sign in sign up
<<
Home , Alclofenac, Fenamic acid, Indoprofen, Isoxicam, Miroprofen, Nefopam

United States Patent (19) 11 Patent Number: 4,985,459 Sunshine et al. 45 Date of Patent: Jan. 15, 1991

54 ANALGESCAND ANTI-NFLAMMATORY 4848M 2/1967 France. COMPOST ONS COMPRISING 1042637 9/1966 United Kingdom . DPHENHYDRAMINE AND METHODS OF OTHER PUBLICATIONS USING SAME Rote Liste 1977/78; 71 021 B. (75) Inventors: Abraham Sunshine, New York; Lear et al., "Comparative Studies of Tranquilizers Used Eugene M. Laska, Larchmont; in Anesthesia", JAMA, 1958, 166(12):1438-1443. Carole E. Siegel, Mamaroneck, all of Cappe, B. E. et al., "Recent Advances in Obstetric N.Y. Analgesia”, JAMA, 1954, 154(5):377-379. (73) Assignee: Richardson-Vicks, Inc., Shelton, Campos, V. M. et al., "The and Hypothermic Conn. Effects of , , , Diphenhydra mine and Placebo', Journal of Clin. Pharmacology, (21) Appl. No.: 420,947 Jan. 1980, pp. 42-49. Fied: Albal, M. V. and Chandorkar, A. G., "Clinical Evalua 22 Oct. 13, 1989 tion of Sedyn-a-Forte, an Analgesic Injection Contain ing Analgin, and ', Indian Related U.S. Application Data Journal of Ophthalmology, 1982, 30:271-273. 62) Division of Ser. No. 180,570, Apr. 12, 1988, Pat. No. Beaver, W.T. and Feise, G., "Comparison of the Anal 4,906,625, which is a division of Ser. No. 41,692, Apr. gesic Effects of Morphine, , and Their 23, 1987, Pat. No. 4,755,532, which is a division of Ser. No. 856,414, Apr. 28, 1986, Pat. No. 4,683,243, which Combination in Patients with Postoperative Pain', Ad is a division of Ser. No. 711,525, Mar. 14, 1985, Pat. vances in Pain Research and Therapy, 1976, 1:553-557. No. 4,585,783, which is a division of Ser. No. 578,288, Bluhm et al., "Potentiation of Analgesia by H1 Feb. 8, 1984, Pat. No. 4,522,826. and H2 Antagonists', Life Sciences, 1982, 31:1229-232. (51) Int. Cl...... A61K 31/135; A61K 31/195 (52) U.S. C...... 514/561; 514/653 Primary Examiner-Stanley J. Friedman (58) Field of Search ...... 514/561, 653 Attorney, Agent, or Firm-Burns, Doane, Swecker & Mathis 56) References Cited U.S. PATENT DOCUMENTS 57 ABSTRACT Novel pharmaceutical compositions of matter are pro 3,167,475 4/1965 Gottfried et al...... 514/557 vided comprising analgesic/non-steroidal anti-inflam 4,322,427 9/1982 Buyniski et al...... 514/557 matory drugs and diphenhydramine and methods of 4,379,789 12/1983 Capetola et al...... 514/557 using said compositions to elicit an enhanced analgesic FOREIGN PATENT DOCUMENTS and/or anti-inflammatory response in mammalian or 1940.6, 4/1976 Austria . ganisms in need of such treatment. 0030092 2/1985 European Pat. Off. . 2544100 10/1975 Fed. Rep. of Germany . 32 Claims, 1 Drawing Sheet U.S. Patent Jan. 15, 1991 4985,459

--- f2, 4:44:/AC45(WDF WHA ASSO/P/70/WAZA 7FEA/E/FWJSAEAD///WA e W0 (7/7 (F 4 A/(AA0/A2/AA) E OF 18UPROFE A10: fe of DPIEWOAWE ALONE A 470 of 10 0 19é £ 470 of 10 ( 924 £ 470 of 70 062 £ 470 of 70 04:32

A770,924

A7062

AA//042

2 4 6 10 2 14 16 f 2022 24 2230 234 is is 40 42 44 WP:WAWF 4,985,459 1 2 York, 1979, Chapter 49:538-550, including structural ANALGESIC AND ANT-NFLAMMATORY formulas for representative group members. COMPOSITIONS COMPRISING Diphenhydramine2-(diphenylmethoxy)-N,N-dime DPHENHYDRAMINE AND METHODS OF thylethylamineis also a well-known therapeutic agent USING SAME in long standing use by clinicians as an . It is recognized in both the U.S.P. and N.F. as an official CROSS-REFERENCE TO RELATED antihistamine of the ethanolamine (or aminoalkyl ether) APPLICATIONS type and is available as the hydrochloride salt in Bena dryl (R) and various alternative sources in 50 milligram This application is a division of application Ser. No. 10 delayed action tablets, 25 and 50 milligram capsules, 180,570, filed Apr. 12, 1988, now U.S. Pat. No. elixirs (12.5 mg/5 ml) and sterile solution for injection 4,906,625; which is a division of application Ser. No. (10 mg/ml). Depending upon the therapeutic indica 041,692, filed Apr. 23, 1987, now U.S. Pat. No. tion, diphenhydramine is recommended in single or 4,755,532; which is a division of Ser. No. 856,414, filed divided doses of between 12.5 to 50 milligrams with a Apr. 28, 1986, now U.S. Pat. No. 4,683,243; which is a 15 maximum daily dosage not to exceed 300 milligrams. division of Ser. No. 711,525, filed Mar. 14, 1985, now The antihistaminic activity of diphenhydramine is di U.S. Pat. No. 4,585,783; which is a division of Ser. No. rectly attributable to its competition with histamine for 578,288, filed Feb. 8, 1984, now U.S. Pat. No. 4,522,826. cell sites on effector cells although diphenhy BACKGROUND OF THE INVENTION dramine also demonstrates, in addition, a number of 20 therapeutic applications attributable to central actions The present invention relates generally to novel phar unrelated to histamine antagonism. Antihistaminic indi maceutical compositions of matter comprising diphen cations for diphenhydramine include perennial and sea hydramine and one or more non-steroidal anti-inflam sonal allergic rhinitis, vasomotor rhinitis, allergic con matory drugs (NSAID) having analgesic and anti-in junctivitis, urticaria and as adjunctive therapy for ana flammatory properties, and to methods of using said 25 phylactic reactions. Central nervous system side effects compositions to elicit an enhanced analgesic or anti-in (non-histaminic actions) which have been capitalized flammatory response in mammalian organisms in need upon include prophylactic and active treatment of no of such treatment. tion sickness and, more broadly, as an antinauseant and Non-narcotic , most of which are also in the treatment of mild forms of Parkinsonism. Diphen known as non-steroidal anti-inflammatory drugs 30 hydramine demonstrates both and depressant (NSAID), are widely administered orally in the treat effects on the central nervous system although stimula ment of mild to severe pain. Within this class, the com tion is only occasionally seen in patients given conven pounds vary widely in their chemical structure and in tional doses with accompanying restlessness, nervous their biological profiles as analgesics, anti-inflammatory ness and inability to sleep. The more predominant seda agents and agents. Aspirin, acetaminophen 35 tive action of diphenhydramine has been beneficially and have long been among the most com capitalized upon with the usage of diphenhydramine as monly used members of this group; more recently, how a somnolent when employed at the maximum 50 milli ever, a large number of alternative non-narcotic agents grams dose in both prescription and over-the-counter offering a variety of advantages over the earlier drugs forms. In this regard, it is noted that the Food and Drug have been developed. Tolernce or addiction to these Administration announced in the November 1983 FDA drugs is not generally a problem with their continuous Drug Bulletin (Vol. 13, No. 3) that diphenhydramine use in the treatment of pain or in the treatment of acute (50 mg.) may now be marketed over-the-counter as a or chronic inflammatory states (notably, rheumatoid nighttime sleep aid. arthritis and osteoarthritis); nevertheless, these drugs An early study (1958) investigated the properties of generally have a higher potential for adverse side-ef 45 diphenhydramine as a pre-anesthetic . (Lear, fects at the upper limits of their effective dose ranges. et al., "Comparative Studies of Tranquilizers Used in Moreover, above each drug's upper limit or ceiling, Anesthesia.' JAMA, 1958, 166(12): 1438-1443). The administration of additional drug does not usually in authors concluded that diphenhydramine, particularly crease the analgesic or anti-inflammatory effect. when used in combination with meperidine, provides Among the newer compounds in the non-narcotic anal 50 beneficial preoperative sedation with less overall de gesic/nonsteroidal anti-inflammatory group are com pression than previously experienced with the use of pounds such as (Dolobid (R)), so routine doses or narcotics and . dium (Zomax (R)), (Motrin (E), (Na Diphenhydramine has also been investigated with prosyn (R), (Nalfon (E)), (Fel varying results with respect to its potential as a weak dene (R), , (Ponstel (R)) and 55 analgesic. Diphenhydramine hydrochloride when intro . See also Physicians' Desk Referenoe, 35th edi duced intravenously has been reported as being useful tion, 1981, and The Merck Index, ninth edition, Merck & in obstetric analgesia alone and in combination with Co., Rahway, N.J. (1976), for information on specific . See Cappe, B. E. et al., "Recent Advances in nonsteroidal anti-inflammatory agents. Also see, gener Obstetric Analgesia', JAMA, 1954, 154(5); 377-379. ally, Wiseman, "Pharmacological Studies with a New Campos et al in a comparative study found that diphen Class of Nonsteroidal Anti-Inflammatory Agents-The hydramine given either orally or intramuscularly could -With Special Reference to Piroxican (Fel not be distinguished from placebo in patients with post dene (R), The American Journal of Medicine, Feb. 16, operative fractures or somatic pain "The Analgesic and 1982:2-8; Foley et al, The Management of Cancer Pain, Hypothermic Effects of Nefopam, Morphine, Aspirin, Volume II-The Rational Use of Analgesics in the Man 65 Diphenhydramine and Placebo', Journal of Clin. Phar agement of Cancer Pain, Hoffman-LaRoche Inc., 1981; macology, January, 1980, pp. 42-49. and Cutting's Handbook of Pharmacology, sixth edition, Albal and Chandorkar studied an injectable combina ed. T. Z. Czaky, M.D., Appelton-Century-Crofts, New tion analgesic consisting of analgin 375 mg, a centrally 4,985,459 3 4. acting analgesic, diazepam 2.5 mg, and diphenhydra tory responses in mammals, including humans, by the mine 20 mg, and found relief from pain. They did not, preselected dosages of a non-steroidal anti-inflamma however, study the unique contribution of diphenhy tory agent, with diphenhydramine. dramine. Albal, M.V., and Chandorkar, A.G. "Clinical A still further object of the present invention is to Evaluation of Sedyn-a-Forte, an Analgesic Injection provide a pharmaceutical composition of matter for Containing Analgin, Diphenhydramine and Diaze obtaining a synergistic analgesic and anti-inflammatory pan.' Indian Journal of Ophthalmology, 1982, response in mammals in which the composition con 30:271-273). Note: analgin referred to in the foregoing prises an analgesically and anti-inflammatorily effective study is dypyrone; see The Merck Index, p. 3361, 1976.) amount of a selected NSAID and a synergistic amount While diphenhydramine has been investigated with 10 of diphenhydramine optionally in the presence of a respect to its weak analgesic properties, it is also evident pharmaceutically acceptable inert carrier. from the foregoing that its sedative and Another object of the invention is to provide suitable properties may, in part, account for its suspected poten dosage unit forms of one or more NSAID's and diphen tial for relieving pain. In the Lear et al, supra, study hydramine adapted for, e.g., oral, rectal, parenteral, diphenhydramine at 25 to 50 milligram doses was insuf 15 topical, etc., administration and useful in the treatment, ficient as a preanesthetic medication and combination management and mitigation of pain and/or inflamma with meperidine (a narcotic analgesic) was proposed to tion. optimize the potential beneficial effects of diphenhydra These and other similar objects, advantages and fea mine as an analgesic. tures are accomplished according to the products, com Hydroxyzine, which is a minor tranquilizer with anti 20 positions and methods of the invention comprised of a histaminic activity, has been evaluated as an analgesic. non-steroidal anti-inflammatory drug or analgesic and Beaver and Feise found that, "This study unequivocally diphenhydramine and analgesic and anti-inflammatory demonstrates analgesic activity for a 100 mg dose of methods employing same. intramuscular hydroxyzine in the general range of that BRIEF DESCRIPTION OF THE DRAWING produced by 8 mg of morphine. In addition, the analge 25 sic activity of hydroxyzine appears additive with that of The Figure of Drawing is a plot of dose of diphenhy morphine when the two drugs are given together." The dramine versus dose of ibuprofen in the phenylquinone findings of the study do not indicate synergistic activity. writhing assay to indicate the number of mice pro (Beaver, W.T. & Feise, G. "Comparison of the Analge tected. sic Effects of Morphine, Hydroxyzine, and Their Com 30 bination in Patients with Postoperative Pain.' Advances DESCRIPTION OF THE PREFERRED in Pain Research and Therapy, 1976, 1:553-557) EMBODIMENTS Only recently have animal studies been conducted in It has now been unexpectedly found in accordance which the analgesic activity of diphenhydramine has with the present invention of the analgesic and anti-in been investigated. Bluhm, et al., in a study conducted on 35 flammatory effects observed upon the administration of mice, found that diphenhydramine potentiates mor a non-narcotic analgesically active non-steroidal anti-in phine, a centrally acting drug, when administered par flammatory drug (i.e., analgesic/NSAID), can be syner enterally. Oral administration of drugs was not studied. gistically enhanced by the coadministration of diphen (Bluhm, et al., "Potentiation of Opioid Analgesia. By Hil hydramine or a non-toxic pharmaceutically acceptable and H2 Antagonists.' LifeSciences, 1982, 31:1229-1232). salt thereof. Diphenhydramine has not been heretofore proposed As used herein, the terms "synergism' and "synergis for use in combination with any of the newer nonsteroi tic' are used to describe the potentiated analgesic and dal analgesic/anti-inflammatory agents (i.e., excluding anti-inflammatory responses elicited by the co-adminis aspirin, acetaminophen and phenacetin). In U.S. Pat. tration of an analgesic NSAID and diphenhydramine No. 4,420,483 issued Dec. 13, 1983, the present appli 45 (or pharmaceutically acceptable salts thereof). More cants disclose the hastening of the onset of analgesic and specifically, these terms as used herein are defined in anti-inflammatory responses observed with several dif contradistinction to merely additive effects. Ihe effects ferent nonsteroidal anti-inflammatory agents as well as of two compounds are additive if the response to a dose the enhancement of the analgesic and anti-inflammatory o both in combination does not change when a portion response with such agents by the concomitant adminis 50 of one component is removed from the mixtures and tration of as a potentiating adjuvant. replaced by an equipotent portion of the other. If such Applicants have now surprisingly found that diphen substitution increases the response, the mixing together hydramine synergistically enhances the analgesic and of the compounds is said to potentiate their effects and anti-inflammatory properties of such non-steroidal anti synergism exists. inflammatory drugs (NSAID). 55 The non-narcotic analgesics/nonsteroidal anti-in flammatory drugs for use in the compositions and meth SUMMARY OF THE INVENTION ods of the present invention can be selected from the It is, therefore, a primary object of the present inven following categories: tion to provide a novel pharmaceutical composition of (1) the derivatives; matter for promoting an enhanced analgesic and anti-in 60 (2) the derivatives; flammatory response in a mammalian organism in need (3) the derivatives; of such treatment comprising an analgesically and anti (4) the biphenylcarboxylic acid derivatives; and inflammatorily effective amount of a non-steroidal anti (5) the oxicans. inflammatory drug (NSAID) in combination with di The term "selected NSAID' as used herein is in phenhydramine or a pharmaceutically acceptable salt 65 tended to mean any non-narcotic analgesic/non-steroi thereof. dal anti-inflammatory compound falling within one of It is a further object of the present invention to pro the five structural categories above but excluding aspi vide methods for obtaining analgesic and anti-inflamma rin, acetaminophen and phenacetin. 4,985,459 5 While some of these compounds are primarily used at the present time as anti-inflammatory agents and others are primarily used as analgesics, in fact all of the con templated compounds have both analgesic and anti-in flammatory activity and can be used at appropriate dosage levels for either purpose in the compositions and COOH methods of the present invention. The compounds in groups (1) through (4) typically contain a carboxylic which can bear a variety of substituents and in which O the free -COOH group can be in the form of a pharma acid function; however, those acids are sometimes ad ceutically acceptable salt group, e.g., -COONa. ministered in the form of their pharmaceutically accept The biphenylcarboxylic acid derivatives for use able acid addition or alkali metal salts, e.g., sodium salts. herein include, but are not limited to, diflunisal and The propionic acid derivatives for use herein include, flufenisal. Structurally related biphenylcarboxylic acid but are not limited to, ibuprofen, naproxen, benoxa 15 derivatives having similar analgesic and anti-inflamma profen, flurbiprofen, fenoprofen, , , tory properties are also intended to be encompassed by , , , , prano this group. Preferred members of this group are diflu profen, , tioxaprofen, , almino nisal and flufenisal. profen, , fluprofen and bucloxic acid. Thus, "biphenylcarboxylic acid derivative' as de Structurally related propionic acid derivatives having 20 fined herein are non-narcotic analgesics/nonsteroidal similar analgesic and anti-inflammatory properties are anti-inflammatory drugs which contain the basic struc also intended to be encompassed by this group. Pres ture ently preferred members of the propionic acid group include ibuprofen, naproxen, flurbiprofen, fenoprofen, 25 ketoprofen and fenbufen. Thus, "propionic acid derivatives' as defined herein are non-narcotic analgesics/nonsteroidal anti-inflamma COOH tory drugs having a free -CH(CH3)COOH or which can bear a variety of substituents and in which -CH2CH2COOH group (which optionally can be in 30 the free -COOH group can be in the form of a pharma the form of a pharmaceutically acceptable salt group, ceutically acceptable salt group, e.g. -COONat. e.g. -CH(CH3)COO. Na+ or -CH2CH The oxicams for use herein include, but are not lim 2COONa), typically attached directly or via a car ited to, piroxicam, sudoxican, and CP-14, 304. bonyl function to a ring system, preferably to an aro 35 Structurally related oxicams having similar analgesic matic ring system. and anti-inflammatory properties are also intended to be encompassed by this group. A preferred member of this The acetic acid derivatives for use herein include, but group is piroxicam. are not limited to, indomethacin, sulindac, tolnetin, Thus, "oxicams' as defined herein are non-narcotic zomepirac, , , , ibufe analgesics/nonsteroidal anti-inflammatory drugs which nac, isoxepac, furofenac, tiopinac, zidometacin, have the general formula , , clidanac and oxpinac. Structur ally related acetic acid derivatives having similar anal OH gesic and anti-inflammatory properties are also intended to be encompassed by this group. Presently preferred 45 N--NH-R members of the acetic acid group include so dium, zomepirac sodium, sulindac and indomethacin. s1 N NoH, Thus, "acetic acid derivatives' as defined herein are non-narcotic analgesics/nonsteroidal anti-inflammatory 50 drugs having a free -CH2COOH group (which option wherein R is an aryl or heteroaryl ring system. ally can be in the form of a pharmaceutically acceptable The precise amount of non-narcotic analgesic/non salt group, e.g., -CH2COONat), typically attached steroidal anti-inflammatory drug for use in the present directly to a ring system, preferably to an aromatic or compositions will vary depending, for example, on the heteroaromatic ring system. 55 specific drug chosen, the dosage form thereof, i.e., stan The fenamic acid derivatives for use herein include, dard versus sustained release, the condition for which but are not limited to, mefenamic acid, meclofenamic the drug is administered and the size and kind of the acid, , and . mammal. Structurally related fenamic acid derivatives having Typical effective doses of the non-narcotic anal similar analgesic and anti-inflammatory properties are gesic/nonsteroidal anti-inflammatory drugs include about 100 mg to 400 mg of propionic acid derivatives, also intended to be encompassed by this group. Pres about 25 mg to 200 mg of acetic acid derivatives, about ently preferred members of the fenamic acid group 125 mg to 250 mg offenamic acid derivatives, about 125 include mefenamic acid and meclofenamate sodium mg to 500 mg of biphenyl-carboxylic acid derivatives (, sodium salt). 65 and about 10 mg to 20 mg of . Thus, "fenamic acid derivative' as defined herein are For humans, typical effective analgesic/anti-inflam non-narcotic analgesics/nonsteroidal anti-inflammatory matory amounts of presently preferred NSAIDs for use drugs which contain the basic structure in unit dose compositions of the invention are about 125 4,985,459 7 8 to 500 mg diflunisal, about 25 to 100 mg zomepirac or non-aqueous solutions or suspensions, optionally sodium, about 50 to 400 mg ibuprofen, most preferably containing appropriate solutes to effectuate isotonicity, 100-400 mg, about 125 to 500 mg naproxen, about 25 to will be employed. 50 mg flurbiprofen, and about 50 to 200 mg fenoprofen, Moreover, in accordance with another preferred about 10 to 20 mg piroxicam, about 125 to 250 mg mefe embodiment of the present invention, where therapeu namic acid, about 100 to 400 mg fenbufen or about 25 to tic indications warrant, such as in the case where the 50 mg ketoprofen; however, greater or lesser amounts level of pain and inflammation associated with the dis can be employed if desired. order may interfere with normal sleep latency and For example, in one preferred embodiment of this maintenance dosage regimens may be contemplated, the invention, the desired therapeutic response for ibu 10 NSAID/diphenhydramine compositions of the inven profen therapy in mild to moderate pain is generally tion may be formulated for administration at bedtime as observed at 200 to 600 milligrams of ibuprofen every 4 an analgesically and anti-inflammatorily effective night to 6 hours as necessary up to about 2400 milligrams total time sleep aid. Accordingly, the NSAID and diphenhy daily dose. Consistent with the synergistic results dramine components of the composition may be formu achieved with the ibuprofen/diphenhydramine compo 15 lated in dosage unit form to provide a dose of diphenhy sitions and methods of the present invention, the desired dramine (compared to the amount necessary to promote analgesic and/or anti-inflammatory response can be the desired synergistic response) to take advantage of achieved upon the administration of ibuprofen and di the sleep-inducing side effect of diphenhydramine. phenhydramine wherein the ibuprofen component can In another preferred embodiment, the advantageous be administered at reduced levels of between about 50 20 analgesic and anti-inflammatory compositions of the to 400 milligrams of ibuprofen and, most preferably, 100 invention ma beformulated in sustained release form to to 400 milligrams. Alternatively, the usual dosage regi provide the rate controlled release of either or both of men for ibuprofen may be followed when the composi the components to optimize analgesic and anti-inflam tion of the present invention additionally comprising matory response while minimizing undesirable side diphenhydramine is employed whereby the levels of 25 effects in, for example, patients unusually sensitive to analgesia and anti-inflammatory results are enhanced. either or both of the active drugs. Suitable dosage forms The amount of diphenhydramine present in the com for sustained release include layered tablets containing positions according to the present invention ranges layers of varying disintegration rates or controlled re between about 12.5 to 50 milligrams and, preferably, lease polymeric matrices impregnated with the active between about 25 to 50 milligrams. 30 components and shaped in tablet form or capsules con In any event, the amounts of NSAID and diphenhy taining such impregnated or encapsulated porous poly dramine to be administered in a total daily dose should meric matrices. Thus, with respect to such layered tab not exceed the generally recognized as safe limits estab lets, one layer may contain an initial dosing amount of, lished for the particular NSAID and diphenhydramine for example, ibuprofen, of 400 milligrams and 25 milli when administered alone for their respective usual ther 35 grams of diphenhydramine, whereas two or more fur apeutic indications. ther layers may contain, for instance, 100 milligrams of In the compositions and methods of the invention, an ibuprofen and 15 to 25 milligrams of diphenhydramine NSAID and diphenhydramine may be co-administered to be released serially every 4 to 6 hours consistent with in the same composition or concomitantly administered the normal dosage schedule. Another advantage af separately. forded the analgesic and anti-inflammatory composi In accordance with the practices of the present inven tions of the present invention by the inclusion of the tion, the NSAID/diphenhydramine compositions may diphenhydramine component is that gastro-intestinal be administered in admixture with suitable pharmaceuti disturbances, which are the most frequent adverse reac cal diluents, carriers or other excipients (collectively tions reported for non-steroidal anti-inflammatory referred to as "carrier' materials) suitably selected with 45 drugs, including complaints involving abdominal dis respect to the intended route of administration and con tress, epigastric pain, indigestion, nausea and vomiting ventional pharmaceutical practices. For instance, for may often be minimized or at least, reduced. The fore oral administration in the form of tablets or capsules, the going advantage is both a function of the synergism active drug components may be combined with any oral exhibited by the NSAID/diphenhydramine composi non-toxic pharmaceutically acceptable inert carrier 50 tion which allows for the use of the NSAID component such as lactose, starch, sucrose, cellulose, in quantities substantially less than dosages presently stearate, dicalcium phosphate, calcium sulfate, mannitol considered necessary as an analgesic or anti-inflamma and the like. Moreover, when desired or necessary, tory agent in humans, which lower doses result in low suitable binders, lubricants, disintegrating agents and ering the incidence or severity of undesirable side ef coloring agents can also be incorporated in the mixture. 55 fects, as well as the presence of diphenhydramine con Suitable binders include starch, gelatin, natural sugars, tributing valuable antinauseant and antiemetic proper corn sweeteners, natural and synthetic gums such as ties to the composition. acacia, sodium alginate, carboxymethylcellulose, poly In patients particularly susceptible to the tendency of glycol and waxes. Among the lubricants there either the NSAID or diphenhydramine to promote may be mentioned for use in these dosage forms, boric drowsiness or, in the extreme, sedation and, otherwise, acid, sodium benzoate, sodium acetate, sodium chloride, in ambulatory patients where drowsiness and/or seda etc. Disintegrators include, without limitation, starch, tion may represent untoward side effects, the composi methylcellulose, agar, bentonite, guar gum, etc. Sweet tions of the present invention may further include caf. ening and flavoring agents and preservatives can also be feine to counteract drowsiness symptoms and to further included where appropriate. Similarly, injectable dos 65 take advantage of the potentiated analgesic and anti-in age units may be utilized to accomplish intravenous, flammatory response effectuated by the addition of intramuscular or subcutaneous administration and, for caffeine as disclosed in applicants U.S. Pat. No. such parenteral administration, suitable sterile aqueous 4,420,483. 4,985,459 9 10 (11,20), (9,24), (6,28), (4,32). Table 2 shows for each of EXAMPLE 1 PHARMACOLOGICTEST FOR these combination doses, the number of mice protected SYNERGISM from writhing activity. IBUPROFEN/DIPHENHYDRAMINE. On the third and fourth days the four specific fixed The unexpected synergistic analgesic effect of the 5 addition of diphenhydramine to ibuprofen is evidenced ratios that achieved 5 or more protected mice were by tests conducted on mice. Blue Spruce Farm male studied in more detail, i.e., the first combination treat mice weighing 18-28 grams at the time of testing are ment used a ratio of ibuprofen to diphenhydramine of used throughout. All mice are dosed orally by gavage 19:8 and the doses of the constituent drugs in mg/kg with ibuprofen and/or diphenhydramine. The formula 10 that were studied were (8,3), (12,5), (16,7) and (28,12). tion of each test article is a solution or suspension in The second combination treatment used a ratio of doses 0.25% methylcellulose manufactured by Fisher Scien of ibuprofen to diphenhydramine of 6:28 and the doses tific Company. A dosing volume of 10 ml/mg is used. of the constituent drugs in mg/kg that were studied All doses are coded and the test is performed under a were (3,14), (4.5,21) and (9,42). The third combination code not known to the observer. Doses are based upon 15 treatment used a ratio of doses of ibuprofen to diphen the weights of the animal taken prior to dosing. hydramine of 9:24 and the doses of the constituent drugs in mg/kg that were studied were (3,8), (6,16), (12,32) METHOD and (15,40). The fourth combination treatment used a A phenylquinone writhing assay in mice was con ratio of doses of ibuprofen to diphenhydramine of 4:32 ducted over a four day period to test for synergism of 20 and the doses of the constituent drugs in mg/kg that the analgesic activity of ibuprofen and diphenhydra were studied were (3,24), (3.5,28) (4.5,36) and (5,40). le. The assay consists of phenyl-p-benzoquinone (PPQ) Under the assumption of additivity each dose of each introduced in mice thirty minutes post dose of the test combination is equivalent to a dose of ibuprofen, based treatment(s). The PPQ is prepared as a 0.02% aqueous 25 on the relative potency (p) of diphenhydramine to ibu solution in 5 ml ethyl alcohol qs. to 100 ml with dis profen obtained from the experiment on the first day. tilled water and is administered intraperitoneally at 0.25 Thus, for example, in the dose ratio 19:8 the combina ml/mouse. The mice are injected with the PPQ solution tion of 28 mg/kg of ibuprofen and 12 mg/kg of diphen and are placed in individual plastic squares 4'x4'x45" hydramine is, under the assumption of additivity, equiv deep and observed for a ten minute period post treat 30 alent to (28--12p) mg/kg of ibuprofen. Table 3 shows ment dose for exhibition of the writhing syndrome. for each dose of each of the combination doses tested Complete blocking of the writhing syndrome for the ten the number of mice observed to be protected and the minute observation period in any one mouse is consid ibuprofen equivalent dose. For each of the four combi ered a positive response for that mouse. Conversely, if nation ratios, ED50's were estimated based on the ob the mouse definitely writhes at least once, it is consid- 35 served number of mice protected at each ibuprofen ered to be not protected from the PPQ. equivalent dose using the method of Finney. Table 4 Three hundred twenty-eight mice were randomly assigned to 40 groups. Two groups of ten mice per displays the estimated ED50's for each ratio. series were assigned to a control group (10 prior to the RESULTS administration of the test treatments and 10 post admin- 40 The surprising synergistic effects of combining ibu istration) to verify the ability of the solutions to produce the writhing response. profen with diphenhydramine can be seen from the The purpose of the assay on the first day is to estimate results of Tables 3 and 4 and the Figure of Drawing. the ED50 (effective dose in 50% of treated mice) of The Figure of Drawing summarizes all of the findings ibuprofen alone and of diphenhydramine alone, and to 45 by depicting the ED50's obtained for each treatment estimate the relative potency,p, of ibupofen to diphen alone, the ED50 line if the treatments were additive, the hydramine, determined as the ratio of the ED50 of ibu number of mice/protected from writhing for each treat profen to the ED50 of diphenhydramine. Eight mice per ment studied and the estimated ED50's for each combi group are dosed orally (via intubation) with 2, 5, 10 and nation ratio. 20 mg/kg of ibuprofen and 5, 10, 20 and 50 mg/kg of 50 The ED50 of ibuprofen alone is estimated to be 24 diphenhydramine. Table 1 shows the number of mice mg/kg and for diphenhydramine to be 38 mg/kg. The protected from writhing activity for each dose of ibu relative potency of diphenhydramine to ibuprofen is profen and diphenhydramine. The method of Finney 24/38. Among the 8 ratios tested on the second day, "Statistical Method of Biological Assay”, McMillan synergism appears to be present for four ratios, and Pub., 3rd Edition, 1978)is used to estimate the ED50's of 55 these ratios were further investigated on days 3 and 4. ibuprofen alone and diphenhydramine alone. The ED50's were found to be for the dosage ratio of On the second day eight combination doses were 19:8, 23 mg/kg of ibuprofen, for the dosage ratio 6:28, studied. The doses were chosen based upon the ED50's established in the preceding day's experiment, which, 19 mg/kg of ibuprofen, for the dosage ratio 9:24, 18 under the assumption of additivity, would provide pro mg/kg of ibuprofen, and for the dosage ratio 4:32, 23 tection for 50% of the mice. These doses were tested in mg/kg of ibuprofen. Two of these ED50's are substan order to observe those ratio(s) of the combination drugs tially less than 24 mg/kg of ibuprofen which is the that would yield a synergistic effect. Combinations for ED50 that would be expected if the effects were addi which five or more mice exhibit blockage of writhing tive. This represents a 25% reduction of the amount of are candidates for further study. The doses of the con 65 ibuprofen that is required to obtain the effect in 50% of stituent drugs in mg/kg for the eight groups were for the animals. The graph in the Figure of Drawing indi ibuprofen (I) and diphenhydramine (D) respectively, cates that many other dose ratios as well would produce abbreviated as (I,D): (22,4), (19,8), (16,12), (14,6), an unexpected synergistic effect. 4,985,459 11 12 ous changes, modifications and substitutions can be TABLE 1 made therein without departing from the spirit of the NUMBER OF MICE AT TESTED DOSE LEVELS OF IBUPROFENAND DEPHENHYDRAMINE invention. For example, effective dosages other than Dose of Dose of Number the preferred ranges set forth hereinabove may be appli Ibuprofen Diphenhydramine of Mice Number of Mice cable as a consequence of variations in the responsive mg/kg mg/kg Protected Not Protected ness of the mammal treated, severity of pain or inflam 2 - O 8 mation, dosage related adverse effects, if any, observed 5 - O 8 and analogous considerations. Likewise, the specific O - 7 pharmacological responses observed may vary depend 20 - 3 5 --- 5 1 7 ing upon the particular relative amounts of active com --- 5 2 6 ponents employed or whether same are used in combi Mr. 10 2 6 nation with suitable pharmaceutical carriers, as well as --- 20 3 5 the type of formulation and mode of administration 40 4. 4. employed, and such expected variations or differences in results are contemplated in accordance with the ob jects and practices of the present invention. It is in TABLE 2 tended, therefore, that the invention be limited only by NUMBER OF MICE PROTECTED AT TESTED DOSES OF THE COMBINATION the scope of the claims which follow. OF BUPROFENAND DIPHENHYDRAMINE What is claimed is: Doses of Dose of Number 20 1. A method for eliciting an enhanced analgesic and Ibuprofen Diphenydramine of Mice of Mice anti-inflammatory response in a mammalian organism in mg/kg mg/kg Protected Not Protected need of such treatment, comprising administering to 22 4 4 4. such organism 19 8 5 3 (i) an analgesically and anti-inflammatorily effective 16 12 3 5 25 14 6 4 4. amount of mefenamic acid, meclofenamic acid, 20 4. 4. flufenamic acid, niflumic acid or tolfenamic acid, 9 24 5 3 or a pharmaceutically acceptable salt thereof; and 6 28 5 3 (ii) an analgesically and anti-inflammatorily potentiat 4 32 5 3 ing amount of diphenhydramine. *Doses were chosen upon EDso's of diphenhydramine which under the assumption 30 2. The method as defined by claim 1, wherein the of additivity would provide protection for 50% of the mice. component (i) comprises an analgesically and anti TABLE 3 NUMBER OF MICE PROECTED AT TESTEd DOSE LEVELS OF FOUR DIFFERENTRATIOS OF DOSES OF BUPROFENTO DIPHENHYDRAMINE Dose of Dose of Ibuprofen Equivalent Dose Combination Ibuprofen Diphenhydramine Under Assumption of Additivity Number of Mice Number of Mice Dose Ratio mg/kg mg/kg mg/kg Protected Not Protected 9:8 8 3 9.9 7 12 5 5.2 3 5 16 7 20.4 2 6 28 2 35.6 6 9 9:24 3 8 8.0 2 6 16 16.1 2 4 12 32 32.2 6 2 15 40 40.2 8 9 6:28 3 14 11.8 2 6 4.5 2 17.7 3 5 9 42 35.5 7 4:32 3 24 18.1 2 6 3.5 28 21.1 3 5 4.5 36 27.2 6 2 s 40 30.2 6 2

TABLE 4 ED50's OF COMBINATION TREATMENTS IN IBUPROFEN EQUIVALENT DOSES inflammatorily effective amount of mefenamic acid. Tested Combination Dose Ratios Ibuprofen Equivalent 55 3. The method as defined by claim 1, wherein the of Ibuprofen to Diphenhydramine ED50 mg/kg component (i) comprises analgesically and anti-inflam I D I matorily effective amount of meclofenamic acid. 100 O 24 4. The method as defined by claim 1, wherein the 9 8 23 component (i) comprises an analgesically and anti 9 24 18 inflammatorily effective amount of flufenamic acid. 6 28 19th 4 32 23 5. The method as defined by claim 1, wherein the O 00 24 component (i) comprises an analgesically and anti EDso's substantially less than 24 mg/kg, the dose that would be expected were the inflammatorily effective amount of niflumic acid. effects additive. 6. The method as defined by claim 1, wherein the 65 component (i) comprises and analgesically and anti While the invention has been described and illus inflammatorily effective amount of tolfenamic acid. trated with reference to certain preferred embodiments 7. The method as defined by claim 1, comprising from thereof, those skilled in the art will appreciate that vari about 125 mg of component (i). 4,985,459 13 14 8. The method as defined by claim 1, comprising from 19. The pharmaceutical composition of matter as about 12.5 mg to 50 mg diphenhydramine. defined by claim 13, further comprising a non-toxic pharmaceutically acceptable inert carrier. 9. The method as defined by claim 8, comprising from 20. The pharmaceutical composition of matter as about 25 mg to 50 mg of diphenhydramine. defined by claim 13, comprising from about 125 mg to 10. The method as defined by claim 1, wherein said about 250 mg of component (i). composition is administered orally. 21. The pharmaceutical composition of matter as 11. The method as defined by claim 1, wherein said defined by claim 13, comprising from about 12.5 mg to component (i) is administered daily in divided doses. about 50 mg diphenhydramine. 12. The method as defined by claim 1, wherein said 10 22. The pharmaceutical composition of matter as composition is administered orally at bedtime as an defined by claim 21, comprising from about 25 mg to about 50 mg diphenhydramine. analgesically and anti-inflammatory effective nighttime 23. The pharmaceutical composition of matter as sleep aid. defined by claim 13, comprising from about 125 mg to 13. A pharmaceutical composition of matter for elicit 15 about 250 mg mefenamic acid and about 12.5 mg to 50 ing an enhanced analgesic and anti-inflammatory re mg diphenhydramine. sponse in a mammalian organism, said composition 24. The pharmaceutical composition of matter as comprising: defined by claim 13, comprising from about 125 mg to (i) an analgesically and anti-inflammatorily effective about 250 mg meclofenamic acid and about 12.5 mg to amount of mefenamic acid, meclofenamic acid, 50 mg diphenhydramine. flufenamic acid, niflumic acid or tolfenamic acid, 25. The pharmaceutical composition of matter as defined by claim 13, comprising from about 125 mg to or a pharmaceutically acceptable salt thereof; and about 250 mg flufenamic acid and about 12.5 mg to 50 (ii) an analgesically and anti-inflammatorily potentiat mg diphenhydramine. ing amount of diphenhydramine. 25 26. The pharmaceutical composition of matter as 14. The pharmaceutical composition of matter as defined by claim 13, comprising from about 125 mg to defined by claim 13, wherein the component (i) com about 250 mg niflumic acid and about 12.5 mg to 50 mg prises an analgesically and anti-inflammatorily effective diphenhydramine. amount of mefenamic acid. 27. The pharmaceutical composition of matter as 15. The pharmaceutical composition of matter as 30 defined by claim 13, comprising from about 125 mg to about 250 mg tolfenamic acid and about 12.5 to 50 mg defined by claim 13, wherein the component (i) com diphenhydramine. prises an analgesically and anti-inflammatorily effective 28. A composition of matter as defined by claim 13, amount of meclofenamic acid. said composition being adapted for oral administration. 16. The pharmaceutical composition of matter as 35 29. A composition of matter as defined by claim 28, defined by claim 13, wherein the component (i) com said composition being formulated as a tablet, capsule prises an analgesically and anti-inflammatorily effective or elixir. amount of flufenamic acid. 30. A composition of matter as defined by claim 28, 17. The pharmaceutical composition of matter as said composition being adapted for oral administration sustained released form. defined by claim 13, wherein the component (i) com 31. A composition of matter as defined by claim 13, prises an analgesically and anti-inflammatorily effective said composition being adapted for parenteral adminis amount of niflumic acid. tration. 18. The pharmaceutical composition of matter as 32. A composition of matter as defined by claim 31, defined by claim 13, wherein the component (i) com 45 said composition being formulated for intramuscular prises an analgesically and anti-inflammatorily effective administration. amount of tolfenamic acid. X : 2.

50

55

65