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Home , Chlorzoxazone, Miroprofen, Orphenadrine, Zoxazolamine

United States Patent (19) 11 Patent Number: 4,780,463 Sunshine et al. (45) Date of Patent: Oct. 25, 1988

(54). , ANTI-INFLAMMATORY AND Ailments of the Musculoskeletal Apparatus), Investiga SKELETAL tion Medica Internactional, pp. 475-478, (1983), and COMPOSITIONS COMPRISING English translation thereof. NON-STEROIDAL ANTI-NFLAMMATORY Socialist Republic of Romania Description of Inven AND MUSCULOSKELETAL tion, 82,717, copy of patent and English translation RELAXANTS AND METHODS OF USING thereof. SAME Rego, "Mio-Relaxantes No Tratamento Das Lom 75 Inventors: Abraham Sunshine, New York; balgias Aguda E Da Lombo-Ciaticas Recentes', Mus Eugene M. Laska, Larchmont; cle Relaxants in the Treatment of Acute Lumbalgias Carole E. Siegel, Mamaroneck, all of and Recent Lumbo-Sciatica Cases, Acta N.Y. Reumatologica Portuguesa, 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.: 114,751. gesic-Antiphlogistic Therapy of Locomotor System Pain), Therapiewoche, 28, 5657-5663, (1978), copy of the 22 Filed: Oct. 30, 1987 original and English translation thereof. Schar, "Medikamentose Behandling von Lumboishial Related U.S. Application Data gien', Treatment of the Lumbago-Sciatic Syn 60 Division of Ser. No. 815,502, Jan. 2, 1986, Pat. No. drome, Schweiz. Rundschau Med., (Praxis), vol. 68, No. 4,722,938, which is a continuation of Ser. No. 686,380, 5, pp. 141-142, (Jan. 30, 1979), copy of original article Dec. 26, 1984, abandoned. and English translation thereof. 51) int. Cl.' ...... A61K 31/19; A61K 31/44; Kolodny and Klipper, "Bone and Joint Diseases in the A61K 3/54; A61K 31/195; A61K 31/205 Elderly', Hospital Practice, pp. 91-101, (Nov., 1976). 52 U.S. Cl...... 514/226.5; 514/279; Nascimento, "Use of an Association Containing an . 514/556; 514/561; 514/570 Analgeisc, a Muscle Relaxant and Vitamin B Complex 58 Field of Search ...... 514/226, 279, 556, 561, in Degenerative Joint Diseases, Extra-Articular Rheu 514A570 matic Ailments and Traumatic Afflications, F med, 56) References Cited (BR), 83(3):361-363, (1981), original article and English translation thereof. U.S. PATENT DOCUMENTS Repschlaeger and McPherson, "Classification, Mecha 4,722,938 2/1988 Sunshine et al...... 514/479 nism and Management of Headache', Clinical Phar FOREIGN PATENT DOCUMENTS mary, vol. 3, pp. 139-150, (Mar.-Apr. 1984). 22529 12/1971 France . Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Burns, Doane, Swecker & OTHER PUBLICATIONS Mathis Armas & Valencia, "Eficacia terapeutica de la associa 57 ABSTRACT cion -carisoprodoi en ciertas enfermedader musculoesqueleticas', Therapeutic Effectiveness of Novel pharmaceutical analgesic, anti-inflammatory and Naproxen- Association in Certain Muscu skeletal muscle relaxant compositions and methods of loskeletal Disorders, in Investigation Medica Interna using same comprising an analgesically and anti-inflam cional, pp. 350-356, (1983), and English translation matory effective amount of at least one non-steroidal thereof. anti-inflammatory drug other than , acetamino Goti & Valencia, "Caracterizacion clinica de una nueva phen and , in combination with an effectiv asociacion (naproxen-carisoprodol) en padecimientos amount of a skeletal muscle relaxant. del aparato musculoesqueletico', Clinical Description of a New Association (Naproxen.--Carisoprodol) in 14 Claims, No Drawings 4,780,463 1. 2 is a conventional non-narcotic analgesic with anti-in ANALGESIC, ANTI-NFLAMMATORY AND flammatory and activity. The most common SKELETAL MUSCLE RELAXANT adverse reactions associated with the use of aspirin in COMPOSITIONS COMPRISING this product have been gastrointestinal, including nau NONSTEROIDAL ANTI-NFLAMMATORY 5 Sea, , gastritis, occult bleeding, constipation DRUGS AND MUSCULOSKELETAL RELAXANTS and diarrhea. Allergic type reactions associated with AND METHODS OF USING SAME aspirin may also involve the respiratory tract and skin. Another commercial skeletal muscle relaxant formu This application is a divisional, of application Ser. lation is Parafon Forte (R) by McNeil Pharmaceutical. No. 815,502, filed Jan. 2, 1986, U.S. Pat. No. 4,722,938 10 Parafon Forte contains 250 mg and 300 which is a continuation of U.S. Ser. No. 686,380 filed mg acetaminophen. Chlorzoxazone is a centrally-acting Dec. 26, 1984, now abandoned. agent which does not directly relax tense skeletal mus cles in man. Acetaminophen, a nonsalicylate analgesic, BACKGROUND OF THE INVENTION is a conventional non-narcotic analgesic with anti 1. Field of the Invention 15 pyretic activity. The present invention relates generally to novel phar Robaxisal (R) by A.H. Robins Company, Inc. is an maceutical compositions of matter comprising one or other commercial muscle relaxant formulation which more non-steroidal anti-inflammatory drugs in combi contains 400 mg and 325 mg aspirin. nation with at least one skeletal muscle relaxant, and to The mechanism of action of methocarbamol in humans methods of using said compositions in the treatment of 20 has not been established, but may be due to general a variety of skeletal muscle disorders including skeletal central nervous system depression. Methocarbamol muscle spasms, certain orthopedic conditions, disk syn does not directly relax tense skeletal muscles in man. dromes, low back pain and the like. Adverse reactions that have been associated with aspi 2. Description of the Prior Art rin in this formulation include: and other gastro Centrally acting skeletal muscle relaxants are gener 25 intestinal discomfort, gastritis, gastric erosion, vomit ally prescribed either as single agents or as components ing, constipation, diarrhea, angioedema, asthma, rash, of combination products. The Food and Drug Adminis pruritis and urticaria. tration has approved indications for these Norgesic (E) and Norgesic (R) Forte are commercial as adjuncts to rest and physical therapy for relief of products by Riker Laboratories, Inc. that contain a acute, painful musculoskeletal problems. Clinically, the 30 muscle relaxant, aspirin and . The specific for mild pain associated with the majority of cases of minor mulation for Norgesic is 25 mg citrate, muscle strains and minor injuries is self limiting. Most 385 mg aspirin and 30 mg caffeine. Norgesic Forte patients usually respond rapidly to rest. An anti-inflam contains 50 mg orphenadrine citrate, 770 mg aspirin and matory drug may be useful when there is considerable 60 mg caffeine. Orphenadrine citrate is 2-dime tissue damage and edema. On the other hand, severe 35 thylaminoethyl 2-methylbenzhydryl ether citrate. The musculoskeletal strains and sprains, trauma, and cervi common side effects and concerns associated with the cal or lumbar radiculopathy as a consequence of degen use of aspirin occur with the use of Norgesic and Nor erative osteoarthritis, herniated disk, spondylitis or lam gesic Forte as well. TABLE I Some Combination Products Containing a Skeletal Muscle Relaxant TYPICAL DOSAGE CONTENTS OF A SINGLE TABLET PRESENTED AS TRADENAME SKELETAL MUSCLE RELAXANT ADDITIONAL INGREDIENTS NO. OF TABLETS SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg 1-2 SOMA COMPOUND Carisoprodol 200 mg aspirin 325 mg WITH codeine PO4. 16 ng 1-2 PARAFON FORTE Corzoxazone 250 mg acetaminophen 300 mg 1-2 ROBAXISAL Methocarbano 400 mg aspirin 325 mg 2 NORGESIC Orphenadrine 25 mg aspirin 385 mg 1-2 Citrate caffeine 30 mg NORGESICFORTE Orphenadrine 50 mg aspirin 770 mg -1 Citrate caffeine 60 mg inectomy, often cause moderate or severe and more chronic painful skeletal muscle spasm. The principal At the present time, one commercial product, Para symptoms include local pain, tenderness on palpation, 55 fon Forte, a skeletal muscle relaxant formulation con increased muscle consistency and limitation of motion. taining acetaminophen, will be the subject of a hearing For these patients skeletal muscle relaxants alone or in granted by the Commissioner of Food and Drugs on a combination with an analgesic are frequently pre proposal to withdraw approval of its new drug applica scribed. Results of some studies have suggested that a tion sometime in 1985. The Director of the Bureau of formulation of a muscle relaxant and an analgesic pro Drugs of the FDA in a notice published in the Federal vides greater benefit in patients with acute musculoskel Register, 1982, 47 F.R. 22599 concluded that he was etal problems than similar doses of an analgesic alone. unaware of any adequate and well-controlled clinical Table I lists several commercial combinations avail investigation conducted by experts qualified by scien able. A current commercial muscle relaxant formulation tific training and experience ... that demonstrates the is Soma (R) Compound by Carter-Wallace, Inc. which 65 effectiveness of Parafon Forte. The present position of contains 200 mg carisoprodol and 325 mg aspirin. Cari the Commissioner of Food and Drugs is set forth below soprodol is a centrally-acting muscle relaxant that does Federal Register, 1984, 49(200): 48212-482.14): not directly relax tense skeletal muscles in man. Aspirin 4,780,463 3 4 Approval of this NDA will be withdrawn unless Another object of the present invention is to provide there exists substantial evidence that Parafon Forte suitable unit dose forms of said composition comprising has the clinical effect that it purports or is repre an effective amount of a non-steroidal anti-inflamma sented to have under the conditions of use pre tory drug and an effective amount of a skeletal muscle scribed, recommended, or suggested in its labeling relaxant. DETAILED DESCRIPTION OF THE It should be noted that all of the previously described INVENTION skeletal muscle relaxant/non-narcotic analgesic formu More specifically, the applicants herein have surpris lations include either aspirin or acetaminophen as the 10 ingly found that certain newer non-steroidal anti-in non-narcotic analgesic agent. However, a number of flammatory agents are ideally suited for use in a formu alternative non-narcotic agents offering a variety of lation with skeletal muscle relaxants by reason of their advantages over these conventionally employed non enhanced analgesic anti-inflammatory and antipyretic narcotic analgesic have now been devel activity and low incidence of untoward side effects, oped These newer non-steriodal anti-inflammatory 1 5 particularly at the optimum dosages provided for in the drugs are widely administered orally in the treatment of present invention, in comparison to aspirin or acetami mild to severe pain, as well as for a variety of disorders nophen. including rheumatoid and osteoarthritis. Within this The superiority of various of the non-narcotic analge class of drugs, the compounds vary widely in their sics belonging to the newer non-steroidal anti-inflam chemical structure and their biological profiles as anal 20 matory drug class in comparative studies with aspirin gesics, anti-inflammatory agents and antipyretic agents. and acetaminophen is well documented in the literature. The principal advantages of these new non-steroidal Cooper in 1977 found that 400 mg had a anti-inflammatory drugs include not only the clinically greater peak effect and longer duration of action than superior analgesic and anti-inflammatory activity of 2 aspirin 650 mg. Cooper, S.A., Needle, A. E., Kruger, 5 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 30 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 3 5 Pharmacology and Therapeutics, 24:254-250, 1983. nophen and phenacetin) 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 SUMMARY OF THE INVENTION pression of Post operative Pain by Preoperative Admin 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 4. 5 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 50 and 100 mg were significantly pain relief and lessened adverse side effects. 50 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. "Analge tory and musculoskeletal relaxing response, said com sic Effect of Graded Doses of Flurbiprofen in Postepisi position comprising an effective analgesic or anti-in 5 5 otomy Pain.' flammatory amount of a newer non-steroidal anti-in Silberman found 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 musculoskilletal pain. further associated with a non-toxic pharmaceutically Silberman, H. M. "Multiple-Dose Comparison of Su acceptable inert carrier therefrom. 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 6 5 the widespread acceptance and usage of these newer administering to said mammal preselected dosages of non-narcotic , 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 and 4,780,463 5 6 osteoarthritis. However, the utilization of these agents -continued in skeletal muscle relaxant compositions has not hereto PROPIONCACID DERVATIVES fore been considered, The non-steroidal anti-inflammatory drugs ths (NSAID's) for use in the pharmaceutical compositions 5 and methods of use of the present invention may be OOC CHCOOH selected from any of the following categories: CH3O (1) the derivatives; naproxen (2) the derivatives; 10 (3) the derivatives; (4) the biphenylcarboxylic acid derivatives; and (5) the oxicans. ( ) HCOOH Accordingly, the term "NSAID' as used herein is CH3 intended to mean any non-narcotic analgesic non-steroi 15 F dal anti-inflammatory compound, including the phar flurbiprofen maceutically acceptable non-toxic salts thereof, falling within one of the five structural categories above but excluding aspirin, acetaminophen and phenacetin. The specific compounds falling within the foregoing 20 ( ) ( ) CCH2CH2COOH definition of the non-steroidal anti-inflammatory drugs for use in the present invention are well known to those skilled in the art and reference may be had to various literature reference sources for their chemical struc 25 tures, pharmacological activities, side effects, normal ()- dosage ranges, etc. See, for example, Physician's Desk ths Reference, 38th Edition, 1984 and The Merck Index, 9th CHCOOH Edition, Merck and Company, Rahway, N.J. (1976) and Cutting's Handbook of Pharmacology, 7th Edition, Ed. 30 T. Z. Csaky, M.D., and B. A. Barnes, Appleton-Cen tury-Crofts, New York, 1984, Chapter 49:604-638. (H, While some of the above-identified compounds are (CH3)2CHCH2 CHCOO AlOH primarily used at the present time as anti-inflammatory 35 agents and others are primarily used as analgesics, in 2 fact all of the contemplated compounds have both anal ibuprofen aluminum gesic and anti-inflammatory activity and can be used at appropriate dosage levels for either purpose in the con th positions and methods of the present invention. The CHCOOH compounds in groups (1) through (4) typically contain a O carboxylic acid function; however, those acids are C sometimes administered in the form of their pharmaceu tically acceptable salts, e.g. sodium salts. The propionic acid derivatives for use herein include, 45. but are not limited to, ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, , ketoprofen, fH, ketoprofen, , carpofen, , prano profen, miroprofen, tioxaprofen, suprofen, almino 50 profen, , fluprofen and bucloxic acid. F Structurally related propionic acid derivatives having fluprofen similar analgesic and anti-inflammatory properties are also intended to be emcompassed by this group. Repre sentative members of the propionic acid group include 55 CCH2CH2COOH ibuprofen, naproxen, flurbiprofen, fenbufen, feno profen, ibuprofen aluminum, ketoprofen, fluprofen and Cl bucloxic acid. Structural formulas for these representa bucloxic acid tive group members are set forth below: 60 Thus, "propionic acid derivatives' as defined herein PROPIONIC ACID DERIVATIVES are non-narcotic analgesics/non-steroidal anti-inflam matory drugs having a free -CH(CH3)COOH or CH3 -CH2CH2COOH group (which optionally can be in (CH3)2CHCH2 CHCOOH 65 the form of a pharmaceutically acceptable salt group, e.g. -CH(CH3)COO-Na+or -CH2CH2COO-Na+), ibuprofen typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system. 4,780,463 7 8 The acetic acid derivatives for use herein include, but -continued are not limited to, indomethacin, , , ACETIC ACID DERIVATIVES , , , ibufenac, isoxepac, furofenac, tiopinac, zidometacin, , , clidanac and oxepinac. Structurally related acetic acid (CH3)2CHCH CH2COOH derivatives having similar analgesic and anti-inflamma tory properties are also intended to be encompassed by ibufenac this group. Representative members of the acetic acid Thus, "acetic acid derivatives' as defined herein are group include tolmetin, sulindac, indomethacin, di O non-narcotic analgesics/non-steroidal anti-inflamma clofenac, alclofenac, and ibufenac. Struc tory drugs having a free -CH2COOH group (which tural formulas for these representative group members optionally can be in the form of a pharmaceutically are set forth below: acceptable salt group, e.g. -CH2COONa), typi 15 cally attached directly to a ring system, preferably to an ACETIC ACID DERVATIVES aromatic or heteroaromatic ring system. CH3 The fenamic acid derivatives for use herein include, O but are not limited to, , meclofenamic N acid, , and . H3C e chool 20 Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are tolmetin also intended to be encompassed by this group. Repre O sentative members of the fenamic acid group include mefenamic acid, meclofenamate sodium (meclofenamic CH3S acid, sodium salt) and flufenamic acid. Structural for 25 mulas for representative group members are set forth H below:

FENAMIC ACID DERVATIVES 30 mefenamic acid F CH2COOH sulindac NH

H3CO CHCOOH 35 C)COOH H3C-) Cl N CH3 O NH

CCOOH -)Cl flufenamic acid C 45 indomethacin NH Cl CH2COOH CCOOH -)CF3 NH 50 Thus, "fenamic acid derivatives: as defined herein are non-narcotic analgesics/non-steroidal anti-inflamma Cl tory drugs which contain the basic structure diclofenac 55 Cl NH CH2=CHCH2O CH2COOH -C) 60 COOH alclofenac which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharma S Cl ceutically acceptable salt group, e.g. -COONar. 65 The biphenylcarboxylic acid derivatives for use N l CH2COOH herein include, but are not limited to, and fenclozic acid flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and anti-inflamma 4,780,463 10 tory properties are also intended to be encompassed by -continued this group. Representative members of this group are diflunisal and flufenisal, whose structural formulas are set forth below: CP-4,304 OH O 5 4-hydroxy-1,2- benzothiazine N c BPHENYLCARBOXYLIC ACD DERVATIVES 1,1-dioxide NH 4-(N-phenyl)- N COOH carboxamide s1 N O2 CH3 O F OH Thus, "oxicams' as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs F which have the general formula diflunisal 15 OCOCH3 OH

F COOH 20 fufenisa Thus, "biphenylcarboxylic acid derivatives' as de wherein R is an aryl or heteroaryl ring system. Of the propionic acid derivatives for use herein, ibu fined herein are non-narcotic analgesics/non-steroidal 25 profen, naproxen, naproxen sodium, flurbiprofen, feno anti-inflammatory drugs which contain the basic struc profen, ketoprofen, suprofen, fenbufen, and fluprofen tle may be mentioned as particularly preferred compounds. Of the acetic acid derivatives, presently preferred members include tolmetin sodium, sulindac and indo methacin. Of the fenamic acid derivatives, particularly pre ( ) ( ) ferred compounds include mefenamic acid and meclo fenemate sodium. which can bear a variety of substituents and in which The particularly preferred biphenylcarboxylic acid the free -COOH group can be in the form of a pharma- 35 derivatives for use in the present invention include di ceutically acceptable salt group, e.g. -COONa. flunisal and flufenisal. The oxicans for use herein include, but are not lim The particularly advantageous oxicams include piroxican, sudoxican and . ited to, , sudoxicam, isoxican and CP-14,304. Of the foregoing non-steroidal anti-inflammatory Structurally related oxicams having similar analgesic 40 drugs, in the practice of the preferred embodiments of and anti-inflammatory properties are also intended to be the present invention, ibuprofen and naproxen are most encompassed by this group. Representative members of preferred. this group are depicted below: With respect to the dosage amount of the non-steroi dal anti-inflammatory drugs in the formulations of the OXICAMS 45 invention, although the specific dose will vary depend ing upon the age and weight of the patient, the severity piroxican OH of the symptoms, the incidence of side effects and the like, for humans, typical effective analgesic amounts of N c. presently preferred NSAID's for use in unit dose com NH / \ 50 positions of the invention presented in milligrams are set N forth in Table II; however, greater or lesser amounts s1'N, N may be employed if desired or necessary. A description O2 CH3 of unit dose dispensing is presented in Remington's sudoxican OH O Pharmaceutical Sciences, Fifteenth Edition, pages ! N 55 1698-9. N N With respect to the compounds set forth hereinabove falling within the propionic acid derivative category, N NH-6 suitable dosage ranges for these compounds will gener s1 Ych S ally fall within the range of about 12.5 mg to 900 mg in O2 3 60 each unit dose. A general dosage range for those com isoxicam OH O pounds that fall within the acetic acid derivative cate gory is about 25 mg to 400 mg in each unit dose. A N N - N general dosage range for those compounds falling NH-6 within the fenamic acid derivative category is about 50 N 65 mg to 500 mg in each unit dose. A general dosage range s1'N, O for those compounds falling within the biphenylcar O2 CH3 boxylic acid derivative category is about 125 mg to 1000 ng in each unit dose. A general dosage range for those 4,780,463 11 12 compounds falling within the category is about reticular formation, response to sensory stimuli is re 10 mg to 40 mg in each unit dose. duced and depression ranging from sedation to anesthe TABLE II sia may occur. Suppression of polysynaptic reflexes at WIDE the spinal cord level is not sufficient to account for RANGE 5 depression of the arousal system. PREFERRED MAX. TOTAL UNIT Most of the clinically useful centrally acting skeletal DRUG UNIT DOSE DALY DOSE DOSE muscle relaxants fall into the following chemical Diflunisal 25-500 1500 125-1000 groups: glycerylmonoethers and derivatives, oxazoles, Ibuprofen 100-400 2400 50-800 substituted alkanediols, benzazoles, , Naproxen 125-500 250 125-750 10 Flurbiprofen 25-50 300 25-150 and miscellaneous. Since not all of the skeletal muscle Fenoprofen 50-200 2400 50-300 relaxants readily lend themselves to such categoriza Piroxican 10-40 80 10-80 tion, a miscellaneous category is required. Mefenamic Acid 25-250 1250 125-500 The formulations of the present invention comprise, Fenbufen 100-500 3000 100-900 Ketoprofen 25-150 200 25-200 in addition to the non-steroidal anti-inflammatory Naproxen Sodium 38-550 1375 138-82.5 15 drugs, at least one active ingredient from the above Suprofen 100-400 1600 50-600 described chemical groups. Typical examples of drugs contained within each chemical group are presented A complete description of the various NSAID's, below: including acceptable analgesically effective amounts a. glycerylmonoethers and derivatives thereof for use in unit dose compositions of the present 20 invention also appears in applicants co-pending U.S. mephenesin carbamate Application Ser. No. 578,288, filed Feb. 8, 1984 and mephenesin acid succinate U.S. Pat. No. 4,486,436, the entire disclosures of which methocarbamol are incorporated herein by reference. The term "skeletal muscle relaxant' as used herein is 25 b. oxazoles intended to mean any compound having skeletal muscle relaxing properties. Any skeletal muscle relaxant is useful in the practice of the present invention. The skel c. substituted alkanediols etal muscle relaxants may be broadly classified as those that act directly on skeletal muscle and those that act on 30 carisoprodol the level of the central nervous system. The centrally d. benzazoles acting muscle relaxants block impulses at the interneu rons of polysynaptic reflex arcs, mainly at the level of chlorZoxazone the spinal cord. This is demonstrated by the abolish e. benzodiazepines ment of the diminution of the flexor and crossed exten 35 chlordiazepoxide HCl sor reflexes which possess one or more interneurons between the sensory and motor fibers. The knee-jerk f. miscellaneous response, which acts through a monosynaptic reflex analexin system and therefore possesses no interneurons is unaf fected by this class of drugs. These drugs also possess mild properties HCl on the CNS; the major sites of action are the brain stem orphenadrine citrate and subcortical areas. The ascending reticular forma Some centrally-acting muscle relaxants are presented tion, which receives and transmits some sensory stimiuli, in Table III along with their chemical structure, dosage transmits and maintains a state of arousal. When the 45 forms and usual unit dose. passage of stimuli is blocked at the level of ascending TABLE III Centrally-Acting Skeletal Muscle Relaxants USUAL GENERICNAME CHEMICAL STRUCTURE DOSAGE FORMS UNIT DOSE Baclofen T: 10 mg 5-20 mg C (HCHCOOH CH2NH2 Carisoprodol (H-CHCH T: 350 mg 350 mg H.NcoochschooCNHCHCH), CH3

Chlorophenesin T: 400 mg 800 mg carbamate ph C OCH2CHCH2OOCNH2 4,780,463 13 14 TABLE III-continued Centrally-Acting Skeletal Muscle Relaxants USUAL GENERICNAME CHEMICAL STRUCTURE DOSAGE FORMS UNIT DOSE Chlorzoxazone O O T: 250 mg 250-750 mg ne NH Cl Cyclobenzaprine T: 10 mg 10 mg Hydrochloride, A.S.P. HCl

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

C Fe N

Mephenesin CH3 T: 500 mg 1-2 g (pH OCH2CHCH2OH

Metaxalone H3C T: 400 mg 800 mg

O

(O- Ne°NH H3C Methocarbamol, OCH3 T: 500, 750 mg 1-2 g. oral U.S.P. I: 100 mg/ml 1-3 g. i.v., OH slowly 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 focHCH."N, HOCCOH H CH3 O I H3C CH2COH T = tablet; I = injection. Mephenesin has been the most extensively studied drug among the skeletal muscle relaxants. Although macological mode of action are the benzodiazepines rarely used today it is a prototype for other skeletal (e.g., diazepam), baclofen and cyclobenzaprine. Diaze muscle relaxants which have similar pharmacological 60 pam and other benzodiazepines are used for a variety of actions. These include carisoprodol, chlorphenesin car spastic states but may be most useful in painful spasms of bamate, chlorZoxazone, metaxalone, methocarbamol flexor muscles. and orphenadrine citrate. Methocarbamol and orphena These drugs appear to have a more selective action drine citrate can be administered either orally or intra on reticular neuronal mechanisms that control muscle venously. In the latter case, it is used to relieve severe, 65 tone than on spinal interneuronal activity, whereas me acute muscle spasm of local origin caused by inflamma phenesin-like drugs exhibit no such selectivity. Baclofen tion or trauma. Other clinically useful skeletal muscle is used for the treatment of spasticity in patients with relaxants which differ from mephenesin in their phar multiple sclerosis. Baclofen's usefulness is limited by its 4,780,463 15 16 adverse effects which include drowsiness, insomnia, AMA Druo Evaluations, 5th Ed., page 103 comment that dizziness, etc. Cyclobenzaprine is closely related to the results of some studies have alleged that a combination tricyclic both structurally and pharma of muscle relaxant and an analgesic provides greater cologically and has side effects which are common with benefit in patients with acute musculoskeletal problems that group of drugs. 5 than similar doses of analgesic alone. The same page of In addition to the centrally-acting muscle relaxants AMA Drug Evaluations lists examples of combination identified above, is a typical non-centrally skeletal muscle relaxants and analgesics. acting muscle relaxant which exerts its effects by direct Surprisingly, the present inventors now find that, the actions on skeletal muscle. Dantrolene has the follow newer non-steroidal anti-inflammatory drugs, which ing chemical structure: 10 differ substantially in chemical structure from aspirin, acetominophen and phenacetin, and which have signifi cantly different biological profiles therefrom can be advantageously formulated into a novel composition together with a skeletal muscle relaxant and adminis 15 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 every 4 to 6 hours; for example, diflunisal and naproxen direct action on excitation-contraction coupling, per 20 are typically administered only twice daily and pirox haps by decreasing the amount of calcium released from ican only once a day. When such long-acting drugs are the sarcoplannic 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 tained release form. do the centrally-acting muscle relaxants. Dantrolene 25 sodium is available for oral use at 25-100 mg in a single Typical therapeutically active components of the dose or for intravenous administration up to a total of 10 present invention, along with their usual adult dosage, mg/kg. for use in the pharmaceutical compositions and methods The preferred muscle relaxants intended for use in the of the present invention are set forth in the following practice of the present invention include diazepam, 30 Table IV. carisoprodol, chlorZoxazone, methocarbamol and or Illustrative of typical unit dose forms are tablets or phenadrine citrate. capsules containing the amounts indicated in Table IV. With respect to the dosage amount of the skeletal Note that the asterisk (*) indicates that the adjacent muscle relaxant in the formulations of the invention, amount is in sustained release form, e.g. "130 mg -- 130 although the specific dose will vary depending upon the 35 mg" means that the first 130 mg is formulated for age and weight of the patient, the severity of the symp immediate release, while the second 130 mg is in sus toms, the incidence of side effects and the like, for hu tained release form. mans, typical effective amounts of the presently pre TABLE IV ferred skeletal muscle relaxants for use in unit dose Typical Unit Doses compositions of the invention are about 2-10 mg diaze Skeletal Muscle Relaxant NSAID pam, 100-600 mg carisoprodol, 100-1000 mg chlorzoxa diazepam - ibuprofen zone, 200-2000 mg methocarbamol and 25-100 mg 2 mg 100 mg orphenadrine citrate. 5 mg 200 mg For those compounds not indicated as members of 10 mg 400 mg the preferred category their typical or suggested ranges 45 diazepam - hapOXC 2 mg + 2 mg 125 mg of unit dose administration are well-known to those in 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 2 mg 100 mg those familiar with skeletal muscle relaxants. 50 5 mg 200 mg 10 mg 200 mg The skeletal muscle relaxant may be centrally-acting 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. chlorzoxazone napCXC Several commercial centrally-acting skeletal muscle 55 250 mg - 250 mg 125 mg relaxants are currently available in the United States in 500 mg + 500 mg 250 mg formulations with aspirin or acetaminophen. The list of 500 mg + 500 mg 500 mg these currently available combination products is pres chlorzoxazone fenoprofen 250 mg 100 mg ented in Table I. These products are intended to pro 500 mg 200 mg vide an analgesic component to help relieve both the chlorzoxazone piroxicam pain and in some cases the anxiety of the pain experi 250 mg + 250 mg" 20 mg ence. Elenbass reviewed the published studies of such 500 mg + 500 mg" 20 mg combination products in American Journal of Hospital carisoprodol ibuprofen Pharmacy, Vol. 37, Oct. 1980, pages 1313-1323. He 200 mg 200 mg 400 mg 400 mg concluded that the combination products provide ingre 65 carisoprodol napoxen dients to treat both the spasm and pain associated with 200 mg - 200 mg 125 mg musculoskeletal disorders, and they appear to provide 200 mg - 200 mg 250 mg better symptom relief than the individual agents. The 400 mg -- 400 mg 500 mg 4,780,463 17 18 suspensions, optionally containing appropriate solutes TABLE IV-continued to effectuate isotonicity, will be employed. Typical Unit Doses The pharmaceutical compositions of the present in Skeletal Muscle Relaxant NSAID carisoprodol difumisal vention may also be formulated and administered by 200 mg - 200 mg 250 mg other methods which are known for administering anal 200 mg -- 200 mg 500 mg gesics. The composition may be adapted fr rectal ad 400 mg -- 400 mg 500 mg ministration, for example, as a suppository The compo methocarbamol ibuprofen sition may also be adapted for topical application, for 400 mg 200 mg example, the composition may be applied in a pharma 800 mg 400 mg 10 ceutically acceptable topical vehicle selected from the methocarbamol apoel group consisting of creams, gels, ointments, powders, 400 mg - 400 mg 125 mg 400 mg -- 400 mg 250 mg aerosols and solutions suitable for topical administra 800 mg - 800 mg 500 mg tion. methocarbamol sulindac As representative suitable formulations consistent 400 mg - 400 mg 150 mg 15 with the objects, features and advantages of the present 800 mg - 800 mg 200 mg invention, the following non-limiting examples are pro orphenadrine citrate ibuprofen vided. 25 mg 200 mg 50 mg 400 mg EXAMPLE orphenadrine citrate able 25 mg -- 25 mg 125 mg 20 ChlorZoxazone-250 mg 25 mg - 25 mg 250 mg Ibuprofen-400 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 25 EXAMPLE 2 Methocarbamol-400 mg In accordance with the practices of the present inven Fenoprofen-200 mg tion, the NSAID/skeletal muscle relaxant composi Triturate active ingredients and q.s. with lactose to tions, may be administered in admixture with suitable selected capsule size pharmaceutical diluents, carriers or other excipients 30 From the foregoing, other typical acceptable phar (collectively referred to as "carrier' materials) suitably maceutical formulations will be apparent to those selected with respect to the intended route of adminis skilled in the art of pharmaceutical formulations. tration and conventional pharmaceutical practices. For While the invention has been described and illus instance, for oral administration in the form of tablets or trated with reference to certain preferred embodiments capsules, the active drug components may be combined 35 thereof, those skilled in the art will appreciate that vari with any oral non-toxic pharmaceutically acceptable ous changes, modifications and substitutions can be inert carrier such as lactose, starch, sucrose, cellulose, made therein without departing from the spirit of the stearate, dicalcium phosphate, calcium sul invention. For example, effective dosages other than fate, mannitol and the like. Moreover, when desired or the preferred ranges set forth hereinabove with respect necessary, suitable binders, lubricants, disintegrating to the active ingredients may be applicable as a conse agents and coloring agents can also be incorporated in quence of variations of the responsiveness of the mam the mixture. Suitable binders include starch, gelatin, mal treated, severity of symptoms, dosage related ad natural sugars, corn sweeteners, natural and synthetic verse effects, if any, observed and similar consider gums such as acacia, sodium alginate, carboxymethyl ations. Accordingly, such expected variations or differ 45 ences in the practice of the present invention and the cellulose, polyethylene glycol and waxes. Among the 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 50 What we claim is: gum, etc. Sweetening and flavoring agents and preser 1. A pharmaceutical composition of matter for use in vatives can also be included where appropriate. the treatment of musculoskeletal disorders in a mamma Of course, additionally, the compositions of the pres lian organism, said composition comprising an analgesi ent invention may be formulated in sustained release cally and anti-inflammatory effective amount of (i) at form to provide the rate controlled release of any one or 55 least one of the propionic acid NSAIDs, ibuprofen, more of the components to optimize the therapeutic naproxen, , flurbiprofen, fenoprofen, fen effects, i.e., analgesia, skeletal muscle relaxation, etc. bufen, ketoprofen, , pirprofen, , while minimizing undesirable side effects. Suitable dos oxaprozin, , moriprofen, ibuprofen alumi age forms for sustained release include layered tablets num, tioxaprofen, suprofen, , tiaprofenic containing layers of varying disintegration rates or con 60 acid, fluprofen, bucloxic acid, or pharmaceutically ac trolled release polymeric matrices impregnated with the ceptable salt thereof, in combinatory immixture with a active components and shaped in tablet form or cap skeletal muscle relaxing amount of (ii) at least one of the sules containing such impregnated or encapsulated po SMRs, analexin, baclofen, chlormezanone, cyclobenza rous polymeric matrices. prine, orphenadrine, or pharmaceutically acceptable Similarly, injectable dosage units may be utilized to 65 salt thereof. accomplish intravenous, intramuscular or subcutaneous 2. The pharmaceutical composition as defined by administration and, for such parenteral administration, claim 1, said NSAID (i) comprising ibuprofen, na suitable sterile aqueous or non-aqueous solutions or proxen, flurbiprofen, fenoprofen, ketoprofen, suprofen, 4,780,463 19 20 fenbufen, fluprofen, or pharmaceutically acceptable salt 11. The pharmaceutical composition as defined by thereof. claim 3, comprising from about 100 mg to 400 mg of 3. The pharmaceutical composition as defined by ibuprofen or pharmaceutically acceptable salt thereof. claim 2, said NSAID (i) comprising ibuprofen or phar 12. A method for the treatment of musculoskeletal disorders in a mammalian organism in need of such maceutically acceptable salt thereof. treatment, comprising administering to such organism a 4. The pharmaceutical composition as defined by symptom relieving analgesically and anti-inflam claim 2, said NSAID (i) comprising naproxen or phar matorily effective amount of (i) at least one of the propi maceutically acceptable salt thereof. onic acid NSAIDs, ibuprofen, naproxen, benoxaprofen, 5. The pharmaceutical composition as defined by 10 flurbiprofen, fenprofen, fenbufen, ketoprofen, indo claim 2, said NSAID (i) comorising ketoprofen or phar profen, pirprofen, carprofen, oxaprozin, pranoprofen, maceutically acceptable salt thereof. miroprofen, ibuprofen aluminum, tioxaprofen, suprofen, 6. The pharmaceutical composition as defined by alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, claim 1, said SMR (ii) comprising cyclobenzaprine or or pharmaceutically acceptable salt thereof, in combina pharmaceutically acceptable salt thereof. 15 tory immixture with a skeletal muscle relaxing amount 7. The pharmaceutical composition as defined by of (ii) at least one of the SMRs, analexin, baclofen, claim 1, further comprising a pharmaceutically accept chlormezanone, cyclobenzaprine, orphenadrine, or able non-toxic carrier. pharmaceutically acceptable salt thereof. 8. The pharmaceutical composition as defined by 13. A method for the treatment of musculoskeletal 20 disordrs in a mammalian organism in need of such treat claim 1, in oral dosage form. ment, comprising adfministering to such organism the 9. The pharmaceutical composition as defined by pharmaceutical composition as defined by claim 1. claim 1, comprising from about 12.5 mg to 900 mg of 14. A method for the treatment of musculoskeletal said NSAID (i). disorders in a mammalian organism in need of such 10. The pharmaceutical composition as defined by 25 treatment, comprising administering to such organism claim 6, comprising from about 5 mg to 100 mg of said the pharmaceutical composition as defined by claim 7. SMR or pharmaceutically acceptable salt thereof. ck sk : sk :k

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