenac in a dosage up to about 75 mg, ibuprofen in a dosage up to about 800 mg, and piroxicam in a dosage up to about 20 mg; and wherein the prostaglandin misoprostol is present in an analgesic-agent-potentiating effective dose up to about 200 meg.

14. A pharmaceutical composition as recited in claim 13, wherein the analgesic agent is selected from diclofenac in a dosage up to about 25 mg, ibuprofen in a dosage up to about 200 mg, and piroxicam in a dosage up to about 10 mg; and wherein the prostaglandin misoprostol is present in an analgesic-agent-potentiating effective dose up to about 200 meg.

15. A pharmaceutical composition as recited in claim

14 comprising diclofenac in an amount from about 0.7 mg to about 25 mg.

16. A pharmaceutical composition as recited in claim

15 comprising misoprostol in an amount from about 5.0 meg to about 200 meg.

17. A pharmaceutical composition as recited in claim 14 comprising ibuprofen in an amount from about

5.33 mg to about 200 mg.

18. A pharmaceutical composition as recited in claim 17 comprising misoprostol in an amount from about 5.0 meg to about 200 meg.

19. A pharmaceutical composition as recited in claim 14 comprising piroxicam in an amount from about 0.15 mg to about 10 mg.

SUBSTITUTE SHEET

20. A pharmaceutical composition as recited in claim 19 comprising misoprostol in an amount from about 5.0 meg to about 200 meg.

21. A pharmaceutical composition as recited in claim 12, wherein the analgesic agent is selected from: diclofenac in a dosage selected from less than 25 mg, greater than 25 mg but less than 50 mg, and greater than 50 mg but less than 75 mg; ibuprofen in a dosage selected from less than 200 mg, greater than 200 mg but less than 300 mg, greater than 300 mg but less than 400 mg, greater than 400 mg but less than 600 mg, greater than 600 mg but less than 800; and piroxicam in a dosage selected from less than 10 mg and greater than 10 mg but less than 20 mg.