United States Patent (19) 11 Patent Number: 4,722,938 Sunshine Et Al

United States Patent (19) 11 Patent Number: 4,722,938 Sunshine et al. (45. Date of Patent: Feb. 2, 1988

(54 METHODS FOR USING 82,717, copy of patent and English translation thereof; MUSCULOSKELETAL RELAXANTS (10/83). Rego, "Mio-Relaxantes No Tratmento Das Lombalgias 75 Inventors: Abraham Sunshine, New York; Agudas E Das Lombo-Ciaticas Recentes'Muscle Re Eugene M. Laska, Larchmont; laxants in the Treatment of Acute Lumbalgias and Re Carole E. Siegel, Mamaroneck, all of cent Lumbo-Sciatica Cases, Acta Reumatologica Por N.Y. tuguesa, II, 2:363-364, (1974), copy of the original and English translation thereof. 73 Assignee: Analgesic Associates, Larchmont, Schror, "Analgetisch-Antiphlogistische Therapie Von N.Y. Schmerzzustanden des Bewegungsapparates'Anal 21 Appl. No.: 815,502 gesic-Antiphlogistic Therapy of Locomotor System Pain), Therapiewoche, 28, 5657-5663, (1978), copy of the (22 Filed: Jan. 2, 1986 original and English translation thereof. Schar, "Medikamentose Behandlung von Lumbois Related U.S. Application Data chialgien'Drug Treatment of the Lumbago-Sciatic Syndrome), Schweiz, Rundschau Med. (Praxis), vol. 68, 63 Continuation of Ser. No. 686,380, Dec. 26, 1984, aban No. 5, pp. 141-142, (Jan. 30, 1979), copy of original doned. article and English translation thereof. 51 Int. Cl...... A61K 31/19; A61K 31/27 Kolodny and Klipper, "Bone and Joint Diseases in the Elderly', Hospital Practice, pp. 91-101, (Nov. 1976). (52) - O - 514/479; 514/568 Nascimento, "Use of an Association Containing an An 58 Field of Search ...... 514/568, 479 algesic, a Muscle Relaxant and Vitamin B Complex in (56) References Cited Degenerative Joint Diseases, Extra-Articular Rheu matic Ailments and Traumatic Afflictions', F med, FOREIGN PATENT DOCUMENTS (BR), 83(3):361-363, (1981), original article and English 2121529 12/1971 France. translation thereof. Repschlaeger and McPherson, "Classification, Mecha OTHER PUBLICATIONS nism and Management of Headache", Clinical Phar Armas & Valencia, "Eficacia Terapeutica de la Asocia macy, vol. 3, pp. 139-150, (Mar.-Apr. 1984). cion Naproxen-Carisoprodol en Ciertas Enfermedader Musculoesqueleticas"Therapeutic Effectiveness of Na Primary Examiner-Stanley J. Friedman proxen-Carisoprodol Association in Certain Musculo Attorney, Agent, or Firm-Burns, Doane, Swecker & skeletal Disorders, in Investigation Medica Interna Mathis cional, pp. 350-356, (1983), and English translation (57) ABSTRACT thereof. Novel pharmaceutical analgesic, anti-inflammatory and Goti & Valencia, "Caracterizacion Clinica de Una skeletal muscle relaxant compositions and methods of Nueva Asociacion (Naproxen -- Carisoprodol) en using same comprising an analgesically and anti-inflam Padecimientos del Aparato Musculoesqueletico'Clini matory effective amount of at least one non-steroidal cal Description of a New Association (Naproxen -- anti-inflammatory drug other than aspirin, acetamino Carisoprodol) in Ailments of the Musculoskeletal Ap phen and phenacetin, in combination with an effective paratus, Investigation Medica Internacional, pp. amount of a skeletal muscle relaxant. 475-478, (1983), and English translation thereof. Socialist Republic of Romania Description of Invention 19 Claims, No Drawings 4,722,938 1. 2 and diarrhea. Allergic type reactions associated with METHODS FOR USENG MUSCULOSKELETAL aspirin may also involve the respiratory tract and skin. RELAXANTS Another commercial skeletal muscle relaxant formu lation is Parafon Forte (R) by McNeil Pharmaceutical. This application is a continuation of application Ser. 5 Parafon Forte contains 250 mg chlorzoxazone and 300 No. 686,380, filed Dec. 26, 1984, now abandoned. mg acetaminophen. ChlorZoxazone is a centrally-acting agent which does not directly relax tense skeletal mus BACKGROUND OF THE INVENTION cles in man. Acetaminophen, a nonsalicylate analgesic, 1. Field of the Invention is a conventional non-narcotic analgesic with anti The present invention relates generally to novel phar 10 pyretic activity. maceutical compositions of matter comprising one or Robaxisal (R) by A. H. Robins Company, Inc. is an more non-steroidal anti-inflammatory drugs in combi other commercial muscle relaxant formulation which nation with at least one skeletal muscle relaxant, and to contains 400 mg methocarbamol and 325 mg aspirin. methods of using said compositions in the treatment of The mechanism of action of methocarbamol in humans a variety of skeletal muscle disorders including skeletal 15 has not been established, but may be due to general muscle spasms, certain orthopedic conditions, disk syn central nervous system depression. Methocarbamol dromes, low back pain and the like. does not directly relax tense skeletal muscles in man. 2. Description of the Prior Art Adverse reactions that have been associated with aspi Centrally acting skeletal muscle relaxants are gener rin in this formulation include: nausea and other gastro ally prescribed either as single agents or as components 20 intestinal discomfort, gastritis, gastric erosion, vomit of combination products. The Food and Drug Adminis ing, constipation, diarrhea, angioedema, asthma, rash, tration has approved indications for these medications pruritis and urticaria. as adjuncts to rest and physical therapy for relief of Norgesic (E) and Norgesic (R) Forte are commercial acute, painful musculoskeletal problems. Clinically, the products by Riker Laboratories, Inc. that contain a mild pain associated with the majority of cases of minor 25 muscle relaxant, aspirin and caffeine. The specific for muscle strains and minor injuries is self limiting. Most mulation for Norgesic is 25 mg orphenadrine citrate, patients usually respond rapidly to rest. An anti-inflam 385 mg aspirin and 30 mg caffeine. Norgesic Forte matory drug may be useful when there is considerable contains 50 mg orphenadrine citrate, 770 mg aspirin and tissue damage and edema. On the other hand, severe 60 mg caffeine. Orphenadrine citrate is 2-dime musculoskeletal strains and sprains, trauma, and cervi 30 thylaminoethyl 2-methylbenzhydryl ether citrate. The cal or lumbar radiculopathy as a consequence of degen common side effects and concerns associated with the erative osteoarthritis, herniated disk, spondylitis or lam use of aspirin occur with the use of Norgesic and Nor inectomy, often cause moderate or severe and more gesic Forte as well. TABLE I Some Combination Products Containing a Skeletal Muscle Relaxant CONTENTS OF A SINGLE TABLET TYPICAL DOSAGE SKELETAL MUSCLE ADDITIONAL PRESENTED AS TRADENAME RELAXANT INGREDIENTS NO. OF TABLETS SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg 1-2 SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg WITH CODENE codeine PO4 16 mg 1-2 PARAFON FORTE Chlorzoxazone 250 mg acetaminophen 300 mg 1-2 ROBAXISAL Methocarbamol 400 mg aspirin 325 mg 2 NORGESC Orphenadrine aspirin 385 mg Citrate 25 mg caffeine 30 mg 1-2 NORGESICFORTE Orphenadrine aspirin 770 mg Citrate 50 mg caffeine 60 mg -l chronic painful skeletal muscle spasm. The principal symptoms include local pain, tenderness on palpation, 50 At the present time, one commercial product, Para increased muscle consistency and limitation of motion. fon Forte, a skeletal muscle relaxant formulation con For these patients skeletal muscle relaxants alone or in taining acetaminophen, will be the subject of a hearing combination with an analgesic are frequently pre granted by the Commissioner of Food and Drugs on a scribed. Results of some studies have suggested that a proposal to withdraw approval of its new drug applica formulation of a muscle relaxant and an analgesic pro 55 tion sometime in 1985. The Director of the Bureau of vides greater benefit in patients with acute musculoskel Drugs of the FDA in a notice published in the Federal etal problems than similar doses of an analgesic alone. Register, 1982, 47 F.R. 22599 concluded that he was Table I lists several commercial combinations avail unaware of any adequate and well-controlled clinical able. A current commercial muscle relaxant formulation investigation conducted by experts qualified by scien is Soma (8) Compound by Carter-Wallace, Inc. which tific training and experience... that demonstrates the contains 200 mg carisoprodol and 325 mg aspirin. Cari effectiveness of Parafon Forte. The present position of soprodol is a centrally-acting muscle relaxant that does the Commissioner of Food and Drugs is set forth below not directly relax tense skeletal muscles in man. Aspirin Federal Register, 1984, 49(200): 48212-482.14): is a conventional non-narcotic analgesic with anti-in flammatory and antipyretic activity. The most common 65 Approval of this NDA will be withdrawn unless adverse reactions associated with the use of aspirin in there exists substantial evidence that Parafon Forte this product have been gastrointestinal, including nau has the clinical effect that it purports or is repre sea, vomiting, gastritis, occult bleeding, constipation sented to have under the conditions of use pre 4,722,938 3 4. scribed, recommended, or suggested in its labeling DETAILED DESCRIPTION OF THE INVENTION It should be noted that all of the previously described More specifically, the applicants herein have surpris skeletal muscle relaxant/non-narcotic analgesic formu- 5 ingly found that certain newer non-steroidal anti-in lations include either aspirin or acetaminophen as the flammatory agents are ideally suited for use in a formu non-narcotic analgesic agent. However, a number of lation with skeletal muscle relaxants by reason of their alternative non-narcotic agents offering a variety of enhanced analgesic anti-inflammatory and antipyretic advantages over these conventionally employed non activity and low incidence of untoward side effects, narcotic analgesic antipyretics have now been devel 10 particularly at the optimum dosages provided for in the oped. These newer non-steriodal anti-inflammatory present invention, in comparison to aspirin or acetami drugs are widely administered orally in the treatment of nophen. mild to severe pain, as well as for a variety of disorders The superiority of various of the non-narcotic analge including rheumatoid and osteoarthritis. Within this sics belonging to the newer non-steroidal anti-inflam class of drugs, the compounds vary widely in their 15 matory drug class in comparative studies with aspirin chemical structure and their biological profiles as anal and acetaminophen is well documented in the literature. gesics, anti-inflammatory agents and antipyretic agents. Cooper in 1977 found that ibuprofen 400 mg had a The principal advantages of these new non-steroidal greater peak effect and longer duration of action than anti-inflammatory drugs include not only the clinically aspirin 650 mg. Cooper, S.A., Needle, A. E., Kruger, superior analgesic and anti-inflammatory activity of 20 G. O. 1977. "An Analgesic Relative Potency Assay these agents compared to aspirin, acetaminophen or Comparing Aspirin, Ibuprofen and Placebo. "J. Oral phenacetin, but also a lessening of the adverse side ef Surg. 35: 898-903. Cooper in another study in 1982 fects experienced with these conventional agents; more found 400 mg of ibuprofen to be more effective than specifically, the gastrointestinal ulcerations and bleed aspirin 650 mg. Cooper, S. A., Engel, J., Ladov, M., ing experienced with aspirin and the hepatic toxicity Precheur, H., Rosenheck, A., Rauch, D. 1982. "Analge prevalent with the use of large doses of acetaminophen. sic Efficacy of an Ibuprofen-codeine Combination.” While aspirin and acetaminophen have been utilized Pharmacotherapy 2: 162-67. Sunshine et al found ibu in those previous compositions, it has not been hereto profen to be significantly superior to aspirin in the relief fore proposed to use any of the newer non-steroidal of post-episiotomy pain. Sunshine, A. et al., Clinical anti-inflammatory drugs (i.e. excluding aspirin, acetami 30 Pharmacology and Therapeutics, 24:254-250, 1983. nophen and phenactin) in combination with skeletal Dionne in 1982 found ibuprofen to be more effective muscle relaxants to achieve more pain relief, a lesser than acetaminophen in delaying the onset and intensity incidence of side effects and thereby a more effective of post operative dental pain. Dionne, R. A., Campbell, treatment of the musculoskeletal disorder. R. A., Cooper, S.A., Hall, D. L., Buckingham, B. "Sup 35 pression of Post operative Pain by Preoperative Admin SUMMARY OF THE INVENTION istration of Ibuprofen in Comparison to Placebo, Acet Surprisingly, the present inventors now find that, the aminophen and Acetaminophen Plus Codeine.” J. Clin. newer non-steroidal anti-inflammatory drugs, which Pharmacol (In press). differ substantially in chemical structure from aspirin, Naproxen sodium 550 mg was compared with 650 mg acetaminophen and phenacetin, and which have signifi of aspirin and was found to provide earlier and better cantly different biological profiles therefrom can be pain relief than aspirin by Sevelius, H., J. Clin. Phar advantageously formulated into a novel composition macol. 20: 480-485, 1980. "Comparative Analgesic Ef together with a skeletal muscle relaxant and adminis fects of Naproxen Sodium, Aspirin and Placebo.' tered to mammals, especially to humans, to obtain more Both flurbiprofen 50 and 100 mg were significantly pain relief and lessened adverse side effects. 45 more effective than aspirin 600 mg. Flurbiprofen 25 mg It is, therefore, a primary object of the present inven was slightly less effective than aspirin 600 mg. Sunshine, tion to provide novel pharmaceutical compositions of A., Olson N.Z., Laska, E. M. Zighelboim, I., DeCastro, matter for use in eliciting an analgesic or anti-inflamma A., Desarrazin, C., Pharmaco Ther. 3: 177-181. "Anal tory and musculoskeletal relaxing response, said com gesic Effect of Graded Doses of Flurbiprofen in Post position comprising an effective analgesic or anti-in 50 episiotomy Pain.” flammatory amount of a newer non-steroidal anti-in Silberman found suprofen 200 mg more effective than flammatory drug and an effective amount of a skeletal aspirin 650 mg for pain relief in the treatment of moder muscle relaxant. Typically, the active ingredients are ate to severe pain resulting from musculoskeletal pain. further associated with a non-toxic pharmaceutically Silberman, H. M. "Multiple-Dose Comparison of Su acceptable inert carrier therefrom. 55 profen, Aspirin and Placebo in the Treatment of Muscu It is a further object of the present invention to pro loskeletal Pain.” Pharmacology 27: S 1, 65-73 (1983). vide methods for the treatment of various skeletal mus The outstanding analgesic and anti-inflammatory cle disorders in a mammal such as skeletal muscle properties of the non-steroidal anti-inflammatory drugs spasms, certain orthopedic conditions, disk syndromes, compared to aspirin or acetaminophen have prompted low back pain and the like, said method comprising 60 the widespread acceptance and usage of these newer administering to said mammal preselected dosages of non-narcotic analgesics, as single entities, for the treat said non-steroidal anti-inflammatory drug and said skel ment and management of acute and chronic pain and etal muscle relaxant. inflammatory states, notably rheumatoid arthritis and Another object of the present invention is to provide osteoarthritis. However, the utilization of these agents suitable unit dose forms of said composition comprising 65 in skeletal muscle relaxant compositions has not hereto an effective amount of a non-steroidal anti-inflamma fore been considered. tory drug and an effective amount of a skeletal muscle The non-steroidal anti-inflammatory drugs relaxant. (NSAID's) for use in the pharmaceutical compositions 4,722,938 5 6 and methods of use of the present invention may be -continued selected from any of the following categories: (1) the propionic acid derivatives; (2) the acetic acid derivatives; (3) the fenamic acid derivatives; 5 CH3 (4) the biphenylcarboxylic acid derivatives; and (5) the oxicans. F Accordingly, the term "NSAID' as used herein is fenbufen intended to mean any non-narcotic analgesic non-steroi dal anti-inflammatory compound, including the phar 10 maceutically acceptable non-toxic salts thereof, falling within one of the five structural categories above but ( )-( )-ascisco excluding aspirin, acetaminophen and phenacetin. The specific compounds falling within the foregoing fenoprofen definition of the non-steroidal anti-inflammatory drugs 15 for use in the present invention are well known to those O skilled in the art and reference may be had to various literature reference sources for their chemical struc tures, pharmacological activities, side effects, normal fH, dosage ranges, etc. See, for example, Physician's Desk 20 CHCOOH Reference, 38th Edition, 1984 and The Merck Index, 9th Edition, Merck and Company, Rahway, New Jersey (1976) and Cutting's Handbook of Pharmacology, 7th ibuprofen aluminum Edition, Ed. T. Z. Csaky, M.D., and B. A. Barnes, Appleton-Century-Crofts, New York, 1984, Chapter 25 H. 49: 604-638. (CH3)2CHCH2 CHCOO AlOH While some of the above-identified compounds are primarily used at the present time as anti-inflammatory agents and others are primarily used as analgesics, in ketoprofen fact all of the contemplated compounds have both anal 30 CH3 gesic and anti-inflammatory activity and can be used at CHCOOH appropriate dosage levels for either purpose in the com positions and methods of the present invention. The compounds in groups (1) through (4) typically contain a carboxylic acid function; however, those acids are 35 sometimes administered in the form of their pharmaceu C-C) tically acceptable salts, e.g. sodium salts. fluprofen The propionic acid derivatives for use herein include, but are not limited to, ibuprofen, naproxen, naproxen H. sodium, flurbiprofen, fenoprofen, fenbufen, ketoprofen, CHCOOH pirprofen, carprofen, oxaprozin, pranoprofen, miro profen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxic acid. Structurally related F propionic acid derivatives having similar analgesic and 45 bucioxic acid anti-inflammatory properties are also intended to be O encompassed by this group. Representative members of the propionic acid group include ibuprofen, naproxen, CCH2CHCOOH flurbiprofen, fenbufen, fenoprofen, ibuprofen alumi num, ketoprofen, fluprofen and bucloxic acid. Struc tural formulas for these representative group members 50 Cl are set forth below: Thus, "propionic acid derivatives' as defined herein are non-narcotic analgesics/non-steroidal anti-inflam PROPIONIC ACID DERIVATIVES matory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in ibuprofen 55 the form of a pharmaceutically acceptable salt group, H. C-3. -CH(CH3)COO-Na+ O -CH2CH (CH3)2CHCH2 CHCOOH 2COONa), typically attached directly or via a car bonyl function to a ring system, preferably to an aro 60 matic ring system. naproxen The acetic acid derivatives for use herein include, but CH3 are not limited to, indomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, CHCOOH furofenac, tiopinac, zidometacin, acemetacin, fentiazac, 65 clidanac and oxepinac. Structurally related acetic acid derivatives having similar analgesic and anti-inflamma CH3O c tory properties are also intended to be encompassed by flurbiprofen this group. Representative members of the acetic acid 4,722,938 7 8 group include tolmetin, sulindac, indomethacin, di Structurally related fenamic acid derivatives having clofenac, alclofenac, fenclozic acid and ibufenac. Struc similar analgesic and anti-inflammatory properties are tural formulas for these representative group members also intended to be encompassed by this group. Repre are set forth below: sentative members of the fenamic acid group include ACETIC ACID DERVATIVES mefenamic acid, meclofenamate sodium (meclofenamic acid, sodium salt) and flufenamic acid. Structural for tometin CH3 O mulas for representative group members are set forth N below: 10 H3C e elico FENAMIC ACID DERIVATIVES suindac O mefenamic acid CH3S 15 O H COOH H3C CH3 l CH3 20 meclofenamic acid Cl F CH2COOH

indomethacin H3CO CH2COOH 25 COOH Cl CH3 N CH3 flufenamic acid O Ce:O 30

COOH CF3

Cl 35 Thus, "fenamic acid derivatives” as defined herein diclofenac Cl CH2COOH are non-narcotic analgesics/non-steroidal anti-inflam matory drugs which contain the basic structure

40 Cl alclofenac Cl C-C)COOH 45 CH2=CHCH2O CH2COOH which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharma ceutically acceptable salt group, e.g. -COONa. The biphenylcarboxylic acid derivatives for use S 50 C herein include, but are not limited to, diflunisal and flufenisal. Structurally related biphenylcarboxylic acid N CH2COOH derivatives having similar analgesic and anti-inflamma ibufenac tory properties are also intended to be encompassed by 55 this group. Representative members of this group are (CH3)2CHCH2 CH2COOH diflunisal and flufenisal, whose structural formulas are set forth below: Thus, "acetic acid derivatives' as defined herein are BPHENYLCARBOXYLIC ACID DERVATIVES non-narcotic analgesics/non-steroidal anti-inflamma tory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically diflunisal COOH acceptable salt group, e.g. -CH2COONa), typi cally attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system. 65 The fenamic acid derivatives for use herein include, but are not limited to, mefenamic acid, meclofenamic F acid, flufenamic acid, niflumic acid and tolfenamic acid. 4,722,938 9 -continued flufenisal OCOCH3 I -( ) ( )-cool 5 N--NH-R Thus, "biphenylcarboxylic acid derivatives' as de wherein R is an aryl or heteroaryl ring system. fined herein are non-narcotic analgesics/non-steroidal 10 Of the propionic acid derivatives for use herein, ibu anti-inflammatory drugs which contain the basic struc profen, naproxen, naproxen sodium, flurbiprofen, feno profen, ketoprofen, suprofen, fenbufen, and fluprofen ture may be mentioned as particularly preferred compounds. Of the acetic acid derivatives, presently preferred 15 members include tolmetin sodium, sulindac and indo methacin. Of the fenamic acid derivatives, particularly pre ( ) ( ) COOH ferred compounds include mefenamic acid and meclo fenemate sodium. 20 The particularly preferred biphenylcarboxylic acid which can bear a variety of substituents and in which derivatives for use in the present invention include di the free -COOH group can be in the form of a pharma flunisal and flufenisal. ceutically acceptable salt group, e.g. -COONa. The particularly advantageous oxicams include The oxicans for use herein include, but are not lim 25 piroxicam, sudoxicam and isoxicam. Of the foregoing non-steroidal anti-inflammatory ited to, piroxicam, sudoxicam, isoxicam and CP-14,304. drugs, in the practice of the preferred embodiments of Structurally related oxicams having similar analgesic the present invention, ibuprofen and naproxen are most and anti-inflammatory properties are also intended to be preferred. encompassed by this group. Representative members of 30 With respect to the dosage amount of the non-steroi dal anti-inflammatory drugs in the formulations of the this group are depicted below: invention, although the specific dose will vary depend OXCAMS ing upon the age and weight of the patient, the severity of the symptoms, the incidence of side effects and the like, for humans, typical effective analgesic amounts of piroxicam OH 35 presently preferred NSAID's for use in unit dose com C positions of the invention presented in milligrams are set n YNH / \ forth in Table II; however, greater or lesser amounts N N may be employed if desired or necessary. A description s1 NoH 40 of unit dose dispensing is presented in Remington's O2 Pharmaceutical Sciences, Fifteenth Edition, pages 1698-9. sudoxicam OH O With respect to the compounds set forth hereinabove N falling within the propionic acid derivative category, suitable dosage ranges for these compounds will gener N NH-6 45 ally fall within the range of about 12.5 mg to 900 mg in N S each unit dose. A general dosage range for those com s1 NoH, pounds that fall within the acetic acid derivative cate O2 gory is about 25 mg to 400 mg in each unit dose. A - 50 general dosage range for those compounds falling SOXC: OH O N within the fenamic acid derivative category is about 50 mg to 500 mg in each unit dose. A general dosage range N1N / for those compounds falling within the biphenylcar N O boxylic acid derivative category is about 125 mg to 1000 s1 NoH, CH3 55. mg in each unit dose. A general dosage range for those O2 compounds falling within the oxicam category is about 10 mg to 40 mg in each unit dose. 4-hydroxy-1,2- OH O benzothia- I TABLE II zine 1,1- N-CN 60 PRE- WIDE dioxide 4-(N- NH FERRED MAX. TOTAL RANGE phenyl)-car- N DRUG UNT DOSE DALY DOSE UNIT DOSE boxamide s1 NoH, Diflunisal 12S-500 1500 25-1000 O2 Ibuprofen 100.400 2400 50-800 Naproxen 125-500 1250 125-750 66-- 99 65 Flurbiprofen 25-50 300 25-150 Thus, "oxicams' as defined herein are non-narcotic Fenoprofen 50-200 2400 50-300 analgesics/non steroidal anti-inflammatoryi-i drugs MefenamicPiroxicam Acid 125-25010-40 125080 25-50010-80 which have the general formula Fenbufen 100-500 3000 100-900 4,722,938 11 12 the spinal cord level is not sufficient to account for TABLE II-continued depression of the arousal system. PRE- WIDE FERRED MAX, TOTAL RANGE Most of the clinically useful centrally acting skeletal DRUG UNT DOSE DALY DOSE UNIT DOSE muscle relaxants fall into the following chemical Ketoprofen 2S-50 200 25-200 5 groups: glycerylmonoethers and derivatives, oxazoles, Naproxen Sodium 38-550 375 138-82.5 substituted alkanediols, benzazoles, benzodiazepines, Suprofen 100-400 1600 50-600 and miscellaneous. Since not all of the skeletal muscle relaxants readily lend themselves to such categoriza A complete description of the various NSAID's, tion, a miscellaneous category is required. including acceptable analgesically effective amounts 10 The formulations of the present invention comprise, thereof for use in unit dose compositions of the present in addition to the non-steroidal anti-inflammatory invention also appears in applicants co-pending U.S. drugs, at least one active ingredient from the above application Ser. No. 578,288, filed Feb. 8, 1984 and U.S. described chemical groups. Typical examples of drugs Pat. No. 4486,436, the entire disclosures of which are contained within each chemical group are presented incorporated herein by reference. 15 below: The term "skeletal muscle relaxant' as used herein is a. glycerylmonoethers and derivatives intended to mean any compound having skeletal muscle mephenesin relaxing properties. Any skeletal muscle relaxant is mephenesin carbamate useful in the practice of the present invention. The skel mephenesin acid succinate etal muscle relaxants may be broadly classified as those 20 methocarbamol that act directly on skeletal muscle and those that act on chlorphenesin carbamate the level of the central nervous system. The centrally b. oxazoles acting muscle relaxants block impulses at the interneu mephenoxalone rons of polysynaptic reflex arcs, mainly at the level of 25 metaxalone the spinal cord. This is demonstrated by the abolish c. substituted alkanediols ment of the diminution of the flexor and crossed exten meprobamate. sor reflexes which possess one or more interneurons carisoprodol between the sensory and motor fibers. The knee-jerk d. benzazoles response, which acts through a monosynaptic reflex Zoxazolamine system and therefore possesses no interneurons is unaf 30 chlorzoxazone fected by this class of drugs. e. benzodiazepines These drugs also possess mild depressant properties chlordiazepoxide HCl on the CNS; the major sites of action are the brain stem diazepam and subcortical areas. The ascending reticular forma f, miscellaneous tion, which receives and transmits some sensory stimuli, 35 analexin transmits and maintains a state of arousal. When the baclofen passage of stimuli is blocked at the level of ascending chlormezanone reticular formation, response to sensory stimuli is re cyclobenzaprine HCl duced and depression ranging from sedation to anesthe orphenadrine citrate sia may occur. Suppression of polysynaptic reflexes at 40 Some centrally-acting muscle relaxants are presented in Table III along with their chemical structure, dosage forms and usual unit dose.

TABLE III Centrally-Acting Skeletal Muscle Relaxants GENERC NAME CHEMICAL STRUCTURE DOSAGE FORMS USUAL UNITDOSE Baclofen T:10 mg 5-20 mg Cl HCHCOOH CH2NH2 Carisoprodol H.CHCH T:350 mg 350 mg H.NcooCHCHOOCNHCHCH), CH3

Chlorphenesin OH T:400 mg 800 mg carbamate OCH2CHCHOOCNH2

Chlorizoxazone O O T:250 mg 250-750 mg

C 4,722,938 13 14 TABLE III-continued Centrally-Acting Skeletal Muscle Relaxants GENERCNAME CHEMICAL STRUCTURE DOSAGE FORMS USUAL UNIT DOSE Cyclobenzaprine T:10 mg 10 mg Hydrochloride, U.S.P. HC

- I HCCH2CH2NCH3)2 Diazepam CH3 O T:2,5,10 mg 2-10 mg oral M I:5 mg/ml 2-15 mg i.m. N y or i.v.

Cl e N

Mephenesin CH3 T:500 mg i-2g ph OCH2CHCH2OH

Metaxalone H3C T:400 mg 800 mg (O- I lo H3C Methocarbamol, OCH3 T:500,750 mg 1-2 g. oral U.S.P. ph I:100 mg/ml slowly1-3 g. i.v., OCH2CH-CH2OOCNH2

Orphenadrine T:100 mg 100 mg. oral Citrate, O I:30 mg/ml 60 mg. i.m. U.S.P. or i.v. CH2CO CH3 O / I COCH2CH2+NH HOCCOH N O H CH3 CH2COH T = tablet; I = injection. Mephensin has been the most extensively studied drug among the skeletal muscle relaxants. Although These drugs appear to have a more selective action rarely used today it is a prototype for other skeletal on reticular neuronal mechanisms that control muscle muscle relaxants which have similar pharmacological 55 tone than on spinal interneuronal activity, whereas me actions. These include carisoprodol, chlorphenesin car phensin-like drugs exhibit no such selectivity. Baclofen bamate, chlorzoxazone, metaxalone, methocarbamol is used for the treatment of spasticity in patients with and orphenadrine citrate. Methocarbamol and orphena multiple sclerosis. Baclofen's usefulness is limited by its drine citrate can be administered either orally or intra adverse effects which include drowsiness, insomnia, venously. In the latter case, it is used to relieve severe, 60 dizziness, etc. Cyclobenzaprine is closely related to the acute muscle spasm of local origin caused by inflamma tricyclic antidepressants both structurally and pharma tion or trauma. Other clinically useful skeletal muscle cologically and has side effects which are common with relaxants which differ from mephensin in their pharma that group of drugs. cological mode of action are the benzodiazepines (e.g., In addition to the centrally-acting muscle relaxants diazepam), baclofen and cyclobenzaprine. Diazepam 65 identified above, dantrolene is a typically non-centrally and other benzodiazepines are used for a variety of acting muscle relaxant which exerts its effects by direct spastic states but may be most useful in painful spasms of actions on skeletal muscle. Dantrolene has the follow flexor muscles. ing chemical structure: 4,722,938 15 16 differ substantially in chemical structure from aspirin, acetoninophen and phenacetin, and which have signifi cantly different biological profiles therefrom can be ON advantageously formulated into a novel composition together with a skeletal muscle relaxant and adminis tered to mammals, especially to humans, to obtain more pain relief and lessened adverse side effects. Certain NSAID's are particularly long-acting and need be administered less frequently than the usual Dantrolene reduces contraction of skeletal muscle by 10 every 4 to 6 hours; for example, diflunisal and naproxen direct action on excitation-contraction coupling, per are typically administered only twice daily and pirox haps by decreasing the amount of calcium released from icam only once a day. When such long-acting drugs are the sarcoplanic reticulum. Although dantrolene pro employed, it is often desirable to include an additional duces some central nervous system depressant effects, it amount of a muscle relaxant in the composition in sus does not impair polysynaptic reflexes preferentially as 5 tained release form. do the centrally-acting muscle relaxants. Dantrolene Typical therapeutically active components of the sodium is available for oral use at 25-100 mg in a single present invention, along with their usual adult dosage, dose or for intravenous administration up to a total of 10 for use in the pharmaceutical compositions and methods mg/kg. of the present invention are set forth in the following The preferred muscle relaxants intended for use in the 20 Table IV. practice of the present invention include diazepam, Illustrative of typical unit dose forms are tablets or carisoprodol, chlorZoxazone, methocarbamol and or capsules containing the amounts indicated in Table IV. phenadrine citrate. Note that the asterisk (*) indicates that the adjacent With respect to the dosage amount of the skeletal amount is in sustained release form, e.g. "130 mg--130 muscle relaxant in the formulations of the invention, 25 mg' means that the first 130 mg is formulated for although the specific dose will vary depending upon the immediate release, while the second 130 mg is in sus age and weight of the patient, the severity of the symp tained release form. toms, the incidence of side effects and the like, for hu mans, typical effective amounts of the presently pre TABLE IV I ferred skeletal muscle relaxants for use in unit dose 30 Typical Unit Doses compositions of the invention are about 2-10 mg diaze NSAD pam, 100-600mg carisoprodol, 100-1000 mg chlorZoxa Skeletal Muscle Relaxant - zone, 200-2000 mg methocarbamol and 25-100 mg diazepam ibuprofen orphenadrine citrate. 2 mg 100 mg 35 5 mg 200 mg For those compounds not indicated as members of 10 mg 400 mg the preferred category their typical or suggested ranges diazepam naproxen of unit dose administration are well-known to those in 2 mg - 2 mg 125 mg 5 mg -- 5 mg 250 mg the art. The package insert of each product sets out the 10 mg - 10 mg 500 mg dosage ranges determined by the manufacturer. These diazepam fenoprofen dosage ranges are the general guidelines followed by 40 2 mg 100 mg those familiar with skeletal muscle relaxants. 5 mg 200 mg The skeletal muscle relaxant may be centrally-acting 10 mg 200 mg chlorzoxazone ibuprofen or it may directly affect skeletal muscle tissue. The 250 mg 200 mg skeletal muscle relaxant may fall within one of the five 500 mg 400 mg structural categories indicated hereinabove. 45 chlorzoxazone naproxen Several commercial centrally-acting skeletal muscle 250 mg -- 250 mg 125 mg relaxants are currently available in the United States in 500 mg - 500 mg 250 mg 500 mg - 500 mg 500 mg formulations with aspirin or acetaminophen. The list of chlorzoxazone fenoprofen these currently available combination products is pres 250 mg 100 mg ented in Table I. These products are intended to pro 50 500 mg 200 mg vide an analgesic component to help relieve both the chlorizoxazone piroxicam 250 mg -- 250 mg 20 mg pain and in some cases the anxiety of the pain experi 500 mg - 500 mg 20 mg ence. Elenbass reviewed the published studies of such carisoprodol ibuprofen combination products in American Journal of Hospital 200 mg 200 mg Pharmacy, Vol. 37, October 1980, pages 1313-1323. He 55 400 mg 400 mg concluded that the combination products provide ingre carisoprodol naproxen 200 mg -- 200 mg 125 mg dients to treat both the spasm and pain associated with 200 mg -- 200 mg 250 mg musculoskeletal disorders, and they appear to provide 400 mg + 400 mg 500 mg better symptom relief than the individual agents. The carisoprodiol diflunisal AMA Drug Evaluations, 5th Ed., page 103 comment that 200 mg -- 200 mg 250 mg 200 mg -- 200 mg 500 mg results of some studies have alleged that a combination 400 mg - 400 mg 500 mg of muscle relaxant and an analgesic provides greater methocarbamol ibuprofen benefit in patients with acute musculoskeletal problems 400 mg 200 mg than similar doses of analgesic alone. The same page of 800 mg 400 mg 65 methocarbamol naproxen AMA Drug Evaluations lists examples of combination 400 mg -- 400 mg 125 mg skeletal muscle relaxants and analgesics. 400 mg -- 400 mg 250 mg Surprisingly, the present inventors now find that, the 800 mg - 800 mg 500 mg newer non-steroidal anti-inflammatory drugs, which methocarbamol sulindac 4,722,938 17 18 aerosols and solutions suitable for topical administra TABLE IV-continued tion. Typical Unit Doses As representative suitable formulations consistent NSAID with the objects, features and advantages of the present 400 mg -- 400 mg" 150 mg 5 invention, the following non-limiting examples are pro 800 mg + 800 mg 200 mg vided. orphenadrine citrate ibuprofen 25 mg 200 mg EXAMPLE 1. 50 mg 400 mg orphenadrine citrate naproxen Chlorzoxazone-250 mg 25 mg + 25 mg 125 mg 10 Ibuprofen-400 mg 25 mg -- 25 mg 250 mg 50 mg -- 50 mg 500 mg Triturate active ingredients and q.s. with lactose to orphenadrine citrate ketoprofen selected capsule size 25 mg 25 mg 50 mg 50 mg EXAMPLE 2 5 Methocarbamol-400 mg Fenoprofen-200 mg In accordance with the practices of the present inven Triturate active ingredients and q.s. with lactose to tion, the NSAID/skeletal muscle relaxant composi selected capsule size tions, may be administered in admixture with suitable From the foregoing, other typical acceptable phar pharmaceutical diluents, carriers or other excipients 20 maceutical formulations will be apparent to those (collectively referred to as "carrier' materials) suitably skilled in the art of pharmaceutical formulations. selected with respect to the intended route of adminis While the invention has been described and illus tration and conventional pharmaceutical practices. For trated with reference to certain preferred embodiments instance, for oral administration in the form of tablets or thereof, those skilled in the art will appreciate that vari capsules, the active drug components may be combined 25 ous changes, modifications and substitutions can be with any oral non-toxic pharmaceutically acceptable made therein without departing from the spirit of the inert carrier such as lactose, starch, sucrose, cellulose, invention. For example, effective dosages other than magnesium stearate, dicalcium phosphate, calcium sul the preferred ranges set forth hereinabove with respect fate, mannitol and the like. Moreover, when desired or to the active ingredients may be applicable as a conse necessary, suitable binders, lubricants, disintegrating 30 quence of variations of the responsiveness of the mam agents and coloring agents can also be incorporated in mal treated, severity of symptoms, dosage related ad the mixture. Suitable binders include starch, gelatin, verse effects, if any, observed and similar consider natural sugars, corn sweeteners, natural and synthetic ations. Accordingly, such expected variations or differ gums such as acacia, sodium alginate, carboxymethyl ences in the practice of the present invention and the cellulose, polyethylene glycol and waxes. Among the 35 results obtained are contemplated in accordance with lubricants there may be mentioned for use in these dos the objects and practices of the present invention. It is age forms, boric acid, sodiumbenzoate, sodium acetate, intended, therefore, that the invention be limited only sodium chloride, etc. Disintegrators include, without by the scope of the claims which follow. limitation, starch, methylcellulose, agar, bentonite, guar What we claim is: gum, etc. Sweetening and flavoring agents and preser 1. A method for the treatment of musculoskeletal vatives can also be included where appropriate. disorders in a mammalian organism in need of such Of course, additionally, the compositions of the pres treatment, comprising administering to such organism a ent invention may be formulated in sustained release symptom relieving analgesically and anti-inflam form to provide the rate controlled release of any one or matorily effective amount of (i) at least one of the propi more of the components to optimize the therapeutic 45 onic acid NSAIDs, ibuprofen, naproxen, benoxaprofen, effects, i.e., analgesia, skeletal muscle relaxation, etc. flurbiprofen, fenoprofen, fenbufen, ketoprofen, indo while minimizing undesirable side effects. Suitable dos profen, pirprofen, carprofen, oxaprozin, pranoprofen, age forms for sustained release include layered tablets miroprofen, ibuprofen aluminum, tioxaprofen, suprofen, containing layers of varying disintegration rates or con alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, trolled release polymeric matrices impregnated with the 50 or pharmaceutically acceptable salt thereof, in combina active components and shaped in tablet form or cap tory immixture with a skeletal muscle relaxing amount sules containing such impregnated or encapsulated po of (ii) at least one of the glycerylmonoether SMRS, rous polymeric matrices. methocarbamol, mephenesin, mephenesin carbamate, Similarly, injectable dosage units may be utilized to mephenesin acid succinate, chlorphenesin carbamate, or accomplish intravenous, intramuscular or subcutaneous 55 pharmaceutically acceptable salt thereof. administration and, for such parenteral administration, 2. The method for the treatment of musculoskeletal suitable sterile aqueous or non-aqueous solutions or disorders as defined by claim 1, said NSAID (i) com suspensions, optionally containing appropriate solutes prising ibuprofen, naproxen, flurbiprofen, fenoprofen, to effectuate isotonicity, will be employed. ketoprofen, suprofen, fenbufen, fluprofen, or pharma The pharmaceutical compositions of the present in ceutically acceptable salt thereof. vention may also be formulated and administered by 3. The method for the treatment of musculoskeletal other methods which are known for administering anal disorders as defined by claim 2, said NSAID (i) com gesics. The composition may be adapted for rectal ad prising ibuprofen or pharmaceutically acceptable salt ministration, for example, as a suppository. The compo thereof. sition may also be adapted for topical application, for 65 4. The method for the treatment of musculoskeletal example, the composition may be applied in a pharma disorders as defined by claim 2, said NSAID (i) com ceutically acceptable topical vehicle selected from the prising naproxen or pharmaceutically acceptable salt group consisting of creams, gels, ointments, powders, thereof. 4,722,938 19 20 5. The method for the treatment of musculoskeletal 13. The method for the treatment of musculoskeletal disorders as defined by claim 2, said NSAID (i) com disorders as defined by claim 3, said combinatory im prising ketoprofen or pharmaceutically acceptable salt mixture comprising from about 100 mg to 400 mg of thereof. ibuprofen or pharmaceutically acceptable salt thereof. 6. The method for the treatment of musculoskeletal 14. The method for the treatment of musculoskeletal disorders as defined by claim 1, said SMR (ii) compris disorders as defined by claim 1, comprising sustainedly ing methocarbamol or pharmaceutically acceptable salt controlledly administering a unit dosage amount of said thereof. combinatory immixture. 7. The method for the treatment of musculoskeletal 15. The method for the treatment of musculoskeletal O disorders as defined by claim i, comprising eliciting a disorders as defined by claim 1, said combinatory ims musculoskeletal relaxing and analgesic/anti-inflamma mixture further comprising a pharmaceutically accept tory response in a mammalian organism afflicted with able non-toxic carrier, diluent or excipient. muscle spasms and the symptoms of rheumatoid arthri 8. The method for the treatment of musculoskeletal tis. disorders as defined by claim 1, comprising oral admin 15 16. The method for the treatment of musculoskeletal istration of a unit dosage amount of said combinatory disorders as defined by claim 1, comprising eliciting a immixture. musculoskeletal relaxing and analgesic/anti-inflamma 9. The method for the treatment of musculoskeletal tory response in a mammalian organism afflicted with disorders as defined by claim 1, comprising parenteral muscle spasms and the symptoms of osteoarthritis. administration of a unit dosage amount of said combina 20 17. The method for the treatment of musculoskeletal tory immixture. disorders as defined by claim 1, comprising eliciting a 10. The method for the treatment of musculoskeletal musculoskeletal relaxing and analgesic/anti-inflamma disorders as defined by claim 1, comprising rectal ad tory response in a mammalian organism afflicted with skeletal muscle spasms. ministration of a unit dosage amount of said combina 25 18. The method for the treatment of musculoskeletal tory immixture. disorders as defined by claim 1, comprising eliciting a 11. The method for the treatment of musculoskeletal musculoskeletal relaxing and analgesic/anti-inflamma disorders as defind by claim 1, said combinatory immix tory response in a mammalian organism afflicted with ture comprising from about 12.5 mg to 900 mg of said lower back pain. NSAID (). 30 19. The method for the treatment of musculoskeletal 12. The method for the treatment of musculoskeletal disorders as defined by claim 1, comprising eliciting a disorders as defined by claim 6, said combinatory in musculoskeletal relaxing and analgesic/anti-inflamma mixture comprising from about 200 mg to 2000 mg of tory response in a mammalian organism afflicted with said methocarbamol SMR or pharmaceutically accept disk syndrome. able salt thereof, 35 k is :