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United States Patent (19) 11 Patent Number: 4,522,826 Sunshine et al. 45) Date of Patent: Jun. 11, 1985 (54) AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING OTHER PUBLICATIONS DPHENHYDRAMINE AND METHODS OF Lear et al., JAMA, 1958, 166(12): 1438–1443. USING SAME Cappe, B. E. et al., JAMA, 1954, 154(5):377-379. Campos, V. M. et al., J. of Clin. Pharmacology, Jan. 75 Inventors: Abraham Sunshine, New York; 1980, pp. 42-49. Eugene M. Laska, Larchmont; Albal, M. V. et al., J. of Ophthalmology, 1982, Carole E. Siegel, Mamaroneck, all of 30:271-273. N.Y. Beaver, W. T. et al., Adv. in Pain Research & Therapy, 1976, 1:553-557. 73) Assignee: Richardson-Vicks Inc., Wilton, Conn. Bluhm et al., Life Sciences, 1982, 31:1229-1232. 21 Appl. No.: 578,288 Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Burns, Doane, Swecker & 22 Filed: Feb. 8, 1984 Mathis 51 Int. Cl...... A61K 31/19; A61K 31/40; (57) ABSTRACT A61K 31/13 Novel pharmaceutical compositions of matter are pro 52 U.S. Cl...... 514/569; 514/222; vided comprising analgesic/non-steroidal anti-inflam 514/420; 514/567; 514/570; 514/648 matory drugs and diphenhydramine and methods of 58) Field of Search ...... 424/317, 330 using said compositions to elicit an enhanced analgesic 56) References Cited and/or anti-inflammatory response in mammalian or U.S. PATENT DOCUMENTS ganisms in need of such treatment. 4,362,728 12/1982 Yellin et al...... 424/249 44 Claims, 1 Drawing Figure

4,522,826 1. 2 divided doses of between 12.5 to 50 milligrams with a ANALGESCAND ANTI-NFLAMMATORY maximum daily dosage not to exceed 300 milligrams. COMPOSITIONS COMPRISING The antihistaminic activity of diphenhydramine is di DIPHENHYDRAMINE AND METHODS OF rectly attributable to its competition with histamine for USING SAME cell receptor sites on effector cells although diphenhy dramine also demonstrates, in addition, a number of BACKGROUND OF THE INVENTION 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 10 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 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 mo of such treatment. 15 tion sickness and, more broadly, as an anti-nauseant and Non-narcotic , most of which are also in the treatment of mild forms of Parkinsonism. Diphen known as non-steroidal anti-inflammatory drugs hydramine demonstrates both stimulant 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 20 their biological profiles as analgesics, anti-inflammatory tional doses with accompanying restlessness, nervous agents and agents. , acetaminophen ness and inability to sleep. The more predominant seda and have long been among the most com tive action of diphenhydramine has been beneficially monly used members of this group; more recently, how capitalized upon with the usage of diphenhydramine as ever, a large number of alternative non-narcotic agents 25 a somnolent when employed at the maximum 50 milli offering a variety of advantages over the earlier drugs grams dose in both prescription and over-the-counter have been developed. Tolerance or addiction to these forms. In this regard, it is noted that the Food and Drug drugs is not generally a problem with their continuous Administration announced in the November 1983 FDA use in the treatment of pain or in the treatment of acute Drug Bulletin (Vol. 13, No. 3) that diphenhydramine or chronic inflammatory states (notably, rheumatoid 30 (50 mg.) may now be marketed over-the-counter as a arthritis and osteoarthritis); nevertheless, these drugs nighttime sleep aid. generally have a higher potential for adverse side-ef. An early study (1958) investigated the properties of fects effects at the upper limits of their effective dose diphenhydramine as a pre-anesthetic . (Lear, ranges. Moreover, above each drug's upper limit or et al., “Comparative Studies of Tranquilizers Used in ceiling, administration of additional drug does not usu 35 Anesthesia." JAMA, 1958, 166(12): 1438–1443). The ally increase the analgesic or anti-inflammatory effect. authors concluded that diphenhydramine, particularly Among the newer compounds in the non-narcotic anal when used in combination with meperidine, provides gesic/nonsteroidal anti-inflammatory group are com beneficial preoperative sedation with less overall de pounds such as (Dolobid (R)), so pression than previously experienced with the use of dium (Zomax (R)), (Motrin (R)), (Na 40 routine doses or narcotics and barbiturates. prosyn (R)), (Nalfon (R), (Fel Diphenhydramine has also been investigated with dene (R)), , (Ponstel (R)) and varying results with respect to its potential as a weak . See also Physicians' Desk Reference, 35th edi analgesic. Diphenhydramine hydrochloride when intro tion, 1981, and The Merck Index, ninth edition, Merck & duced intravenously has been reported as being useful Co., Rahway, N.J. (1976), for information on specific 45 in obstetric analgesia alone and in combination with nonsteroidal anti-inflammatory agents. Also see, gener alcohol. See Cappe, B. E. et al, "Recent Advances in ally, Wiseman, "Pharmacological Studies with a New Obstetric Analgesia' , JAMA, 1954, 154(5); 377-379. Class of Nonsteroidal Anti-Inflammatory Agents-The Campos et al in a comparative study found that diphen -With Special Reference to Piroxicam (Fel hydramine given either orally or intramuscularly could dene (R))", The American Journal of Medicine, Feb. 16, 50 not be distinguished from placebo in patients with post 1982:2-8; Foley et al, The Management of Cancer Pain, operative fractures or somatic pain. "The Analgesic Volume II-The Rational Use of Analgesics in the Man and Hypothermic Effects of Nefopam, Morphine, Aspi agement of Cancer Pain, Hoffman-LaRoche Inc., 1981; rin, Diphenhydramine and Placebo", Journal of Clin. and Cutting's Handbook of Pharmacology, sixth edition, Pharmacology, January, 1980, pp. 42-49.) ed. T. Z. Czaky, M.D., Appelton-Century-Crofts, New 55 Albal and Chandorkar studied an injectable combina York, 1979, Chapter 49:538-550, including structural tion analgesic consisting of analgin 375 mg, a centrally formulas for representative group members. acting analgesic, diazepam 2.5 mg, and diphenhydra Diphenhydramine2-(diphenylmethoxy)-N,N-dime mine 20 mg, and found relief from pain. They did not, thylethylamine) is also a well-known therapeutic agent however, study the unique contribution of diphenhy in long standing use by clinicians as an antihistamine. It 60 dramine. Albal, M. V., and Chandorkar, A. G. "Clini is recognized in both the U.S.P. and N.F. as an official cal Evaluation of Sedyn-a-Forte, an Analgesic Injection antihistamine of the ethanolamine (or aminoalkyl ether) Containing Analgin, Diphenhydramine and Diaze type and is available as the hydrochloride salt in Bena pam.” Indian Journal of Ophthalmology, 1982, dryl (R) and various alternative sources in 50 milligram 30:271-273). Note: analgin referred to in the foregoing delayed action tablets, 25 and 50 milligram capsules, 65 study is dypyrone; see The Merck Index, p. 3361, 1976.) elixirs (12.5 mg/5 ml) and sterile solution for injection While diphenhydramine has been investigated with (10 mg/ml). Depending upon the therapeutic indica respect to its weak analgesic properties, it is also evident tion, diphenhydramine is recommended in single or from the foregoing that its sedative and local anesthetic 4,522,826 3 4. properties may, in part, account for its suspected poten Another object of the invention is to provide suitable tial for relieving pain. In the Lear et al, supra, study dosage unit forms of one or more NSAID's and diphen diphenhydramine at 25 to 50 milligram doses was insuf hydramine adapted for, e.g., oral, rectal, parenteral, ficient as a preanesthetic medication and combination topical, etc., administration and useful in the treatment, with meperidine (a narcotic analgesic) was proposed to management and mitigation of pain and/or inflamma optimize the potential beneficial effects of diphenhydra tion. nine as an analgesic. These and other similar objects, advantages and fea Hydroxyzine, which is a minor tranquilizer with anti tures are accomplished according to the products, con histaminic activity, has been evaluated as an analgesic. positions and methods of the invention comprised of a Beaver and Feise found that, "This study unequivocally non-steroidal anti-inflammatory drug or analgesic and demonstrates analgesic activity for a 100 mg dose of diphenhydramine and analgesic and anti-inflammatory intramuscular hydroxyzine in the general range of that methods employing same. produced by 8 mg of morphine. In addition, the analge BRIEF DESCRIPTION OF THE DRAWING sic activity of hydroxyzine appears additive with that of morphine when the two drugs are given together.” The 15 The FIGURE of drawing is a plot of dose of diphen findings of the study do not indicate synergistic activity. hydramine versus dose of ibuprofen in the phenylqui (Beaver, W.T. & Feise, G. "Comparison of the Analge none writhing assay to indicate the number of mice sic Effects of Morphine, Hydroxyzine, and Their Com protected. bination in Patients with Postoperative Pain.” Advances 20 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 that the analgesic and anti-in been investigated. Bluhm, et al., in a study conducted on flammatory effects observed upon the administration of mice, found that diphenhydramine potentiates mor 25 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 co-administration of diphen (Bluhm, et al., "Potentiation of Opioid Analgesia By H1 hydramine or a non-toxic pharmaceutically acceptable and H2 Antagonists." Life Sciences, 1982, 31:1229-1232). salt thereof. Diphenhydramine has not been heretofore proposed 30 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 (or pharmaceutically acceptable salts thereof). More cants disclose the hastening of the onset of analgesic and 35 specifically, these terms as used herein are defined in anti-inflammatory responses observed with several dif contradistinction to merely additive effects. The 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 of both in combination does not change when a portion response with such agents by the concomitant adminis of one component is removed from the mixtures and tration of caffeine as a potentiating adjuvant. 40 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). The non-narcotic analgesics/nonsteroidal anti-in 45 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 (2) the derivatives; flammatory response in a mammalian organism in need 50 (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 tended to mean any non-narcotic analgesic/non-steroi thereof. 55 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. tory responses in mammals, including humans, by the While some of these compounds are primarily used at administration of preselected dosages of a non-steroidal the present time as anti-inflammatory agents and others anti-inflammatory agent, with diphenhydramine. 60 are primarily used as analgesics, in fact all of the con A still further object of the present invention is to templated compounds have both analgesic and anti-in provide a pharmaceutical composition of matter for flammatory activity and can be used at appropriate obtaining a synergistic analgesic and anti-inflammatory dosage levels for either purpose in the compositions and response in mammals in which the composition com methods of the present invention. The compounds in prises an analgesically and anti-inflammatorily effective 65 groups (1) through (4) typically contain a carboxylic amount of a selected NSAID and a synergistic amount acid function; however, those acids are sometimes ad of diphenhydramine optionally in the presence of a ministered in the form of their pharmaceutically accept pharmaceutically acceptable inert carrier. able acid addition or alkali metal salts, e.g., sodium salts. 4,522,826 5 6 The propionic acid derivatives for use herein include, anti-inflammatory drugs which contain the basic struc but are not limited to, ibuprofen, naproxen, benoxa profen, flurbiprofen, fenoprofen, , , ture , , , , prano profen, miroprofen, tioxaprofen, , almino profen, , fluprofen and bucloxic acid. Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties are COOH also intended to be encompassed by this group. Pres ently preferred members of the propionic acid group 10 which can bear a variety of substituents and in which include ibuprofen, naproxen, flurbiprofen, fenoprofen, the free -COOH group can be in the form of a pharma ketoprofen and fenbufen. ceutically acceptable salt group, e.g. -COO-Na+. Thus, "propionic acid derivatives" as defined herein The oxicans for use herein include, but are not lim are non-narcotic analgesics/nonsteroidal anti-inflamma ited to, piroxican, sudoxicam, and CP-14, 304. tory drugs having a free -CH(CH3)COOH or 5 Structurally related oxicams having similar analgesic -CH2CH2COOH group (which optionally can be in and anti-inflammatory properties are also intended to be the form of a pharmaceutically acceptable salt group, encompassed by this group. A preferred member of this e.g. -CH(CH3)COO-Na+ or -CH2CH2COO-Na+), group is piroxican. typically attached directly or via a carbonyl function to Thus, "oxicams' as defined herein are non-narcotic a ring system, preferably to an aromatic ring system. 20 analgesics/nonsteroidal anti-inflammatory drugs which The acetic acid derivatives for use herein include, but are not limited to, indomethacin, sulindac, , have the general formula zomepirac, , , , ibufe nac, isoxepac, furofenac, tiopinac, zidometacin, OH , , clidanac and oxpinac. Structur ally related acetic acid derivatives having similar anal 25 gesic and anti-inflammatory properties are also intended to be encompassed by this group. Presently preferred members of the acetic acid group include tolmetin so dium, zomepirac sodium, sulindac and indomethacin. Thus, "acetic acid derivatives' as defined herein are 30 non-narcotic analgesics/nonsteroidal anti-inflammatory wherein R is an aryl or heteroaryl ring system. drugs having a free -CH2COOH group (which option The precise amount of non-narcotic analgesic/non ally can be in the form of a pharmaceutically acceptable steroidal anti-inflammatory drug for use in the present salt group, e.g., -CH2COONat), typically attached compositions will vary depending, for example, on the directly to a ring system, preferably to an aromatic or 35 specific drug chosen, the dosage form thereof, i.e., stan heteroaromatic ring system. dard versus sustained release, the condition for which The fenamic acid derivatives for use herein include, the drug is administered and the size and kind of the but are not limited to, mefenamic acid, meclofenamic mammal. acid, , and . For humans, typical effective analgesic/anti-inflam Structurally related fenamic acid derivatives having 40 matory amounts of presently preferred NSAIDs for use similar analgesic and anti-inflammatory properties are in unit dose compositions of the invention are about 125 also intended to be encompassed by this group. Pres to 500 mg diflunisal, about 25 to 100 mg zomepirac ently preferred members of the fenamic acid group sodium, about 50 to 400 mg ibuprofen, most preferably include mefenamic acid and meclofenamate sodium 100-400 mg, about 125 to 500 mg naproxen, about 25 to (, sodium salt). 45 50 mg flurbiprofen, and about 50 to 200 mg fenoprofen, Thus, "fenamic acid derivative' as defined herein are about 10 to 20 mg piroxican, about 125 to 250 mg mefe non-narcotic analgesics/nonsteroidal anti-inflammatory namic acid, about 100 to 400 mg fenbufen or about 25 to drugs which contain the basic structure 50 mg ketoprofen; however, greater or lesser amounts can be employed if desired. For example, in one preferred embodiment of this invention, the desired therapeutic response for ibu NH profen therapy in mild to moderate pain is generally observed at 200 to 600 milligrams of ibuprofen every 4 55 to 6 hours as necessary up to about 2400 milligrams total COOH daily dose. Consistent with the synergistic results which can bear a variety of substituents and in which achieved with the ibuprofen/diphenhydramine compo the free -COOH group can be in the form of a pharma sitions and methods of the present invention, the desired ceutically acceptable salt group, e.g., -COONa. analgesic and/or anti-inflammatory response can be The biphenylcarboxylic acid derivatives for use 60 achieved upon the administration of ibuprofen and di herein include, but are not limited to, diflunisal and phenhydramine wherein the ibuprofen component can flufemisal. Structurally related biphenylcarboxylic acid be administered at reduced levels of between about 50 derivatives having similar analgesic and anti-inflamma to 400 milligrams of ibuprofen and, most preferably, 100 tory properties are also intended to be encompassed by to 400 milligrams. Alternatively, the usual dosage regi this group. Preferred members of this group are diflu 65 men for ibuprofen may be followed when the composi misal and flufenisal. tion of the present invention additionally comprising Thus, "biphenylcarboxylic acid derivative' as de diphenhydramine is employed whereby the levels of fined herein are non-narcotic analgesics/nonsteroidal analgesia and anti-inflammatory results are enhanced. 4,522,826 7 8 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. 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 milligams and 25 milli when administered alone for their respective usual ther grams of diphenhydramine, whereas two or more fur apeutic indications. O 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 15 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 drugs, including complaints involving abdominal dis respect to the intended route of administration and con 20 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 tion which allows for the use of the NSAID component such as lactose, starch, Sucrose, cellulose, magnesium 25 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. fects, as well as the presence of diphenhydramine con Suitable binders include starch, gelatin, natural sugars, 30 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 ethylene 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, 35 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 take advantage of the potentiated analgesic and anti-in age units may be utilized to accomplish intravenous, 40 flammatory response effectuated by the addition of intranuscular or subcutaneous administration and, for caffeine as disclosed in applicants U.S. Pat. No. such parenteral administration, suitable sterile aqueous 4,420,483. or non-aqueous solutions or suspensions, optionally containing appropriate solutes to effectuate isotonicity, Example 1-Pharmacologic Test for will be employed. 45 Synergism-Ibuprofen/Diphenhydramine. Moreover, in accordance with another preferred The unexpected synergistic analgesic effect of the embodiment of the present invention, where therapeu addition of diphenhydramine to ibuprofen is evidenced tic indications warrant, such as in the case where the by tests conducted on mice. Blue Spruce Farm male level of pain and inflammation associated with the dis mice weighing 18-28 grams at the time of testing are order may interfere with normal sleep latency and 50 used throughout. All mice are dosed orally by gavage maintenance dosage regimens may be contemplated, the with ibuprofen and/or diphenhydramine. The formula NSAID/diphenhydramine compositions of the inven tion of each test article is a solution or suspension in tion may be formulated for administration at bedtime as 0.25% methylcellulose manufactured by Fisher Scien an analgesically and anti-inflammatorily effective night tific Company. A dosing volume of 10 ml/mg is used. time sleep aid. Accordingly, the NSAID and diphenhy 55 All doses are coded and the test is performed under a dramine components of the composition may be formu code not known to the observer. Doses are based upon lated in dosage unit form to provide a dose of diphenhy the weights of the animal taken prior to dosing. dramine (compared to the amount necessary to promote the desired synergistic response) to take advantage of Method the sleep-inducing side effect of diphenhydramine. 60 A phenylquinone writhing assay in mice was con In another preferred embodiment, the advantageous ducted over a four day period to test for synergism of analgesic and anti-inflammatory compositions of the the analgesic activity of ibuprofen and diphenhydra invention may be formulated in sustained release form le. to provide the rate controlled release of either or both The assay consists of phenyl-p-benzoquinone (PPQ) of the components to optimize analgesic and anti-in 65 introduced in mice thirty minutes post dose of the test flammatory response while minimizing undesirable side treatment(s). The PPQ is prepared as a 0.02% aqueous effects in, for example, patients unusually sensitive to solution in 5 ml ethyl alcohol q.s. to 100 ml with dis either or both of the active drugs. Suitable dosage forms tilled water and is administered intraperitoneally at 0.25 4,522,826 10 ml/mouse. The mice are injected with the PPQ solution alent to (28-12p) mg/kg of ibuprofen. Table 3 shows and are placed in individual plastic squares 4'x4'x5" for each dose of each of the combination doses tested deep and observed for a ten minute period post treat the number of mice observed to be protected and the ment dose for exhibition of the writhing syndrome. ibuprofen equivalent dose. For each of the four combi Complete blocking of the writhing syndrome for the ten 5 nation ratios, ED50's were estimated based on the ob minute observation period in any one mouse is consid ered a positive response for that mouse. Conversely, if served number of mice protected at each ibuprofen the mouse definitely writhes at least once, it is consid equivalent dose using the method of Finney. Table 4 ered to be not protected from the PPQ. displays the estimated ED50's for each ratio. Three hundred twenty-eight mice were randomly 10 Results assigned to 40 groups. Two groups of ten mice per series were assigned to a control group (10 prior to the The surprising synergistic effects of combining ibu administration of the test treatments and 10 post admin profen with diphenhydramine can be seen from the istration) to verify the ability of the solutions to produce results of Tables 3 and 4 and the FIGURE of Drawing the writhing response. 15 summarizes all of the findings by depicting the ED50's The purpose of the assay on the first day is to estimate obtained for each treatment alone, the ED50 line if the the ED50 (effective dose in 50% of treated mice) of treatments were additive, the number of mice/- ibuprofen alone and of diphenhydramine alone, and to protected from writhing for each treatment studied and estimate the relative potency, p, of ibuprofen to diphen the estimated ED50's for each combination ratio. hydramine, determined as the ratio of the ED50 of ibu- 20 The ED50 of ibuprofen alone is estimated to be 24 profen to the ED50 of diphenhydramine. Eight mice per mg/kg and for diphenhydramine to be 38 mg/kg. The group are dosed orally (via intubation) with 2, 5, 10 and relative potency of diphenhydramine to ibuprofen is 20 mg/kg of ibuprofen and 5, 10, 20 and 50 mg/kg of 24/38. Among the 8 ratios tested on the second day, diphenhydramine. Table 1 shows the number of mice synergism appears to be present for four ratios, and protected from writhing activity for each dose of ibu- 25 these ratios were further investigated on days 3 and 4. profen and diphenhydramine. The method of Finney The ED50's were found to be for the dosage ratio of "Statistical Method of Biological Assay', McMillan 19:8, 23 mg/kg of ibuprofen, for the dosage ratio. 6:28, Pub., 3rd Edition, 1978) is used to estimate the ED50's of 19 mg/kg of ibuprofen, for the dosage ratio 9:24, 18 ibuprofen alone and diphenhydramine alone. mg/kg of ibuprofen, and for the dosage ratio 4:32, 23 On the second day eight combination doses were 30 mg/kg of ibuprofen. Two of these ED50's are substan studied. The doses were chosen based upon the ED50's tially less than 24 mg/kg of ibuprofen which is the established in the preceding day's experiment, which, ED50 that would be expected if the effects were addi under the assumption of additivity, would provide pro tive. This represents a 25% reduction of the amount of tection for 50% of the mice. These doses were tested in ibuprofen that is required to obtain the effect in 50% of order to observe those ratio(s) of the combination drugs 35 the animals. The graph in the FIGURE of Drawing that would yield a synergistic effect. Combinations for indicates that many other dose ratios as well would which five or more mice exhibit blockage of writhing produce an unexpected synergistic effect. are candidates for further study. The doses of the con TABLE 1 stituent drugs in mg/kg for the eight groups were for NUMBER OF MICE PROTECTED AT TESTED dOSE ibuprofen (I) and diphenhydramine (D) respectively, 40 LEVELS OF IBUPROFENAND DIPHENHYDRAMINE abbreviated as (I,D): (22,4), (19,8), (16,12), (14,6), Dose of Dose of Number of (11,20), (9,24), (6,28), (4,32). Table 2 shows for each of Ibuprofen Diphenhydramine Mice Number of Mice these combination doses, the number of mice protected mg/kg mg/kg Protected Not Protected from writhing activity. 2 0 8 On the third and fourth days the four specific fixed 45 5 - 0 8 ratios that achieved 5 or more protected mice were 10 -- 1 7 20 - 3 5 studied in more detail, i.e., the first combination treat - 5 7 ment used a ratio of ibuprofen to diphenhydramine of - 10 2 6 19:8 and the doses of the constituent drugs in mg/kg - 20 3 5 that were studied were (8.3), (12,5), (16,7) and (28,12). 50 - 40 4 4 The second combination treatment used a ratio of doses of ibuprofen to diphenhydramine of 6:28 and the doses of the constituent drugs in mg/kg that were studied TABLE 2 were (3,14), (4.5,21) and (9,42). The third combination NUMBER OF MICE PROTECTED AT TESTED DOSES treatment used a ratio of doses of ibuprofen to diphen 55 OF THE COMBINATION OF IBUPROFENAND hydramine of 9:24 and the doses of the constituent drugs DIPHENHYDRAMINE Dose of Dose of Number of in mg/kg that were studied were (3,8), (6,16), (12,32) Ibuprofen Diphenhydramine Mice Number of Mice and (15,40). The fourth combination treatment used a mg/kg mg/kg Protected Not Protected ratio of doses of ibuprofen to diphenhydramine of 4:32 22 4 4. 4. and the doses of the constituent drugs in mg/kg that 60 19 8 5 3 were studied were (3,24), (3.5,28) (4.5,36) and (5,40). 16 12 3 5 Under the assumption of additivity each dose of each 14 16 4 4 combination is equivalent to a dose of ibuprofen, based 11 20 4 4. 9 24 5 3 on the relative potency (p) of diphenhydramine to ibu 6 28 5 3 profen obtained from the experiment on the first day. 65 4. 32 5 3 Thus, for example, in the dose ratio 19:8 the combina "Doses were chosen based upon Edso's of ibuprofen and diphenhydramine which tion of 28 mg/kg of ibuprofen and 12 mg/kg of diphen under the assumption of additivity would provide protection for 50% of the mice. hydramine is, under the assumption of additivity, equiv 4,522,826 11 12 TABLE 3 NUMBER OF MICE PROTECTED 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 19:8 8 3 9.9 l 7 12 5 15.2 3 5 16 7 20.4 2 6 28 12 35.6 6 2 9:24 3 8 8.0 2 6 6 6 16.1 2 6 12 32 32.2 6 2 15 40 40.2 8 0 6:28 3 14 11.8 2 6 4.5 21 17.7 3 5 9 42 35.5 7 l 4:32 3 24 18.1 2 6 3.5 28 21.1 3 5 4.5 36 27.2 6 2 5 40 30.2 6 2 profen, tiaprofenic acid, fluprofen or bucloxic acid LE 4 or a pharmaceutically acceptable salt thereof, and TAB (ii) an analgesically and anti-inflammatorily potentiat ED50's OF COMBINATION TREATMENTS ing amount of diphenhydramine. IN IBUPROFEN EQUIVALENT DOSES 25 2. A method as defined by claim 1, wherein the con Telegation ponent (i) comprises an analgesically and anti-inflam of Ibuprofen Ibuprofen Equivalent matorily effective amount of ibuprofen. to Diphenhydramine ED50 mg/kg 3. A method as defined by claim 1, wherein the com I D I ponent (i) comprises an analgesically and anti-inflam 100 O 24 30 matorily effective amount of naproxen. 19 8 23 4. A method as defined by claim 1, wherein the com 9 24 1. ponent (i) comprises an analgesically and anti-inflam matorily effective amount of flurbiprofen. 0 100 24 5. A method as defined by claim 1, wherein the com EDso's substantially less than 24 mg/kg, the dose that would be expected were the 35 ponent (i) comprises an analgesically and anti-inflam effects additive. matorily effective amount of fenoprofen. 6. A method as defined by claim 1, wherein the com While the invention has been described and illus ponent (i) comprises an analgesically and anti-inflam trated with reference to certain preferred embodiments matorily effective amount of ketoprofen. thereof, those skilled in the art will appreciate that vari 40 7. A method as defined by claim 1, wherein the con ous changes, modifications and substitutions can be ponent (i) comprises an analgesically and anti-inflam made therein without departing from the spirit of the matorily effective amount of fenbufen. invention. For example, effective dosages other than 8. A method as defined by claim 1, comprising from the preferred ranges set forth hereinabove may be appli about 50 to 400 mg ibuprofen. cable as a consequence of variations in the responsive 45 9. A method as defined by claim 8, comprising from ness of the mammal treated, severity of pain or inflam about 100 to 400 mg ibuprofen. mation, dosage related adverse effects, if any, observed 10. A method as defined by claim 1, comprising from and analogous considerations. Likewise, the specific about 12.5 to 50 mg diphenhydramine. pharmacological responses observed may vary depend 11. A method as defined by claim 10, comprising ing upon the particular relative amounts of active com 50 from about 25 to 50 mg diphenhydramine. ponents employed or whether same are used in combi 12. A method as defined by claim 1, wherein said nation with suitable pharmaceutical carriers, as well as composition is administered orally. the type of formulation and mode of administration 13. A method as defined by claim 12, wherein said employed, and such expected variations or differences composition is administered daily in divided doses com in results are contemplated in accordance with the ob 55 prising from about 100 to 400 mg ibuprofen and 25 to 50 jects and practices of the present invention. It is in mg diphenhydramine. tended, therefore, that the invention be limited only by 14. A method as defined by claim 1, wherein said the scope of the claims which follow. composition is administered orally at bedtime as an What is claimed is: analgesically and anti-inflammatorily effective night 1. A method for eliciting an enhanced analgesic and 60 time sleep aid. anti-inflammatory response in a mammalian organism in 15. A pharmaceutical composition of matter for elicit need of such treatment, comprising administering to ing an enhanced analgesic and anti-inflammatory re such organism sponse in a mammalian organism, said composition (i) an analgesically and anti-inflammatorily effective comprising: amount of ibuprofen, naproxen, , flur 65 (i) an analgesically and anti-inflammatorily effective biprofen, fenoprofen, fenbufen, ketoprofen, indo amount of ibuprofen, naproxen, benoxaprofen, flur profen, pirprofen, carprofen, oxaprozin, prano biprofen, fenoprofen, fenbufen, ketoprofen, indo profen, miroprofen, tioxaprofen, suprofen, almino profen, pirprofen, carprofen, oxaprozin, prano 4,522,826 13 14 profen, miroprofen, tioxaprofen, suprofen, almino 29. The composition of matter as defined by claim 15, profen, tiaprofenic acid, fluprofen or bucloxic acid wherein the component (i) comprises an analgesically or a pharmaceutically acceptable salt thereof, and and anti-inflammatorily effective amount of tioxa (ii) an analgesically and anti-inflammatorily potentiat profen. ing amount of diphenhydramine. 30. The composition of matter as defined by claim 15, 16. The composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically wherein the component (i) comprises an analgesically and anti-inflammatorily effective amount of suprofen. and anti-inflammatorily effective amount of ibuprofen. 31. The composition of matter as defined by claim 15, 17. The composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically wherein the component (i) comprises an analgesically 10 and anti-inflammatorily effective amount of almino and anti-inflammatorily effective amount of naproxen. profen. 32. The composition of matter as defined by claim 15, 18. The composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically wherein the component (i) comprises an analgesically and anti-inflammatorily effective amount of tiaprofenic and anti-inflammatorily effective amount of benoxa 15 acid. profen. 33. The composition of matter as defined by claim 15, 19. The composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically wherein the component (i) comprises an analgesically and anti-inflammatorily effective amount of fluprofen. and anti-inflammatorily effective amount of flurbi 34. The composition of matter as defined by claim 15, profen. 20 wherein the component (i) comprises an analgesically 20. The composition of matter as defined by claim 15, and anti-inflammatorily effective amount of bucloxic wherein the component (i) comprises an analgesically acid. and anti-inflammatorily effective amount offenoprofen. 35. The composition of matter as defined by claim 15, 21. The composition of matter as defined by claim 15, further comprising a non-toxic pharmaceutically ac wherein the component (i) comprises an analgesically 25 ceptable inert carrier. and anti-inflammatorily effective amount offenbufen. 36. The composition of matter as defined by claim 16, 22. The composition of matter as defined by claim 15, comprising from about 50 to 400 mg ibuprofen. wherein the component (i) comprises an analgesically 37. A composition of matter as defined by claim 15, and anti-inflammatorily effective amount of ketoprofen. comprising from 12.5 to 50 mg diphenhydramine. 23. The composition of matter as defined by claim 15, 30 38. A composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically wherein said diphenhydramine is present as the pharma and anti-inflammatorily effective amount of indoprofen. ceutically acceptable salt thereof. 24. The composition of matter as defined by claim 15, 39. A composition of matter as defined by claim 15, wherein the component (i) comprises an analgesically comprising from about 100 to 400 mg ibuprofen and and anti-inflammatorily effective amount of pirprofen. 35 from about 25 to 50 mg diphenhydramine. 40. A composition of matter as defined by claim 15, 25. The composition of matter as defined by claim 15, said composition being adapted for oral administration. wherein the component (i) comprises an analgesically 41. A composition of matter as defined by claim 40, and anti-inflammatorily effective amount of carprofen. said composition being formulated as a tablet, capsule 26. The composition of matter as defined by claim 15, 40 or elixir. wherein the component (i) comprises an analgesically 42. A composition of matter as defined by claim 15, and anti-inflammatorily effective amount of oxaprozin. said composition being adapted for oral administration 27. The composition of matter as defined by claim 15, in sustained release form. wherein the component (i) comprises an analgesically 43. A composition of matter as defined by claim 15, and anti-inflammatorily effective amount of prano 45 said composition being adapted for parenteral adminis profen. tration. 28. The composition of matter as defined by claim 15, 44. A composition of matter as defined by claim 43, wherein the component (i) comprises an analgesically said composition being formulated for intramuscular and anti-inflammatorily effective amount of miro administration. profen. 50 ak sk sk k xic

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