ANALGESIC MIXTURE OF NALBUPHINE AND ACETYLSALICYLIC ACID, DERIVATIVE OR SALT THEREOF

Abstract: A composition consisting essentially of nalbuphine and acetylsalicyclic acid, derivative or salt thereof, gives unexpec­ tedly enhanced analgetic activity.

Description: CROSS-REFERENCES TO RELATED APPLICATIONS This application is a continuation-in-part of application Serial No. 160,437 filed on June 17, 1980, which in turn is a continuation-in-part of application Serial No. 69,083 filed on August 23, 1979, now abandoned. BACKGROUND OF THE INVENTION This invention relates to a pharmaceutical com bination of compounds having analgetic activity. U.S. Patent 3,393,197 issued to Pachter and Matossian on July 16, 1968 discloses N-substituted-14hydroxydihydronormorphines, including the N-cyclobutylmethyl derivatives, commonly called nalbuphine : EMI1.1 Pachter and Matossian and others, such as H. W. Elliett, et al., J. Me. (Basel) , 1, 74-89 (1970); H. Blumberg, et al., Pharmacologist, 10, 189, Fall 1968 ; P. Roberts, Drugs of the Future, 2, 613-5 (1977), disclose the use of nalbuphine as an analgesic fcr the control of moderate to severe pain. D. M. Woodbury and E. Fingl, "Analgesic-anti pyretics, Anti-inflamnatory Agents,and Drugs Employed in the Therapy of Gout," in "The Pharmacological Basis cf Therapeutics," 5th edition, Macmillan Publishing Co., Inc., 1975, Pt. 325-358, report that oral combinations of acetylsalicylic acid, also known as aspirin, with codeine or with other narcotic analgesics are known to produce additive analgesic effects in than. U.S. Patent 4,049,803, issued to Cotty et al. on September 20, 1977, discloses a composition for oral administration comprising per dose a mixture containing about 5-15 grains of acetaminophen and about 10 gratis oi acetylsalicylic acid. The composition gives increased blood levels of unhydrolyzed aspirin. Mcre active analgesic combinations are in constant derand because they offer the attractive possibility of relieving pain with reduced dosages,thereby diminishing the expected side effects and toxicity that would result fro the otherwise required higher dosages. STUMMARY OF THE INVENTION According to the present invention there is provided an analgesic composition consisting essentially cf (a) nalbuphine or a pharmaceutically suitable acid addition salt thereof and (b) acetylselicylic acid, socur. acetylsalicylate, calcium acetylsalicylate, salicylic acid, or sodium salicylate or any combination thereof in a weight ratio of (a) to (b) of from about 1:1.76 to about 1:61.7. There are also provided methods of using said composition to alleviate pain in mammals. BRIEF DESCRIPTION OF THE DRAWING Fiqs. 1 and 2 are graphs showing the interaction of nalbuphine and the herein specified acetylsalicylic acid, derivatives or salts thereof on phenyl- p-benzoquinone induced writhing in mice. DETAILED DESCRIPITION OF THE INVENTION Nalbuphine, which has the chemical name (-)17-(cyclobutylmethyl)-4, 5o-epoxymorphinan-3, 6a, 14-trial, the pharmaceutically suitable addition salts of nalbuphine, particularly the hydrochloride, and acetylsalicylic acid, derivatives or salts thereof, as described herein, all have analgetic properties in man and in other mammals. AE used herein, the expression "acetylsalicylic acid, derivatives or salt thereof means and is limited to acetylsalicylic acid, sodium acetylsalicylate, calcium acetylsalicylate, salicylic acid and sodium salicylate. This group of compounds or any one of the group shall be hereinafter sometimes referred to by the acronym, AS.'. Although it is expected that the alumimum salt of acetylselicylic acid and salicylamide may also provide unexpectedly enhanced activity in combination wit nalbuphine, the have not been include within the definition because of their minimal commercial value. Preferatly the ASAS compound is acetylsalicylic acid, socium. acetylsalicylate or calcium acetylsalicylate, anc, eferably is acetylsalicylic acid or its sodiur salt In the composition of the invention nalbuphine cr a pharraceutically suitable acid addition salt thereof and ASA are combined in a weight ratic of nalbuphine to ASA of from about 1:1.76 to about 1:61.7 preeferably, from about 1:3 to about 1:50, and most preferably from 1:12 t 1:45, respectively. It has been found that when these compounds are combined in these ranges, the resulting composition gives unexpectedly enhanced analgetic activity, i.e., the resulting activity is greater than the activity expected from the sum of the activities of the individual components. Compositions within the preferred range give the highest analgetic activity. The composition of the invention presents the opportunity of obtaining relief from pain with reduced dosages cf nalbuphine and ASA, thereby diminishing the side effects and toxicity which would result fro the otherwise required amounts of the individual druc components. POSAGE FORMS The combinetion of analgetic agents of the invention can be administered to treat pain by any means that produces contact of the active agent with the agent's site of action in the body of a mammel. The composition of the invention can be administered by any conventional means available for use in conjunction with pharmaceuticals. It can be administered alone, but is generally administered with a pharma- ceutical carrier selected on the basis of the chosen route of ad-inistratiop and standard pharmacettical practice. The dosage administered will, of course, vary depending upon known factors such as the pharma- todynemit characteristics of the particular agent, an its mode ane route of administration; age, health, and weight of the recipient ; nature and extent of aymptone, kind of concurrent treatment, frequency of treatment, an- the effect desired, Usually a daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.25 to 7.5 milligrams s per kilogram. (mg/kg) of body weight of nalbuphine and fre abut 10.8 to 54 mg/kg of ASA. Ordinarily, administration of the composition of the invention in divided doses 2-5 tines per day or in sustained release form is effective to obtain desired results. Dosage forms (compositions) suitable fcr internal ac-.inistration contain from. about 50 milligrams to about 600 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95t b weight based on the total weight of the composition. The active ingredient can be administered crally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets an capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastro- intestinal tract. Licud dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. Suitable pharmaceutical carriers are described in Remingten's Pharmaceutical Sciences, E. W. Martin, 2 standard reference text in this field. Useful pharmaceutical dosage-forms for adminis tration of the composition of the invention can be illustrated by the following examples in whic. the word "aspirin" refers to acetylsalicylic acid. EXAMPLE 1 Nalbuphine/Aspirin Tablets 7.5/325 mgtTablet Formula (1:43) mc/Tablet Nalbuphine HCl 7.50 Aspirin 325.00 Lactose. Anhydrous 229.80 Microcrystalline Cellulose 200.00 Ste@@tex@ hydrogenated vegetable oil 7.70 TOTAL 770.00 mg A large number of tablets can be prepared by conventional methods, utilizing the formula above. EXAMPLE 2 Nalbuphine/Aspirin Tablets a) Formul@ (1:16) 20/325 mg/Tablet mg/Tablet Nalbuphine.HCl 20.00 Aspirin 325.00 Lactose, Anhydrous 217.30 Microcrystalline Cellulose 200.00 Sterctex@ hydrogenated ve@etable oil 7.70 TOTAL 770.00 mg b) Formula (1:8) 40/325 mg/Tablet mg/Tablet Nalbuphine.HCl 40.00 Asp@rin 325.00 Lact@se, Anhydrous 197.30 Microcrystalline Cellulose 200.00 Sterotex@ hydrogenated vegetable oil 7.70 TOTAL 770.00 mg A large number of tablets can be prepared by conventional methods, utilizing the formulas above. EXAMPLE 3 Nalbuphine/Aspirin Capsules a F@rmula (1:43) 7.5/325 mg/Capsules mg/CAP Nalbuphine. HCl 7.50 Aspirin 325.00 Lactose, Anhydrous 95.90 Starch 6.60 TOTAL 435.00 mg b) Formul@ (1:16) 20/325 mg/Capsules mc/CAP Nalbuphine.HCl 20.00 Aspirin 325.00 Lactose, Anhydrous 83.40 Starch 6.60 TOTAL 435.00 mg EXAMPLE 3 (cont.) Nalbuphine/Aspirin C2psules c) Formula (1: :8) 40/325 mg/Capsules mg/CAP Nalbuphine.HCl 40.00 Aspirin 325.00 Lactese, Anhydrous 63.40 Starch 6.60 TOTAL 435.00 mg A large number of unit capsules may be prepared by filling standard two@piece hard gelatin capsules with the above formulations. utilizing conventional techniques. UTILITY Test Methods The unexpectedly enhanced analgetic activity of the composition of the invention is evidenced by tests conducted on mice. Male CF1 mice obtained from Charles River Breeding Laboratories, fasted for 16-22 hours, and weighing 18-22a at the time of testing are used through- out. All mice are dosed sequentially by the oral route with suspensions of acetylsalicylic acid and/or cf nalbu- phne solutions (Method 1) or of calcium acetylsa-licylate (calcium aspirin) and/or of nalbuphine solutions (Metho 2). In each case the aspirin component is calculated as the equivalent free acid content, ane nalbuphine is calculated as the hydrochloride salt. A dosing volume cf 10 ml/kg is used for each sequential solution cr suspension. All doses are coded and the test is performed un-er a code not known to the observer. Method 1 : Sequential combinations of aspririn suspensions and nalbuphine. HCl A stock suspensicn of aspirin is prepared by mixing 2.016 gm aspirin with 40 ml of an aqueous vehicle containing 28 by volume of Tween SOT, a pharmacclogical dispersant manufactured by Fisher Scientific Company and containing 10% polysorbate 80, and 18 by weight of Methocelc MC powder, a pharmacological suspending agent manufactured by DOW Chemical Company and contain 100E methylcellulose, in distilled water. The mixture is sonicated at 150 watts for 10-15 seconds with an untre- sound system, then shaken for 1 hour at 280 oscillations,' minute with 15-20 gm of glass beads. The resultant suspension contains 50.4 mg/ml of aspirin; all dosing suspensions are prepared by dilution of the stock suspension with the Methocele/Tween BOC vehicle: the vehicle control is MethocelO/Tween 80t. All suspensions are used within two hours of preparation, then discarded. Stock solutions of nalbuphine.HCl are prepared by dissolving dry nalbuphine hydrochloride powder with distilled water. All dosing solutions are prepared by dilution of the stock solutions with distilled water. the vehicle control is distilled water. Method 2: Combinations of calcium aspirin and nalbuphine.HC1 A stock solution of calcium asririn is prepared by mixing 4.032 gm of aspirin and 1.120 gm of precipitated calcium. carbonate with 50 ml of distilled water at 40-500C until the solids are completely dissolved,then diletin te 60 ml with distilled water at ambient temperature chtain a solution containing 67.2 mg/ml of aspirin equivalent All dosing solutions are prepared by dilution of the stock sclution with distilled water; the vehicle control is distilled water. All solutions are "se within two hours of preraratic.., then discarded. Stock solutions of nalbuphine.Hcl are prepared -s described for Method 1. ANALGETIC ACTIVITY IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST A standard procedure for detecting and ctrt---- the analgetic activity of different classes cf analgesic drugs for which there is a good correlation with human analaetic activity is the prevention of phenyl-p-benzoquinone induced writhing in mice t Blumberg et al., Proc. Soc. Exp. Biol. Med., 118, 7630-766 (1965)]. Nice, intubated with various doses cf nalbu- phine. HCl. aspirin suspensions (Method 1), calcium aspirin solution (Method 2), or immediately sequential doses of nalbuphine. HCl and of the aspirin preparations as defined further, or cf the respective vehicles, are injected intraperitoneally with a standard challenge dose of phenyl-P-benzoquinone 5 min. prior to a designated observation period. The phenyl-E-benzoquinone is prepared as a 0.1 mg/ml solution in 5% by volute of ethanol in water. the writhing dose is 1.25 mg/k5 injected at a volume of 0.25 n1/20g. For scoring purposes a "writhe" is indicated by whole body stretching or contraction of the abdomen during a 10 min. observation period beginning 5 min. after receiving the phenyl-p-benzoguinone dose. Each mouse is used only once, then discarded. All ED50 values and their 95% confidence limits are determined numerically by the methods of Thompson tW. F. Thompson, Bacteriological Rev., 11, 115-145 (1947)], Litchfield and Wilcoxon [J. T. Litchfield, Jr. and F. Wilcoxon, J. Pharm. Exp. Ther., 96, 99-113 (1949) ),or Finney [D. J. Finney, "Rmbit Analysis", third edition, Cambridge University Press, Cambridge, England, (1971)]. As used herein in ED50 means the dosage at which 50% of the mice in a test group exhibit an analgetic response. The interaction of nalbuphine.HCL and aspirin suspensions on phenyl-p-benzoquinone induced writhing in mice is demonstrated by the data in Table 1 and by the Loewe isobologram [S. Loewe, Pharm. Rev., 9, 237242 (1957)] in Fig. 1. The interaction between nalbu phine.HCL and calcium aspirin solutions is demonstrated in Table 2 and by the Loewe isobologram in Fig. 2. In the isobolographic figures, the analgetic effects of nalbuphine alone are presented on the Y axis and of aspirin alone (or calcium aspirin, expressed as aspirin equivalent dosages) on the X axis. The dotted lines radiating from the origin represent the fixed dosage ratios of nalbuphine HCl:aspirin in the ranges of 1:2.44 to 1:60.9 and 1:1.76 to 1:61.7 for Figs. 1 and 2, respectively. ED50 values representing the calculated dosages where 50% of a group of animals would be expected to exhibit an analgetic response are marked on the Y and X axes, representing nalbuphine and aspirin ED50's alone, and on the dotted radial lines, representing the nalbuphine and aspirin components of the fixed dosage ratios. The arrows extending above and below each ED50 point represent the 95% confidence limits of the ED50's. The solid line connecting the ED50 dosages of nalbuphine (alone) and aspirin (alone) represents the "ED50 addition line", which indicates the expected location of the EDSO's for nalbuphine and aspirin combinations if simple additivity were to describe their combined effects. The 95% confidence range for the ED50 addition line is shown by the area between the broken lines above and below the ED50 addition line. According to Loewe's isobolographic theory, if the analgetic effects of nalbuphine and aspirin were simply additive to one another, the expected location for the ED50's of the nalbuphine and aspirin components of each fixed dosage ratio would be contained within, or overlap, the region of the ED50 addition line. Combination ED50's located significantly below the ED50 addition line would represent unexpectedly enhanced analgetic activity and combination ED50's located above the line would represent unexpectedly diminished analgetic activity. One method to establish the significance of such unexpected enhanced or diminished activity is to calculate the best fitting polynominal regression line to the observed ED50's using standard mathematical techniques. This "ED50 regression line" is represented in Figs. 1 and 2 by the curvilinear line connecting all of the ED50 points within their 95% confidence limits. For Fig. 1 the following equation applies: Y = 5.762-0.08112 (x-93.83) + 0.0009289 (x93.83)2 0.00000594 7 -93.83)3 where Y represents the ED50 dosage component of nalbuphine and X represents the ED50 dosage component of aspirin. For Fig. 2 the equation given below applies: X = 56.62 - 4.476 (Y-11.77) + 0.3168 (Y-11.77)2 - 0.0075 (Y-11.77)3 In both cases, analysis of variance demonstrates that the quadratic regressions are significantly different from the ED50 addition lines at the level of P < 0.05. Therefore, an unexpectedly enhanced analgetic response can be proven in a mathematically rigorous model utilizing the entire body of data to demonstrate that a curvilinear regression line encanpassinq the ED50's of each fixed dosage ratio fits the data significantly better than the linear ED50 addition line. While the linear regression analysis demonstrates unexpected enhancement of the analgetic response and predicts that unexpectedly enhanced analgetic activity occurs in theory for all possible combinations of nalbuphine and aspirin, the statistical significance for the endpoint ratios of nalbuphine and aspirin that were actually tested may be proven using either the "Least Significant Differences" or the "Studentized Q method" tests described by Snedecor and Cochran [G. W. Snedecor and W. G. Cochran, "Statistical Methods", sixth edition, Iowa State University Press, Ames, Iowa (1967)]. The "expected ED5O's" may be read from the graph or alternatively may be calculated by using the formula: EMI14.1 where Y is the expected ED50 for the nalbuphine component of a mixture, Y0 is the ED50 for nalbuphine alone, Z is the potency ratio between aspirin and nalbuphine, and R is the ratio of nalbuphine in the total drug composition T=X+Y. Similarly, the expected ED50 for the aspirin component is found according to: EMI15.1 Thus, using the data in Table 2 and Fig. 2: TOTAL DOSE COMBINATION Expected ED50 Observed ED50 Signi Nalbuphine : Aspirin (95% Conf. Limits) (95% Conf. Limits) ficance 1:61.7 163 mg/kg 129 mg/kg p < 0.05 (143-186) (111-150) 1:1.76 81.7 mg/kg 57.4 mg/kg F < 0.05 (70.7-94.5) (49.1-67.0) Unexpectedly enhanced analgetic activity can also be proven by showing that the net analgetic response produced by a drug mixture is greater than predicted from the sum of individual responses of the components. Thus, using the data in Table 1: COMBINATION DOSE (mg/kg) RESPONSE Nalbuphine:Aspirin Nalbuphine Aspirin Expected Chserved 5.18 63 8.3% 29.2% 1:12.2 10.4 126 54.28 83.3% 20.7 252 #100% 95.8% 41.4 504 #100% 100% In this case, the 1:12.2 drug ratio is the only one where the combination dosages are exactly the same as dosages found in the individual component tests. For the two lowest dosages tested, the observed percentage response is clearly greater than the expected response. For the two highest dosages tested, the expected response would actually exceed 100% by summation of the effects of the individual component dosages; since the observed response cannot actually exceed 100%, enhancement cannot be measured even though it has most likely occurred with these dosages as well. Using this method, responses that differ by less than 5% can not be considered to be significantly different from each other; thus, a response rate of 95.8% in the observed column is not significantly less than a 100% response rate. Similarly, using the date from Table 2: DOSE (mg/kg) RESPONSE Nalbwhi ne:Aspirin Naibuphine Aspirin Expected Observed 5.45 48 20.4% 16.7% 1:8.81 10.9 96 29.7% 50.0% 21.8 192 90.8% 98.1% 43.6 384 ¯100% 98.1% In this situation, the 1:8.81 drug ratio is the only one where the combination dosages are exactly the same as dosages found in the individual component tests. For the two mid-range dosages tested, the observed percentage response is clearly greater than the expected response. For the highest dosage tested, the observed response is again limited by the restraint that it con rupt exceed a 100% response rate; however, enhancement of the analgetic response has most likely occurred here as well (a 98.1% response is not significantly different from a 100% response using this method). For the lowest dosage tested, analgetic synergism was not observed; however, for reasons previously given, a 16.7% response is not significantly different than a 20.4% response. This conventional method would also be expected to show unexpected enhanced analgetic activity for all of the other dosage ratios tested, but since none of the other dosages are identical with the dosages in the individual component tests, the actual test of significance cannot be performed. Therefore, Figs. 1 and 2 and a variety of statistical approaches show that compositions of the invention having a ratio of nalbuphine.HCl to aspirin from about 1:1.76 to 1:61.7 given unexpectedly enhanced analgetic activity. The isobolographic technique, rather than the technique using the sum of the individual component responses, has been used in establishing enhancement for several reasons. First, this technique allows the use of a full range of doses and the calculation of ED50's and 95% confidence limits for these doses whereas in the conventional method, i.e., the method of comparing the sum of the individual component responses to the response of the combination, the maximum response must be limited to less than 50% for each component. If, in this conventional method, the individual responses are not less than 50%, then it will not be possible to measure enhancement. Secondly, with the isobolographic technique statistical significance is straightforward and can be seen graphically. The calculation of statistics for the technique of using the sum of the individual component responses is more involved. Thirdly, for certain ratios the isobolographic technique as utilized here gives also a presentation of evidence of enhancement via use of the sum of the individual component responses, thereby providing additional corraboration of the results. TABLE 1 ORAL NALBUPHINE.HCl/ASPIRIN SUSPENSION COMBINATIONS IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST AT 20 MINUTES = 24 Mice/Dose) EMI18.1 <tb> <SEP> DRUG. <SEP> ED50 <SEP> at <SEP> 20 <SEP> MIN. <tb> CONBINATIONS <SEP> DRIC <SEP> DOSE <SEP> (mg/kg) <SEP> %MICE <SEP> (95% <SEP> Confidence <tb> <SEP> Nalbu- <SEP> BLOCKED <SEP> Limits) <tb> <SEP> hire <SEP> HCl <SEP> : <SEP> Nalbu <SEP> Nalbu <tb> <SEP> Aspirin <SEP> phie. <SEP> RCl <SEP> Aspirin <SEP> phine.HCl <SEP> Aspirin <tb> (Contrcl) <tb> <SEP> 0:0 <SEP> 0 <SEP> 0 <SEP> 0 <SEP> % <SEP> - <SEP> <tb> <SEP> (Nalbu- <SEP> 5.18 <SEP> 0 <SEP> 16.7% <SEP> 26.1 <SEP> mg/kg <tb> phine. <SEP> HCl <SEP> 10.4 <SEP> 0 <SEP> 50.0% <SEP> (20.0-38.1) <tb> <SEP> only) <SEP> 2.7 <SEP> 0 <SEP> 62.5% <tb> <SEP> 1:0 <SEP> 41.4 <SEP> 0 <tb> <SEP> 1:2.44 <SEP> 4.32 <SEP> 10.5 <SEP> 4.2 <SEP> % <tb> <SEP> 8.63 <SEP> 21. <SEP> 16.7 <SEP> % <tb> <SEP> 17.3 <SEP> 42. <SEP> 45,8% <SEP> 16,9 <SEP> mg/kg <SEP> 39.1 <SEP> mg/kg <tb> <SEP> 34.5 <SEP> 84. <SEP> 91.7% <SEP> (13.0-19.7) <SEP> (31.5-48.1 <tb> <SEP> 69.0 <SEP> 168. <SEP> 100.0 <SEP> <tb> <SEP> 3.45 <SEP> 21. <SEP> 8.3% <tb> <SEP> 6.90 <SEP> 42. <SEP> 20.8% <tb> <SEP> 1:6.09 <SEP> 13.8 <SEP> 84. <SEP> 70.2% <tb> <SEP> 27.6 <SEP> 168 <SEP> 100.0% <SEP> 9.04 <SEP> mg/kg <SEP> 55.1 <SEP> mg/kg <tb> <SEP> 55.2 <SEP> 336. <SEP> 100.0% <SEP> (7.44-10.9) <SEP> (45.3-66.7) <tb> <SEP> 2.59 <SEP> 31.5 <SEP> 8.3 <tb> <SEP> 5.18 <SEP> 63. <SEP> 29.2 <SEP> % <tb> <SEP> 1:12.2 <SEP> 10.4 <SEP> 126. <SEP> 83.3% <SEP> 6.49 <SEP> mg/kg <SEP> 79.0 <SEP> mg/kg <tb> <SEP> 20.7 <SEP> 252. <SEP> 95.8% <SEP> (5.26-7.97) <SEP> (64.0-97.0) <tb> <SEP> 41.4 <SEP> 504. <SEP> 100.0% <tb> <SEP> 1.73 <SEP> 42. <SEP> 8.3% <tb> <SEP> 3.45 <SEP> 84. <SEP> 25.0% <SEP> 5.01 <SEP> mg/kg <SEP> 122 <SEP> mg/kg <tb> <SEP> 1:24.4 <SEP> 6.90 <SEP> 168. <SEP> 70.8% <SEP> (3,98-6.31) <SEP> (97.0-154) <tb> 13.8 <SEP> 336. <SEP> 91.7% <tb> <SEP> 0.86 <SEP> 52.5 <SEP> 4.2% <tb> <SEP> 1.73 <SEP> 105. <SEP> 29.2% <SEP> 2.55 <SEP> mg/kg <SEP> 155 <SEP> mg/kg <tb> <SEP> 1:60.9 <SEP> 3.45 <SEP> 210. <SEP> 79.2% <SEP> (2.02-3.25) <SEP> (123-198) <tb> <SEP> 6.90 <SEP> 420 <SEP> 83.3% <tb> TABLE 1 (cont.) ORAL NAIBUPHINE. HCl/ASPIRIN SUSPENSION CONBINATIONS IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST AT 40 MINUTES (N - 24 Mice/Dose) EMI19.1 <tb> <SEP> DRUG <SEP> ED50 <SEP> at <SEP> 20 <SEP> MIN. <tb> COMBINATIONS <SEP> DRUG <SEP> DOSE <SEP> (mg/kg) <SEP> %MICE <SEP> (95% <SEP> Confidence <tb> <SEP> Naltu- <SEP> BLOCKED <SEP> litits) <tb> <SEP> phine-HCl <SEP> : <SEP> Nalbu- <SEP> Nalbu <tb> <SEP> Aspirin <SEP> phine. <SEP> HCl <SEP> Aspirin <SEP> phine.HCl <SEP> Aspirin <tb> <SEP> 0 <SEP> 63, <SEP> 8,3% <tb> Aspirin <SEP> 0 <SEP> 126. <SEP> 37.5% <tb> <SEP> only) <SEP> 0 <SEP> 252. <SEP> 58.3% <SEP> - <SEP> 206 <SEP> mg/kg <tb> <SEP> 0:1 <SEP> 0 <SEP> 504. <SEP> 79.2% <SEP> (154-284) <tb> TABLE 2 ORAL NALBUPHINE.HCl/CALCIUM ASPIRIN* COMBINATIONS IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST AT 40 MINUTES (N = 54 Mice/Dose) EMI20.1 <tb> <SEP> DRUG <SEP> ED50 <SEP> at <SEP> 40 <SEP> MIX. <tb> <SEP> COMBINATIONS <SEP> DRUG <SEP> DOSE <SEP> (mg/kg) <SEP> % <SEP> MICE <SEP> (95% <SEP> Confidence <tb> <SEP> Nalbu- <SEP> BLOCKED <SEP> limits) <tb> <SEP> phine.HCl: <SEP> Nalbu- <SEP> Nalbu <SEP> Aspirin <SEP> phine. <SEP> HCl <SEP> Aspirin <SEP> phine.HCl <SEP> Aspirin <tb> <SEP> (Control) <tb> <SEP> 0:0 <SEP> 0 <SEP> 0 <SEP> 5.6% <SEP> - <SEP> (Nalbu- <SEP> 5.45 <SEP> 0 <SEP> 13.0% <tb> <SEP> phine <SEP> 10.9 <SEP> 0 <SEP> 16.7% <tb> <SEP> only) <SEP> 21.8 <SEP> 0 <SEP> 27.8% <SEP> 42.6 <SEP> mg/kg <tb> <SEP> 1:0 <SEP> 43.6 <SEP> 0 <SEP> 50.0% <SEP> (32.9-55.1) <tb> <SEP> 1:0 <SEP> 87.2 <SEP> 0 <SEP> 74.1% <tb> <SEP> 4.54 <SEP> 8 <SEP> 3.7% <tb> <SEP> 9.08 <SEP> 16 <SEP> 16.7% <tb> <SEP> 1: :1.76 <SEP> 18.2 <SEP> 32 <SEP> 29.6% <SEP> 20.8 <SEP> mg/kg <SEP> 36.6 <SEP> mg/kg <tb> <SEP> 36.3 <SEP> 64 <SEP> 83.3% <SEP> (17.8-24.3) <SEP> (31.3-42.7) <tb> <SEP> 72.7 <SEP> 128 <SEP> 100.0% <tb> <SEP> 3.63 <SEP> 16 <SEP> 16.7% <tb> <SEP> 7.27 <SEP> 32 <SEP> 33.3% <tb> <SEP> 1:4.41 <SEP> 14.5 <SEP> 64 <SEP> 50.0% <SEP> 10.4 <SEP> mg/kg <SEP> 46.0 <SEP> mg/kg <tb> <SEP> 29.1 <SEP> 128 <SEP> 98.1% <SEP> (8.68-12.6) <SEP> (38.1-55.5) <tb> <SEP> 58.1 <SEP> 256 <SEP> 100.0% <tb> <SEP> 2.73 <SEP> 24 <SEP> 3.7% <tb> <SEP> 5.45 <SEP> 48 <SEP> 16.7% <tb> <SEP> 10.9 <SEP> 96 <SEP> 50.0% <SEP> 9.71 <SEP> mg/kg <SEP> 85.5 <SEP> mg/kg <tb> <SEP> 21.8 <SEP> 192 <SEP> 98.1% <SEP> (8.38-11.2) <SEP> (73.8-99.0) <tb> <SEP> 43.6 <SEP> 384 <SEP> 98.1% <tb> <SEP> 1.82 <SEP> 32 <SEP> 5.6% <tb> <SEP> 3.63 <SEP> 64 <SEP> 20.4% <tb> <SEP> 1: :17.6 <SEP> 7.27 <SEP> 128 <SEP> 63.0% <SEP> 5.73 <SEP> mg/kg <SEP> 101 <SEP> mg/kg <tb> <SEP> 14.5 <SEP> 256 <SEP> 96.3% <SEP> (4.80-6.88) <SEP> (84.4-121) <tb> <SEP> 29.1 <SEP> 512 <SEP> 100.0% <tb> <SEP> 0.908 <SEP> 40 <SEP> 14.8% <tb> <SEP> 1.82 <SEP> 80 <SEP> 13.2% <tb> <SEP> 1:44.1 <SEP> 3.63 <SEP> 160 <SEP> 64.8% <SEP> 2.85 <SEP> mg/kg <SEP> 126 <SEP> mg/kg <tb> <SEP> 7.27 <SEP> 320 <SEP> 94.4% <SEP> (2.45-3.33) <SEP> (108-147) <tb> <SEP> 14.5 <SEP> 640 <SEP> 100.0% <tb> TABLE 2 (cont.) ORAL NALBUPHINE.HCl/CALCIUM ASPIRIN* COMBINATIONS IN THE MOUSE ANTIPHENYLQUINONE WRITHING TEST AT 40 MINUTES (N = 54 Mice/Dose) EMI21.1 <tb> <SEP> DRUG <SEP> ED50 <SEP> at <SEP> 40 <SEP> MIN. <tb> <SEP> OMBINATIONS <SEP> DRUG <SEP> DOSE <SEP> (mg/kg) <SEP> % <SEP> MICE <SEP> (95% <SEP> Confidence <tb> <SEP> Nalbu- <SEP> BLOCKED <SEP> Limits) <tb> <SEP> phine.HCl <SEP> : <SEP> Nalbu- <SEP> Nalbu <SEP> Aspirin <SEP> phine. <SEP> HCl <SEP> Aspirin <SEP> phine.HCl <SEP> Aspirin <tb> <SEP> 0.681 <SEP> 42 <SEP> 5.6% <tb> <SEP> 1.36 <SEP> 84 <SEP> 22.2% <tb> <SEP> 1:61.7 <SEP> 2.73 <SEP> 168 <SEP> 64.8% <SEP> 2.07 <SEP> mg/kg <SEP> 127 <SEP> mghkg <SEP> <tb> <SEP> 5.45 <SEP> 336 <SEP> 98.1% <SEP> (1.77-2.40) <SEP> (109-148) <tb> <SEP> 10.9 <SEP> 672 <SEP> 98.1% <tb> 0 <SEP> 0 <SEP> 48 <SEP> 7.4% <tb> (Aspirin <SEP> O <SEP> <SEP> 96 <SEP> 13.0% <SEP> 171 <SEP> ingkg <SEP> <tb> <SEP> only) <SEP> 0 <SEP> 192 <SEP> 63.0% <SEP> (150-195) <tb> <SEP> 0: :1 <SEP> 0 <SEP> 384 <SEP> 87.0% <tb> * All dosages of calcium aspirin are expressed in terms of equivalent free aspirin content

Claims: tGAT IS CLAIMED IS: 1. A pharmaceutical composition consisting essentially of (a) nalbuphine or a pharmaceutically suitable acid addition salt thereof and (b) acetylsalicylic acid, sodium acetylsalicylate. calcium acetylsalicylate, salicylic acid, or sodium salicylate or any combination thereof in a weight ratio of (a) to (b) of from about 1:1.76 to about 1:61.7. 2. A composition of Claim 1 wherein component (b) is acetylsalicylic acid, sodium acetylsalicylate or calcium acetylsalicylate. 3. A composition of Claim 2 wherein component (b) is acetylsalicylic acid. 4, A composition of Claim 2 wherein component (b) is sodium acetylsalicylate. 5. A composition of Claim 2 wherein component (b) is calcium acetylsalicylate. 6. A composition of Claim 2 wherein the weight ratio is from about 1 3 two about 1:50. 7, A composition of Claim 2 wherein the weight ratio is from about 1:12 to about 1:45. 8. A composition of Claim 2 wherein the nawbu- phine is present as the hydrochloride salt. 9. A composition of claims 1 - 8 which contains in addition a suitable pharmaceutical carrier.

Inventors: DUDZINSKI, JOHN RAYMOND, SCHMIDT, WILLIAM KOCH
Applicants: E.I. DU PONT DE NEMOURS AND COMPANY
Application year: 1980
Main classification: A61K31
IPC codes: A61K31