PT97563A - METHOD FOR PREPARING A PHARMACEUTICAL COMPOSITION CONTAINING MISOPROSTOL AND AN ANALGESIC AGENT, FOR EXAMPLE DICLOFENAC, AND METHOD FOR THE TREATMENT OF PAIN USING THE REFERENCE COMPOSITION - Google Patents

Description

The present invention is directed to a novel pharmaceutical composition useful in the treatment of pain comprising two active ingredients, namely a non-steroidal anti-inflammatory agent and a prostaglandin, prostaglandin which exhibits analgesic activity. The non-steroidal anti-inflammatory agent may be selected from diclofenac, ibuprofen and piroxicam. Prostaglandin is misoprostol, < +, 1a, 1a-dihydro-9-methyl-9 " OKOprost-13E-en-1-oate. The present invention is also directed to a novel method for the treatment of mild to moderate pain by administering one of the non-steroidal anti-inflammatory agents in an amount which in itself will produce a minor effect than the non-steroidal anti-inflammatory effect analgesic and misoprostol in an amount sufficient to potentiate the analgesic effect of the non-steroidal anti-inflammatory agent up to the desired therapeutic analgesic effect.

Non-steroidal 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 those experienced in inflammatory diseases such as osteoarthritis (OA) and arthritis rheumatoid arthritis (RA). NSAIDs are also widely regarded as having a highly therapeutic value in the treatment of mild to moderate pain. Although NSAIDs have a beneficial therapeutic value, they have also been recognized to exhibit undesirable side effects. A particularly undesirable side effect of administration of NSAIDs is the set of ulcerogenic effects usually associated with their chronic use. In the chronic use of NSAIDs, the use of high dosages of NSAIDs and especially the use of NSAIDs by the elderly can lead to induced ulcers by ΒΑΙΝΕ. Ulcers induced by DAINE in the stomach can be dangerous. Such η r

ulcers exhibit few or minor symptoms and can cause dangerous haemorrhages while they are disliked. The United States Food and Drug Administration requires a class of warnings for all ADLs that you establish. Serious gastrointestinal toxic effects such as bleeding ulcerations and perforations? with or without warning symptoms, in patients treated chronically with NSAID therapy.

Some prostaglandins have been shown to prevent ulcers induced by NSAIDs. The prostaglandin compound commercially available under the name U8AN (United States Footwear Name) of misoprostol is a farro-acceptable prostaglandin which has been accepted for use in the prevention of ulcers induced in many countries. Misoprostol is commercially available by prescription in such countries .

Type E protaglandins are recognized as pain sensitivity modulators. However, the extent e > nature of modulation is not well understood or practicable. "An observation of the scientific literature reveals that the nature and direction of this modulating effect may differ depending on the experimental design and the researcher. Not only PBE ^ but also PGE.-t have been reported for potentiating the behavioral response.

Jm. such (contortion) è. intraperitoneal injection of phenylbenzoquinone

Taiwo and in rats CS »W» L »James and Μ» K. Church, Arzneimittelforschung 59, 804-7 (1978) 3 and to the intra-carotid injection of bradykinin in CT rats. Mikami and K. Miyasaka, J. Pharm. Pharmacol. 51, 85, 7 (1979) 3 after systemic administration. Î ± 8Î ± Î ± has also been reported to potentiate bradykinin-induced contortion in rats by Vialter, T "Chau and B" Vichichman, Agents and Actions 27, 375-7 (1979) 3, for increasing the sensitivity. to damaging mechanical and thermal stimulus following spinal cord administration in CY Taiwo and JD D Levine, J. Neurosis 8, 4

Ρ 1346-9 (1988) 3. Subdermal injection of PBE has been shown to increase the sensitivity of pain sensory fibers (nociceptors), which respond to a variety of CS sensory stimuli. Pateromiche 1 akis, JR Rood, Brain Research 232, 89-96 (1982). However, Sanyal et al. report that PBE can induce an analgesic effect on the rat after peripheral CA administration. K. Sanyal, S. K. Bhattacharya, P. R. Keshary, D. N. Srivastava, P. K. Debnath, Clin. Exp. Pharmacol. Physiol. 4, 247-255 (1977), and intracerebroventricular CA »K« Sanyal, D »N. Srivastava, S» K. Bhattacharya, PR Keshary, P »Reddy, Pu Kr. Debnath, A»! »Sanyal, Clin. Exp. Pharmacol. Physiol. 2, 353-357 (1975). However, these results conflict with an earlier report, which indicates that PSE antagonizes the analgesic effect of morphine CS Ferri, A Santagostino, P Boraga, I Balatulas, Psychopharmacology 35. Î'1-5 (19/4/3.

An observation of these references shows that the effects of PSE on pain sensitivity have been reported to be both (hyperalgesic) and analgesic facilitators. It is therefore impossible to predict the nature of the effects of a PBE analog such as misoprost1 , on the pain response. In view of the unpredictability of any of the analgesic effects of a PSE analogue, it is also unpredictable to calculate the analgesic effect of a prostaglandin PSE2 and non-steroidal anti-inflammatory agent (DAIME), esp. analog of PGE1 on the analgesic activity of i / ΑΙΝΕ. The literature reports that ADlNEs and prostaglandins of type E have opposite effects on sensitivity to CS pain. W. L. James and Μ. K. Church, Arzneimittel-Forschung 28, 804- / (19/8)% V »0-

Taiwo and J.D. Levine. J. Neurosci 8, 1346-9 (1988).

It would be desirable to produce a pharmaceutical composition which exhibits the beneficial properties of an NSAID and which

exhibits the beneficial properties of a prostaglandin to counteract inhibition, reduction or prevention) the undesirable effect of ulcerogenesis, induced by the administration of DAI NE, and? which exhibited marked analgesic activity. Such a composition may thereby provide the same or a greater analgesic therapeutic benefit by using less NSAID b, thereby further decreasing the likelihood of the undesirable ulcerogenic side effect of DAIME due to the lower amount of NSAIDs and the prostaglandin cytoprotective activity . Such a combination will provide an improved NSAID, both for efficacy and safety.

SUMMARY OF THE INVENTION The present invention is directed to a method for the delivery of mild to moderate pain relief analgesia to a patient in need thereof by coadministering or simultaneously administering a non-steroidal anti-inflammatory agent at a dose effective for potentiate the analgesic effect of DAINE. In particular, the present invention is directed to a method for the treatment of mild to moderate pain in a subject in need of such therapy, which method provides a desired therapeutic analgesic effect sufficient to alleviate mild to moderate pain. The method is carried out by administering an analgesic agent selected from the non-steroidal anti-inflammatory agents (DIDES) diclofenac, ibuprofen and piroxicam, or the pharmaceutically acceptable salts thereof, in a dosage which in itself will produce a lesser effect than the effect therapeutic analgesic and administration of misoprostol at an effective dosage which is sufficient to potentiate the analgesic effect of the chosen dosage of the analgesic agent up to the desired therapeutic analgesic effect.

V

This invention 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 and piroxicam, or pharmaceutically acceptable salts thereof, in an amount of analgesic agent which in itself will produce a lower effect than the desired therapeutic analgesic effect. The composition also includes prostaglandin, misoprostols in an amount that is sufficient to potentiate the ringgic effect of the analgesic agent to the desired therapeutic analgesic effect '

Brief Description of the Drawings The method and composition which is the subject of the present invention will be better understood if reference is made to the figures accompanying this specification;

Figure 1 is an isobologratical analysis of the calculated values " of co-administered misoprostol and diclofenac;

I

Figure 5 is an isobologratic analysis of the co-administered calculated ED50 values of misoprostol and ibuprofen;

Fiaure. 3 and 4; an isobologratic analysis of the calculated values of misoprostol and pyroKicam co-administered ™

Figure 4 shows a graphical analysis of misoprostol and diclofenac as admixed showing a comparison of the current versus predicted responses?

Figure 5 is a graphical analysis of co-administered misoprostol and ibuprofen showing a comparison of the current predicted responses: [a is a graph of misoprostol and piroxicam co-administered shows a comparison of the current versus predicted responses; i.e >

Figure 7 is a graphical representation which illustrates the possible dose ranges for misoprostol and an analgesic agent.

Detailed Description of the Invention The present invention is directed to a composition and a method for the treatment of mild to moderate pain in a subject (either human or animal, mammal) in need of such treatment by the administration, either cocomitantly or simu- larly -te5 of misoprostol and a non-steroidal anti-inflammatory agent

The present invention provides a method for the treatment of misoprostol with a compound of the general formula: ## STR1 ## wherein R 1, R 2, R 3, R 4 and R 5 are each independently selected from the group consisting of diclofenac, ibuprofen and pyroxyl, or pharmaceutically acceptable salts thereof. , such that the analgesic agent can be used in a dosage lower than the dosage that would be used if the analgesic agent were used on its own. Administration of misoprostol accentuates the analgesic activity of the analgesic agent by potentiation such that the amount of the agent analgesic administered to obtain a desired therapeutic analgesic effect may be reduced, but the desired therapeutic analgesic effect can be achieved "

The opportunity to use less NSAIDs, especially in combination with an ectoprotective prostaglandin, reduces the likelihood of the undesirable side effect of NSAID inducing an ulcer. In view of the known adverse side effect of incubating ulcerogenesis with the use of NSAIDs, practice of the method and use of the present composition may decrease the likelihood and / or occurrence of such a deleterious side effect, it is also possible that other benefits may derive of the composition and method present. For example, prostaglandins, including misoprostol, have shown anti-inflammatory activity. Therefore, the combination of prostaglandin and DAINE may benefit or increase the anti-inflammatory activity of the combination regimen or co-administration. That is, the combination regimen or co-administration may exhibit a higher anti-inflammatory activity than the administration of the isolated DAINE,

It has been found in the present invention that prostaglandin misoprostol exhibits a potentiating effect on the analgesic activity exhibited by the analgesic agents described above. Misoprostol is illustrated by the following structure formula

and the

In relation to the illustrated structure, the striped line indicates that the group extends behind the plane of the paper line by full, triangular and black indicates that the croup projects from the plane of the paper. the prostaglandin misoprostol may be prepared by known reaction schemes, such as by the methods taught in U.S. Patents 3,965,144, 4,452,949, 4,529,811, and 4,777,275. Individual isomers may be obtained by chromatographic separation , as taught in U.S. Patent 4,661,691.

An effective but non-toxic amount of. prostaglandin is used in the treatment. The dosage regimen for the method of this invention is chosen according to a variety of factors including the patient's type, age, weight, sex and medical condition, route of administration, extent of mild to moderate pain of the patient, and non-steroidal amphiphilatory agent employed. Dosages of misoprostol useful in the present method are in the range of up to 10% pg per day. A preferred range is up to 80æg per day. Larger or larger dosages may be used. According to the above factors, it is preferred to use a dose of misoprostol as small as possible to achieve the desired potentiation of the therapeutic analgesic benefit of the analgesic agent. The lower dose of misoprostol depends on the analgesic agent with which it is to be administered and is balanced in view of the desire to use a low dosage of the chosen analgesic agent. Based on the studies described hereinafter, misoprostol may be used in an amount of from about 5æg to about 20æg per tablet and at a dosage of from about 25æg to about 16ægæg per day. " non-steroidal anti-inflammatory agent " and the term " analgesic agent ", as used herein, include

diclofenac, piroxicam, ibuprofen, and the like are generally acceptable, > The term " effective analgesic therapeutic dosage desires " as used herein means, in relation to the non-steroidal anti-inflammatory agent, the sufficient dose for the communication of the required mild to moderate suppression / relief of dof in a patient in need of such therapy. The specific dose depends on the same factors as noted hereinabove. relation to. dosage of prostaglandin. Determination of the specific dosage for the subject is well within the physician's prescribing physician's prescription. The Pharmaceutical Division lists the daily dosages for various agents non-steroidal anti-inflammatory drugs > The term "mild to moderate pain" is a term accepted and understood by those skilled in the medical art, especially, by trained physicians. Generally, a term like mild pain means a pain that does not cause the modification of the individual's behavior and a moderate pain means a pain that will cause modification of an individual's behavior. "Furthermore, a term such as mild to moderate pain refers to a pain for which a physician would prescribe the general class of DftlNEs as an analgesic agent for pain relief." Although pain is a subjective condition , physicians are trained to assess the overall condition, history, and description of the patient's level of discomfort, in order to assess, and thereby to diagnose, the extent of pain. Following this observation and evaluation, the physician may prescribe the dosage and dosage regimen of the desired analgesic, dosage which the analgesic agent is below may be present in any amount t is acceptable amount, when such agent is administered alone. The analgesic in such dosage for Physician''5 Sesk Risf erance, 44§

Edition, states that the recommended dosage of diclofenac for the treatment of osteoarthritis is iô® at 15® μα per day in divided doses. For the treatment of rheumatoid arthritis, the recommended dosage is 15 to 2 μg per day in divided doses. For the treatment of ankylosing spondylitis the recommended dosage is 1® to 125 pg per day in divided doses. Currently, diclofenac is commercially available by prescription in tablets containing 25, 25 and 75 mg and is administered in prescribed dosage ranges using these 25 mg, 5 mg and 75 mg tablets. The present pharmaceutical composition may comprise up to about 75 mg of diclofenac. Such an amount up to 75 mg may produce an analgesic effect up to or greater than that produced by the larger commercially available amount of 75 mg. In a preferred practice of the present invention, the composition may contain up to but less than 25 mg of diclofenac and exhibits the same or better therapeutic analgesic effect as the standard commercially available 25 mg tablet. The composition may contain up to but less than 25 mg of diclofenac. which is 5Θ mg or greater than 25 mg but less than 5 mg of diclofenac and exhibits the same or better therapeutic analgesic effect than the current commercially available 5 mg tablet. The composition may contain up to but less than which is 75 mg or greater than 5 mg but less than 75 mg diclofenac and exhibits the same or better therapeutic analgesic effect than the current commercially available tablet of 75 mg. Preferably the pharmaceutical composition includes a dosage of up to about 25 mg. An amount up to 25 mg is desirable since it is less than the lowest available amount but is an amount which can provide the same or better therapeutic analgesic effect than the commercially available 25 mg tablet. Such a dosage provides an advantage which can produce a therapeutic benefit using a relatively low dosage of DAINE. Various excipients may be combined with diclofenac as is well known in the pharmaceutical art, with the proviso that such excipients do not show a destabilizing effect on prostaglandin. For the practice of the present method, diclofenac may be administered in an amount of up to about 20 mg per day and preferably in an amount of up to about 10 mg per day in divided doses or in a single dose. For the practice of the present method, commercially available diclofenac creatine tablets may be administered. DAINE may be piroxicam. Current and commercially available piroxicam capsules contain either mg or 2 mg of piroxicam. The PDR, 44th Edition, recommends that piroxicam be administered in a single daily dose of 2 mg for rheumatoid arthritis and osteoarthritis. The pharmaceutical composition present may contain up to 20 mg and preferably contains less than 10 mg piroxicam. The use of an amount up to 20 mg may provide an analgesic therapeutic benefit equivalent to or greater than a dosage of 2 μg piroxicam alone. Similarly, use of an amount up to i mg may provide a therapeutic benefit analgesic equivalent or greater than a dosage of 10 mg of piroxicam per se, wherein 1 mg is the lowest dosage now commercially available. In a preferred practice of the present invention, the composition may contain up to but less than , 1 mg of piroxicam and exhibits the same or better therapeutic analgesic effect than the current commercially available tablet of 1 mg The composition may contain up to but less than 2 mg or more than 1 mg or less than 2 mg of piroxicam and exhibits the same or better therapeutic analgesic effect than the tablet

commercially available 20 mg stream. * Various excipients may be present with the proviso that such excipients do not exhibit a destabilizing effect, either on pyroxioam? either on prostaglandin. For the practice of the present method, piroxicam may be administered in an amount of up to about 20 mg per day and preferably in an amount of up to about 1000 mg per day in either divided doses or in a single dose. For the practice of the present method, commercially available piroxicam tablets can be administered. ► DAINE may be ibuprofen. Ibuprofen is available in the form of an analgesic agent sold directly without a prescription in 200 mg tablets. Ibuprofen is available by prescription in tablets containing 300, 400, 000 mg of ibuprofen. PDR, 44th Edition, recommends that ibuprofen be given in dosages of 200 mg to 3200 mg daily for rheumatoid arthritis and for osteoarthritis? at 400 mg dosages every 4 to 6 hours as needed for mild to moderate pain relief? and in dosages 400 mg

all 4 hours for dysmenorrhea. The PDR establishes. In controlled clinical analgesic trials, doses greater than 40 mg were not effective than the 400 mg dose. The present pharmaceutical composition may comprise up to 800 mg ibuprofen and, preferably, < up to 200 mg ibuprofen. An amount up to 8-60 mg may provide a therapeutic equivalent analgesic benefit greater than the use of 800 mg ibuprofen for use of up to 200 mg may provide an anaerobic benefit In a preferred practice of the present invention, the composition may be up to but less than 200 mg of ibuprofen and exhibits a better therapeutic effect than the commercially available 200 mg tablet. The composition may contain up to but less than 3 mg or greater than 200 mg less than 3 mg of ibuprofen and and> the same or better therapeutic analgesic effect than the usual commercially available 300 mg tablet. The composition may contain up to but less than 4.0 mg or more than 300 mg but less than 400 mg of ibuprofen and exhibits α m The composition may contain up to but less than 600 mg or more than 400 mg but less than 600 mg of ibuprofen and exhibits the amount of the active compound. even or better therapeutic analgesic effect than the commercially available tablet current of 600 mg. The composition may contain up to but less than 60 mg or more than 60 mg but less than 800 mg of ibuprofen and exhibits the same or better therapeutic analgesic effect than the commercially available active tablet of 800 mg. A number of excipients may be present provided such excipients do not exhibit a destabilizing effect on either ibuprofen or prostaglandin. For the practice of the present method, ibuprofen may be administered in an amount of up to about 3200 mg per day and , preferably in an amount up to about 120 mg per day either in divided doses or in a single dose. For the practice of the present method, commercially available ibuprofen tablets can be administered.

Regardless of the route of administration chosen, the present misoprostol, DAINE or composition may be formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art. For the purposes of the practice of the present method the commercially available forms, formulations and compositions of the NSAIDs and misoprostol may be used. Similar formulations but with smaller amounts of the NSAIDs may be used in the practice of the present invention. A particularly preferred formulation misoprostol is taught in US Patent 4,141,146. Misoprostol, DAINE or present composition may be administered in dosage forms such as tablets, capsules, pills, powders or granules. They may be administered intraperitoneally, sufacuteurally or intramuscularly, using forms known in the pharmaceutical art. In general the preferred form of administration is oral. An advantage of the present method and composition is that misoprostol is an orally available prostaglandin and can be formulated into orally available dosage forms. An advantage of oral availability is that the method of administration is easy to follow and does not require specialized medical professional care The availability of the oral form is also an accepted method of treatment for mild to moderate pain relief. The present method is carried out by the administration of a non-steroidal anti-inflammatory agent and misoprostol to the patient in need of such therapy the dosage forms and the dosages set forth herein. The two components may be added concomitantly or similarly to the order of administration of the two non-active ingredients, although it may be beneficial to administer misoprostol in the first place , to benefit from cytoprotective properties in preventing ulcers will be induced by a DAIME 'mind-A particularly preferred manner of treatment is the co-administration of the two active ingredients in a unit dosage form such as a tablet or capsule. The sequence and time of performing the steps of the present method are well within the knowledge of a physician prescribing an analgesic regimen,

The dose selection of DAINE and misoprostol may be further understood by taking into account the graph shown in Figure 7. Figure 7 shows a graph of the dosage of DAINE versus dosage of misoprostol. The dosage for the DAINE is plotted on the YY axis and the dosage for misoprostol is plotted on the x-axis. D point represented by A on the XX axis is the minimum effective amount of misoprostol which potentiates the analgesic activity of an NSAID, which amount is about 25 micrograms or. pg 5 per day or about 5 pg per tablet. The point represented by B on the YY axis is the maximum tolerable daily dosage for misoprostol, which was found to be high as Ι6Θ p pg per day. Edition, states that cumulative daily doses of 160 Âμg have been tolerated by humans only with symptoms of gastrointestinal discomfort to be reported. Therefore, it is preferable to use 160 Âμg daily and possible when administered. A misoprostol amount of up to about, preferably, a low as well as balanced dosage for the dosage of DAINE PDR also states that the oral dose recommends

(an 8 'D. Searl and Co mark for misoprostol) for the prevention of gastric ulcers induced by DESsine is 2 pg four times daily with feed, thereby providing a recommended daily dosage of 8ΦΦ pg.

The points along the XX axis will be described in general terms since the specificities of the locations of such points will depend on the chosen DAINE. The point represented by C on the YY axis is the minimum dosage of a DAINE which will provide a therapeutic benefit in the relief of soft to moderate pain. The dot represented by D in the graph is the maximum dosage of a DAINE. The dot represented by E is the combined dosage for DAINE and misoprostol and represents the activity for the minimum dosage of DAINE s minimal dosage of misoprostol . The point represented by F is the intersection of the extended lines from the lowest dosages for both misoprostol and ΒΑΙΝΕ. ft EF line represents the line that will be formed interconnecting the minimum dosages for misoprostol and DAI NE in combination for. the values ED, and g, ED50, ED50, ED50, etc. The area bounded by the lines A8 F D C A represents the pharmaceutically acceptable dosages for the combination of misoprostol and a Ε. The area bounded by line E F D C E represents the preferred dosages for the combination of DAI NE and misoprostol, insofar as such an area represents the highest analgesic activity with the minimum acceptable dose of misoprostol. For each of the NSAIDs present, such an area is reflected in a range of DAINE for misoprostol from 3æl to diclofenac, 5æl for ibuprofen and from 1æl to pyrimidine. The effectiveness of the present method has been demonstrated by of animal models. Animal model studies are well analgesic, from compounds et al., &Quot; Prediction of Antin-1 Immunizing Drugs. &Quot;, Arch, Int. Pharma- accepted for the evaluation of chemical activity, as shown in Pong

Human Analgesic Dosages of Nonsteroidal

NSAIDs) from Analgesic ED, Values in H J + 273, 212-22® < 1985) 5 Otterness et al, Journal of

Pharmaceutical Sciences, Vol. 77, M9 9, September 1988, pp 79Θ-7955 and Dubinsky et al., Agents and Actions, Vol., 1/2 (1987), pp. 60-60. The effectiveness of the present composition for use in the treatment of mild to moderate pain has been shown in the rat phenyl-benzoquinone-induced writhing test. This model is widely used as a screening of the primary in vivo efficacy for the detection of a wide variety of analgesic agents

Diclofenac · [Co-256-dichlorophenylaminophenyl] sodium acetate * is an NEI DAI which exhibits an Eu · value in this rat contortion assay of 2. mg / kg. The following Example illustrates the effect of misoprostol and NSAIDs present on pain relief in the rat contortion assay.

Example 1 > Method for the Contortion Test in the Mouse because a value of 4.3 mg / kg ical Properties of Di clofenac is present in this assay. d. Rheuma tology 22 Csupl.),

This experiment is recognized for the screening of compounds for use as analgesic agents. Diclofenac has been reported in the literature following oral administration, t.gif, tisnasse et al. , " Pharmacolc Sodium and its Metabolites ", Bear 5-165 1,978. In this experiment, the ability of misoprostol, some NSAIDs and misoprostol combinations with such NSAIDs, to suppress the chemically induced contortion response in rats was determined.

Male albino rats (Charles River Laboratory, CD-2, -3 €> g) were randomly divided into groups of ten and heavy. Twenty-five minutes after the intragastric administration (i.e.) of the test compound, phenylbenzoquinone (PBMC), 0.25% w / v was injected intraperitoneally (i.e., 1 ml / l grams of body weight). Five minutes after injection of PBQ, each animal was placed in a large glass wide mouth glass and counted within the next ten minutes of the number of writhes that occurred. A contortion consists of a back pain, extension of the hind limbs, and strong contortion of the abdominal musculature. The test compounds were considered to have significantly inhibited the writhing response when the number of observed writhes was less than which is equal to half the mean number of writhes recorded for the same day control group CTaber, R, I, " Predxctive Value of Analgesia Assays in Mice and Rats ", Advances in Biochemical Psychopharmacology, vol. 8, p. The effective dose (ED50) which inhibited 50% of the writhes, as compared to the control values, was determined by a regression analysis by the method of Based on these results, an estimate of the number of writhes for each drug at various dosage levels could be determined. If a statistical prediction is made for the additive effects of various combinations of misoprostol and NSAIDs. The differences between the number of predicted and actual writhes were calculated.These differences were analyzed for their significance using a t-test.Isoobologratic analysis was used to determine if the current effect of the combinations of the two drugs was additive, synergistic or antagonistic CCriteria For Analyzing Interactions Between

Biologically Active Agent ", M. C. Berenbaum; Advances in Cancer Research, vol. 25, pp 269-335 (1981).

In a simplistic way, this method of analysis is performed by first determining the EB? Values. for the two agents separately and plotting on these values on separate bells. A line is drawn between the two values, which line represents the line of additivity of the theoretical dose. The pharmacological effects of the two drugs when co-administered are added together, then any dose combination represented by a dot on the line produces an efficacy of ED50. The next step in the analysis was the evaluation of a series of dose combinations and the identification of combinations

are that they will give rise to a response of EDr-1 "values are plotted on graph." If values stay on the line, then drugs are additive. If the values are in the inner part of the line (to the source side) then the effects are super-additive, that is, they synergize with each other to produce a much greater effect than the one predicted. If the valves are outside the line, then the two drugs are infra - additive, which means that the effect of the combination is less than expected. As can be seen from the graphs of the isobolography in Figures 1 through 3 which depict graphically the results of the present experiments, the combinations studied herein, and which comprise the present invention, are within the lines. The isobolograms for the combination of misoprostol with diclofenac, piroxicam and ibuprofen all show that the values determined empirically are within the range of additivity and therefore synergize

In relation to Figure 1, the isobolo- gical analysis of misoprostol and co-admi- nistrated diclofenac is shown. ED 50 for diclofenac alone was 1.8 mg / kg. The ED50 for misoprostol alone was 3.5 mg / kg. The isoborphic analysis shows that one for misoprostol and diclofenac co-administered. could be obtained using 0.05 mg / kg diclofenac with Θ, Φ'Ζ mg / kg misoprostol. This represents a 36-fold decrease of the EEW value 50 50

Referring to Figure 2, an isoborphic analysis of misoprostol co-administered with diclofenac is shown, based on the results of the mouse writhing assay. As can be seen from the graph, ED50 for misoprostol is 0.6 mg / kg and for ibuprofen it is 3 mg / kg. When ibuprofen was co-administered with misoprostol, misoprostol was present in an amount of 0.01 mg / kg. Ibuprofen was present in an amount of ®8 mg / kg. Q ibuprofen exhibited a decrease of about 38æ fold in the dose. I mean, 1/38 of that. the amount of ibuprofen can be used when it is co-administered with misoprostol in order to thereby achieve the same analgesic activity as would be predicted for a 38-fold higher dose. Figure 3 represents the isobologratic analysis of misoprostol co-administered with piroxicam. Misoprostol is plotted on the XX axis and piroxicam is plotted on the YY axis. As can be seen from Figure 3 and the results of the mouse contortion assay performed using misoprostol co-administered with pyroxam-cam, there was a decrease of about 87-fold in the amount of piroxicam required when combined with ®9 mg / kg misoprostol "

The graphs shown in Figures i-3 also show that there was about a 30-fold increase in the analgesic effect of misoprostol when combined with any of the DAXNEs. Hand taking into account the chosen DAINE, a thirty-fold increase in such effect was observed. The amount of misoprously chosen to be used in the combination or present method may be 1/3 of the amount that would normally be prescribed if prescribed alone without the presence of an NSAID.

The results were further analyzed statistically 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 isolated DAINE were used to calculate the predicted level of answer for each. one of several dose combinations studied. A determination was made of the difference between the current and

predicted The difference showed that the actual values were statistically clearly different from those predicted. Figures 4 to 6 show the graphical representation of the difference in the predicted response versus the observed response to the combined dosages of misoprostol and NSAIDs. The results of the mouse contortion assay that were performed for misoprostol for the various NSAIDs and for the misoprostol combinations with the NSAIDs chosen are shown in Table 1. > QUftPRO 1

Compound Emg / kgj Results ED, -, v

Misoprostol 0? 3 02 / 1Θ 0.60 15θ 07/10 10.0 10/10 Diclofenac 1.00 03/10 1.8 © 3.00 06/10 10.00 10/10 Misoprostol + 0.003 + 0.01 02/10 0.010 4 1.0 Diclofenac 0.003 + 1.00 03/1 0 ^ 020 + 0.01 0 j 030 + 0.01 06/10 0.060 4 0.1 0.030 + 0.10 04/10 0.30 4 0,004 0 ^ 030 4 * 1.00 66/09 0,300 + 0,01 06/10 0,300 • f 0,10 07/10 0,300 + 1.00 08/10 3,000 + 1.00 09/10 Ibuprofen 10.0 09/10 3.0 3.0 05/10 1.0 01/10 Misoprostol + 0.3 4 1.5 08/10 0.015 4 0.076 IbLiprofen 0.03 4 0.15 06/10 0.001 4 0.005 02/10 Piroxicam 10.0 10/10 0.6 3.0 09/10 1.0 06 / 1Θ 0.3 03/10 Misoprostol + 0.3 + 0.3 10/10 0.008 + 0.008 Piroxicam 0.03 4 0.03 05/10 0.001 4 0.001 03/10 24

These studies show that there is clear evidence of the accentuation of analgesic activity between misoprostol and non-steroidal antiinflammatory agents. The use of the present method may accentuate the analgesic effect of a mild to moderate pain relief regimen which includes administration of a non-steroidal anti-inflammatory agent. The method may therefore provide the desired extent of pain relief using a lower dose of the non-steroidal anti-inflammatory agent. The method may therefore reduce the incidence of gastrointestinal side effects of anti-inflammatory agents non-steroidal. The use of an amount of DAINE that is less than and normal amount that should be prescribed, i.e., the amount is significant over normal therapy, Current C DAI therapy regimen To date, prostaglandins have been shown to be useful in adjunctive therapy with normal therapeutic dosages of NSAIDs in order to decrease the ulcerogenic side effects of NSAID administration. The present improved method compositions are beneficial in that they provide the opportunity to use less DAINE (lower dosage) than previously thought to be therapeutic. Combination of a DAINE with misoprostol creates an attractive therapy for the relief of mild to moderate pain. The present invention, which employs a prostaglandin potentiating the analgesic effect of a particular DAIME (one that is capable of interacting with a potentiating prostaglandin to produce an enhanced analgesic effect) in an amount effective to potentiate this effect, is especially beneficial in reducing the amount of DAINE administered because it reduces the likelihood of ulcer formation by helping to cure ulcers (if

formed) and by alleviating the. mild to moderate pain. which was administered.

In the formulation of the present composition, the formulation may be formed into a blend, as disclosed in copending US Patent Application Serial No. 1- et al. " ref. No. 269), or in a tablet as disclosed in copending Patent Application Serial No. ----, entitled " Pharmaceutical Composition Containing Ibuprofen and a Prastaglanidine " 5 of Chemburkar et al. &Quot; ref "nS 2fct® > and Patent Application

Copper with ο Serial N9--, with the title " Composition

Pharmaceutical ", by Gimet et al. (ref. No. 2611), the disclosures of which are hereby incorporated by reference herein, and incorporated by reference herein, >

Claims (3)

Re di v a n t in a subject in a method for the treatment of mild to moderate pain! The present invention relates to a method of treatment comprising administering to a subject in need of such treatment, which method produces an effect by comprising the desired therapeutic analgesic, a method of administration to the subject of; ado an analgesic agent selected from diclofenac, ibuprofen, pyrocarboxylic acid and its pharmaceutically acceptable salts, in a dosage of the analgesic agent which in itself will produce a lesser effect than the therapeutic analgesic effect provided? and misoprostol at a dosage which analgesic effect of the agent is sufficient to potentiate the analgesic to the desired therapeutic analgesic effect. A method for the treatment of mild to moderate pain of claim 1, comprising the agent selected from diclofenac, in a dosage up to per day, ibuprofen in a dosage of up to about according to the analgesic is about 2 €> 32 mg per day, and pyrogenic, at a dosage of up to about 20 mg per day. and that the prostaglandin misoprostol is present in an effective dose which potentiates the analgesic agent to about 16% pg per day 31. A method for treating mild to moderate pain according to claim 2, wherein the analgesic agent is selected from diclofenac in a dosage of up to about 3,000 mg per day, ibuprofen, in a dosage of up to about 12 Âμg per day, and pyrogenic, at a dosage of up to about 2 Âμg per day? and the prostaglandin misoprostol is present in dose effective potency, analgesic agent to about 0.1% per day. 4â. A method for the treatment of mild to moderate pain according to claim 1, characterized in that the prostaglandin misoprostol is administered in an effective dose which potentiates the analgesic agent from about 25æg to about 10æg per day. . A method for the treatment of mild to moderate pain according to claim 1, characterized in that the prostaglandin misoprostol is administered in an effective dose which potentiates the analgesic agent to about 16 Âμg per day and the weight ratio diclofenac to misoprostol is at least 3%, the weight ratio of ibuprofen to misoprostol being at least 5% of the pyrazolam moiety ratio to misoprostol being at least 1: 1. > 6. A method for treating mild to moderate pain of claim 1 wherein the analgesic agent comprises diclofenac administered in an amount of up to about 20 mg per day and in that the prostaglandin misoprostol is administered in an effective dose which potentiates the analgesic agent to about 16% pg per day and the weight ratio of diclofenac: to misoprostol is at least 3%. 7â. Method for treating mild to moderate pain according to claim 1. characterized in that the analgesic agent comprises ibuprofen administered in an amount of up to about 32 mg per day; and in that the prostaglandin, misoprostol is administered in an effective dose which potentiates the analgesic agent to about 16æg per day and the weight ratio of ibuprofen to. be misoprostol skin? less than 5æl, 28g. A method for the treatment of mild to moderate pain according to claim 1, characterized in that the analgesic agent comprises pyroalkyl administered in a ratio of up to about 20 mg per day. and in that the prastaglandin misoprostol is administered in an effective dose which potentiates the analgesic agent to about p pg per day and the weight ratio of pyroxyl bed to misoprostol to at least 1: 1. 9a. A method for the treatment of mild to moderate pain according to claim 1, characterized in that the analgesic agent and misoprostol are administered simultaneously. 10. A method for the treatment of mild to moderate pain according to claim 1, wherein the analgesic agent and misoprostol are administered concomitantly. lane. A method of gentle treatment for moderating the pain according to claim 1, characterized in that a. administered by oral administration. 12â. A process for the preparation of 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, characterized in that an analgesic agent selected from diclofenac, ibupro- hay, piroxicam in a dosage of the analgesic agent which in itself will produce a lesser effect than the therapeutic analgesic effect; and misoprostol in a dosage which is sufficient to potentiate the analgesic effect of the analgesic agent until the therapeutic analgesic effect. 131. The method of claim 12, wherein the analgesic agent diclofenac in a dosage to about to be selected from 75 mg, ibuprofen, in a dosage to about 800 mg, and piroxicam, in a dosage to about > of 2 mg; and in that the prostaglandin misoprostol is an effective dose which potentiates the analgesic agent to be preferably up to about 200 μg. 14. A process according to claim 13, characterized in that: the analgesic agent is dosed to about the chosen one of diclofenac in a: 5 mg, ibuprofen in a dosage to about 20 mg, and piroxicam in a dosage of up to about 1 €> mg and the prostaglandin misoprostol is present in an effective dose which potentiates the analgesic agent to about 2 Âμg " character dichlofen 15. A process according to claim 14 wherein a composition is prepared comprising in an amount of from about 7.0 mg to about ng. 16. A composition according to claim 15 for preparing a composition comprising misoprostol in an amount of from about 200 μ. 5.0 pg to about 17Â ° C. Process according to Claim 14, characterized in that the monohydrate is prepared in an amount of from about 100 mg to about 200 mg. The composition of Claim 17, wherein the composition comprises comprises misoprostol in an amount of from about 5, A process according to claim 14 for preparing a composition comprising pyroalkyl in an amount of from about 0.15 mg to about 10 mg. 20a. A process according to claim 19, characterized in that a composition comprising misoprostol is prepared in an amount from about 5.0 μα to about 20 μg, 21a. A method according to claim 12, wherein the analgesic agent is selected from diclofenac at a dosage chosen of less than 25 mg, more than 25 mg but less than 50 mg and more than 50 mg less than 75 mg ibuprofen, at a dosage chosen of less than 200 mg, more than 200 mg but less than 300 mg, more than 30 mg but less than 40 mg more than 400 mg less than 600 mg and more than ΘΦ mg but less than ΘΘΘ mg 5 and than at a chosen dosage of 11- mg and may be less than 20 mg but less than 20 mg. J. PEREIRA DA CRUZ Official Agent of Industrial Property RUA VICTOR CORDON, 10-A 3rd 1200 USBOA