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US006007841A United States Patent (19) 11 Patent Number: 6,007,841 Caruso (45) Date of Patent: Dec. 28, 1999

54). COMPOSITION AND METHOD 5,556,838 9/1996 Mayer et al.. FOR TREATING PAIN 5,654,281 8/1997 Mayer et al.. 5,750,534 5/1998 Yoa-Pu et al...... 514/282 75 Inventor: Frank S. Caruso, Colts Neck, N.J. FOREIGN PATENT DOCUMENTS 73 Assignee: Algos Pharmaceutical Corporation, 97/04780 2/1997 WIPO. Neptune, N.J. OTHER PUBLICATIONS 21 Appl. No.: 09/042,248 Weisenfeld-Hallin Z, “Combined -NMDA Antago 1-1. nist Therapies. What Advantages Do They Offer for the 22 Filed: Mar 13, 1998 Control of Pain Syndromes?", Drugs (Jan. 1998) 55(1), pp. (51) Int. Cl." ...... A61K9/20 1-4.

52) U.S. C. ------424/464; 424/468; 424/489 Primary Examiner Thurman K. Page 58 Field of Search ...... 424/489,468 is S. ASSistant Examiner William E. Benston, Jr. s s/ Y-s 1 Yus 57 ABSTRACT 56) References Cited The analgesic effectiveness of a -antagonist U.S. PATENT DOCUMENTS analgesic is significantly potentiated by administering a narcotic agonist-antagonist analgesic together with at least s al 514/282 one nontoxic NMDA . 4,935,428 6/1990 Lewis. 5,321,012 6/1994 Mayer et al.. 19 Claims, No Drawings 6,007,841 1 2 ANALGESC COMPOSITION AND METHOD The term “N-methyl-D-aspartate receptor' shall be under FOR TREATING PAN stood to include all of the binding site Subcategories asso ciated with the NMDA receptor, e.g., the glycine-binding BACKGROUND OF THE INVENTION Site, the phenylcyclidine (PCP)-binding site, etc., as well as This invention relates to an analgesic composition and the NMDA channel. Thus, the invention herein contemplates method for alleviating pain. More particularly, this invention the use of nontoxic substances that block an NMDA receptor is concerned with alleviating pain by administering to a binding site, e.g., , or block the NMDA mammal exhibiting pain (a) an analgesia-effective amount channel, e.g., a Source of magnesium Such as magnesium of at least one narcotic agonist-antagonist analgesic, and, (b) Sulfate. a narcotic agonist-antagonist analgesic-potentiating amount The term "nontoxic' as used herein shall be understood in of at least one nontoxic antagonist, or blocker, for the a relative Sense and is intended to designate any Substance N-methyl-D-aspartate (NMDA) receptor. that has been approved by the United States Food and Drug Administration (“FDA) for administration to humans or, in Narcotic agonist-antagonist are known. In keeping with established regulatory criteria and practice, is general, narcotic agonist-antagonist analgesics constitute a 15 susceptible to approval by the FDA for administration to distinct subclass of and are differentiated from the humans. The term "nontoxic' is also used herein to distin latter by their mixed actions, meaning, they are not full guish the NMDA receptor antagonists, or blockers, that are at all opioid receptors, e.g., u, Ö, K, etc. receptors. useful in the practice of the present invention from NMDA Instead, narcotic agonist-antagonist analgesics are believed receptor antagonists Such as MK 801 (the compound to either exert their analgesic action by working as agonists 5-methyl-10,11-dihydro-SH-dibenzea,d) cyclohepten-5,10 at Some opioid receptors and antagonists or very weak imine), CPP (the compound 3-2-carboxypiperazin-4-yl) agonists at other opioid receptors, i.e., mixed narcotic propyl-1-phosphonic acid) and PCP (the compound 1-(1- agonist-antagonists, or exert their analgesic action by work phenylcyclohexyl)piperidine) whose toxicities effectively ing as agonists at Some opioid receptors, i.e., partial ago preclude their therapeutic use. nists. Mixed narcotic agonist-antagonist analgesics will typi 25 cally be the combination of u antagonism coupled with K The terms “potentiate' and “potentiating” are used herein agonism. analgesics will typically be u ago in their art-recognized Sense, i.e., as referring to a significant increase in the level of pain-alleviating activity for the S. combination of narcotic agonist-antagonist analgesic and Heretofore, there has been no recognition or appreciation nontoxic NMDA receptor antagonist compared with that that the analgesic effectiveness of a narcotic agonist which could have been expected based on the activities of antagonist analgesic can be appreciably potentiated, or the narcotic agonist-antagonist analgesic administered alone enhanced, by administration of a narcotic agonist-antagonist analgesic prior to, with or following the administration of a and nontoxic NMDA receptor antagonist administered narcotic agonist-antagonist analgesic-potentiating amount alone. The term “pain-alleviating” shall be understood herein to of a nontoxic NMDA receptor antagonist. 35 include the expressions “pain-Suppressing” and "pain SUMMARY OF THE INVENTION inhibiting” as the invention is applicable to the alleviation of existing pain as well as the Suppression or inhibition of pain In accordance with the present invention, an analgesic which would otherwise ensue from an imminent pain composition for alleviating pain is provided which com 40 causing event. prises (a) an analgesia-effective amount of at least one The expression “analgesia-effective amount as applied to narcotic agonist-antagonist analgesic; and, (b) a narcotic the narcotic agonist-antagonist analgesic employed in the agonist-antagonist analgesic-potentiating amount of at least composition and method of this invention shall be under one nontoxic N-methyl-D-aspartate receptor antagonist. stood to mean an amount of narcotic agonist-antagonist Further in accordance with the present invention, a 45 analgesic which when administered by itself or in combi method of alleviating pain is provided which comprises nation with the nontoxic NMDA receptor antagonist pro administering to a mammal exhibiting pain (a) an analgesia vides significant analgesic activity. effective amount of at least one narcotic agonist-antagonist analgesic, and, (b) a narcotic agonist-antagonist analgesic DESCRIPTION OF THE PREFERRED EMBODIMENTS potentiating amount of at least one nontoxic N-methyl-D- 50 aspartate receptor antagonist. Any of the narcotic agonist-antagonist analgesics hereto The analgesic composition and method of alleviating pain fore used to alleviate pain can be used herein. For listings of of this invention are applicable to the treatment of all narcotic agonist-antagonist analgesics, See, e.g., Goodman varieties of pain, e.g., arthritic pain, lumboSacral pain, and Gilman’s “The Pharmaceutical Basis of Therapeutics”, musculo-skeletal pain, pain associated with a Sore throat, 55 8th ed., McGraw-Hill, Inc. (1990), pp. 510–514 and “Rem etc. Thus, for a mammal in need of pain relief, an enhanced ington's Pharmaceutical Sciences”, 17th ed., Mack Publish level of analgesia for an equivalent dosage of at least one ing Company (1985), pp. 1099-1110. Specific narcotic narcotic agonist-antagonist analgesic, or an equivalent level agonist-antagonist analgesics that can be used herein include of analgesia for a reduced dosage of at least one narcotic , pentazocine hydrochloride, , nalbu agonist-antagonist analgesic, can be achieved when at least 60 phine hydrochloride, , butorphanol tartrate, one narcotic agonist-antagonist analgesic is administered , buprenorphine hydrochloride, , prior to, with or following the administration of the nontoxic , nalorphine, , their pharmaceutically NMDA receptor antagonist. acceptable Salts and the like. The term “narcotic agonist-antagonist analgesic' shall be Among the nontoxic substances that block the NMDA understood as referring to those analgesics which exhibit 65 receptor and as Such are useful for potentiating the analgesic mixed narcotic agonist-antagonist or partial agonist proper activity of the foregoing narcotic agonist-antagonist analge ties. Sics in accordance with this invention are dextromethorphan 6,007,841 3 4 ((+)-3-hydroxy-N-methylmorphinan), its metabolite dex propylene glycol, PEG's and ethanol, or an oleaginous trorphan ((+)-3-hydroxy-N-methylmorphinan), amantadine medium, e.g., peanut oil, liquid paraffin or olive oil. (1 - a mino a dam antine), me mantine (3,5 For topical administration in the mouth, the analgesic dimethylaminoadamantone), their mixtures and their phar compositions can take the form of buccal or Sublingual maceutically acceptable Salts. Other useful nontoxic Sub stances that block the NMDA receptor include pyrroloquino tablets, drops or lozenges formulated in conventional man line quinone, 4-hydroxy-2(1H)-quinolone derivatives and C. cis-4-(phosphono-methyl)-2-piperidinecarboxylic acid. Of For topical administration to the epidermis the com the foregoing nontoxic substances that block the NMDA pounds of the invention can be formulated as creams, gels, receptor, dextromethorphan in the form of its hydrobromide ointments or lotions or as transdermal patches. Such com Salt is preferred for use herein due to its ready availability positions can, for example, be formulated with an aqueous and its established use in over-the-counter medications or oily base with the addition of Suitable thickening, gelling, where it functions as a cough SuppreSSant. emulsifying, Stabilizing, dispersing, Suspending, and/or col With regard to dosage levels, the narcotic agonist oring agents. antagonist analgesic must be present in an analgesia 15 The compounds of the invention can also be formulated as effective amount, e.g., at a level corresponding to the gen depot preparations. Such long acting formulations can be erally recommended adult human dosages for a particular administered by implantation (for example Subcutaneously narcotic agonist-antagonist analgesic, and the nontoxic or intramuscularly) or by intramuscular injection. Thus, for NMDA receptor antagonist must be present at a level that example, the compounds can be formulated with Suitable potentiates the effectiveness of the narcotic agonist polymeric or hydrophobic materials (for example as an antagonist analgesic. Specific dosage levels for the narcotic emulsion in an acceptable oil) or ion exchange resins, or as agonist-antagonist analgesic that can be used herein as sparingly Soluble derivatives, for example as a sparingly given, inter alia, in the “Physicians’ Desk Reference”, 1997 Soluble salt. Edition (Medical Economics Data Production Company, The compounds of the invention can be formulated for Montvale, N.J.) as well as in other reference works including 25 parenteral administration by injection, conveniently Goodman and Gilman’s “The Pharmaceutical Basis of intravenous, intramuscular or Subcutaneous injection, for Therapeutics” and “Remington's Pharmaceutical Sciences” example by bolus injection or continuous intravenous infu both of which as referred to above. Given the wide variation Sion. Formulations for injection can be presented in unit in dosage level of the narcotic agonist-antagonist analgesic dosage from e.g. in ampoules or in multi-dose containers, which depends to a large extent on the Specific narcotic with an added preservative. The compositions can take Such agonist-antagonist analgesic being administered, there can forms as Suspensions, Solutions or emulsions in oily or Similarly be a wide variation in the dosage level of the aqueous vehicles, and can contain formulatory agents Such nontoxic NMDA receptor antagonist. These amounts can be as Suspending, Stabilizing and/or dispersing agents. determined for a particular drug combination in accordance Alternatively, the active ingredient can be in powder form with this invention employing routine experimental testing. 35 for constitution with a Suitable vehicle, e.g. Sterile pyrogen In the case of pentazocine and the nontoxic NMDA receptor free water, before use. antagonist dextromethorphan, dosages of from about 30 to The compounds of the invention can also be formulated in about 250 mg/day of the former coadministered with from rectal compositions Such as Suppositories or retention about 30 to about 120 mg/day of the latter will usually enemas. e.g. containing conventional Suppository baseS Such provide acceptable results. 40 as cocoa butter or other glyceride. While the narcotic agonist-antagonist analgesic and For intranasal administration, the compounds of the potentiating nontoxic NMDA receptor antagonist need not invention can be used, for example, as a liquid Spray, as a be administered together, they must both be present in the powder or in the form of drops. patient at effective levels at the same time. While it is within For administration by inhalation, the compounds accord the Scope of the invention to Separately administer the 45 ing to the invention are conveniently delivered in the form narcotic agonist-antagonist analgesic and the nontoxic of an aeroSol Spray presentation from pressurized packs or a NMDA receptor antagonist, as a matter of convenience, it is nebulizer, with the use of a Suitable propellant, e.g. preferred that these drugs be coadministered in a single dichlorodifluoromethane, trichlorofluoromethane, dosage form. All modes of administrations are dichlorote trafluoroethane, tetrafluoroethane, contemplated, e.g., orally, rectally, parenterally, topically, or 50 heptafluoropropane, carbon dioxide or other Suitable gas. In by intravenous, intramuscular, intrastemal or Subcutaneous the case of a preSSurized aerosol the dosage unit can be injection or in a form suitable by inhalation. The formula determined by providing a valve to deliver a metered tions can, where appropriate, be conveniently presented in amount. Capsules and cartridges of, for example, gelatin, for discrete dosage units and can be prepared by any of the use in an inhaler or insulator can be formulated containing methods well known in the art of pharmacy. 55 a powder mix of a compound of the invention and a Suitable An analgesic composition containing the narcotic agonist powder base Such as lactose or Starch. antagonist analgesic and nontoxic NMDA receptor antago Aqueous Suspensions can include pharmaceutically nist will ordinarily be formulated with one or more phar acceptable excipients Such as Suspending agents, e.g., maceutically acceptable ingredients in accordance with Sodium carboxymethyl cellulose, methylcellulose, known and established practice. Thus, the analgesic com 60 hydroxypropylmethylcellulose, Sodium alginate, position can be formulated as a liquid, powder, elixir, polyvinylpyrrollidone, gum tragacanth and gum acacia, dis injectable Solution, etc. Formulations for oral use can be persing or wetting agents Such as naturally occurring provided as tablets or hard capsules wherein the pharmaco phosphatide, e.g., lecithin, or condensation products of an logically active ingredients are mixed with an inert Solid alkylene oxide with fatty acids, e.g., polyoxyethylene diluent Such as calcium carbonate, calcium phosphate or 65 Stearate, or condensation products of ethylene oxide with kaolin, or as Soft gelatin capsules wherein the active ingre long chain aliphatic , e.g., heptadecaethylene dients are mixed with water or miscible Solvents Such as Oxycetanol, or condensation products of ethylene oxide with 6,007,841 S 6 partial esters derived from fatty acids and a hexitol, e.g., -continued polyoxyethylene Sorbitol monoleate or condensation prod ucts of ethylene oxide with partial esters derived from fatty Ex- Narcotic Nontoxic acids and hexitol anhydrides, e.g., polyoxyethylene Sorbitan am- Agonist-Antagonist NMDA Receptor Additional Active monoleate. The aqueous Suspensions can also contain one or ple Analgesic (mg) Blocker (mg) Component (mg) more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy hydrobromide (30) 30 dezocine (30) benzoate, one or more coloring agents, one or more flavor hydrobromide (30) ing agents and one or more Sweetening agents, Such as 31 dezocine (30) amantadine (30) Sucrose, Saccharin or Sodium or calcium cyclamate. 32 dezocine (30) (30) 33 dezocine (25) memantine (30) ibuprofen (325) In addition to the narcotic agonist-antagonist analgesic 34 nalorphine (35) dextromethorphan and nontoxic NMDA receptor antagonist, the analgesic hydrobromide (30) composition herein can contain at least one other pharma 35 nalorphine (25) dextromethorphan ibuprofen (325) cologically active Substance, e.g., a non-narcotic analgesic hydrobromide (30) 36 nalorphine (30) dextrorphan Such as acetaminophen, aspirin, diclofenac, difluSinal, hydrobromide (30) etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, 15 37 cyclazocine (35) dextromethorphan ibuprofen, indomethacin, ketoprofen, ketorolac, meclofe hydrobromide (30) 38 cyclazocine (25) dextromethorphan acetaminophen (325) namic acid, mefenamic acid, nabu metone, naproxen, hydrobromide (30) Oxaprozin, phenylbutaZone, piroXicam, Sulindac, tolmetin, 39 cyclazocine (30) dextrorphan , Zomepirac, and the like. hydrobromide (30) EXAMPLES 1-39 In each of these dosage units, the nontoxic NMDA The following unit dosage forms are illustrative of the receptor antagonist dextromethorphan hydrobromide Sig pain-alleviating drug combinations in accordance with the nificantly potentiates the pain-alleviating activity of the present invention: 25 narcotic agonist-antagonist analgesic. What is claimed is: 1. An analgesic composition comprising (a) an analgesia Ex- Narcotic Nontoxic am- Agonist-Antagonist NMDA Receptor Additional Active effective amount of at least one narcotic agonist-antagonist ple Analgesic (mg) Component (mg) analgesic and (b) a narcotic agonist-antagonist analgesic Blocker (mg) potentiating amount of at least one nontoxic N-methyl-D- 1 pentazocine (35) dextromethorphan aspartate receptor antagonist. hydrobromide (30) 2 pentazocine (30) dextromethorphan acetaminophen (325) 2. The analgesic composition of claim 1 wherein the hydrobromide (30) narcotic agonist-antagonist analgesic is Selected from the 3 pentazocine (35) dextrorphan group consisting of pentazocine, nalbuphine, butorphanol, hydrobromide (30) 35 buprenorphine, meptaZinol, dezocine, nalorphine, cyclazo 4 pentazocine (35) amantadine (30) 5 pentazocine (35) memantine (30) cine and pharmaceutically acceptable Salts thereof. 6 pentazocine (35) memantine (30) ibuprofen (325) 3. The analgesic composition of claim 1 wherein the 7 malbuphine (30) dextromethorphan nontoxic NMDA receptor antagonist is at least one member hydrobromide (30) Selected from the group consisting of dextromethorphan, 8 nalbuphine (10) dextromethorphan acetaminophen (325) hydrobromide (30) 40 dextrorphan, amantadine, memantine and pharmaceutically 9 nalbuphine (25) dextrorphan acceptable Salts thereof. hydrobromide (30) 4. The analgesic composition of claim 1 wherein (a) and 10 nalbuphine (30) amantadine (30) 11 nalbuphine (30) memantine (30) (b) each is present in the same or different Sustained release 12 nalbuphine (30) memantine (30) ibuprofen (325) carrier. 13 butorphanol (10) dextromethorphan 45 5. The analgesic composition of claim 1 containing a hydrobromide (30) therapeutically effective amount of at least one other phar 14 butorphanol (5) dextromethorphan ibuprofen (325) hydrobromide (30) maceutically active Substance (c). 15 butorphanol (10) dextrorphan 6. The analgesic composition of claim 5 wherein the hydrobromide (30) pharmacologically active Substance (c) is a non-narcotic 16 butorphanol (10) amantadine (30) 50 analgesic. 17 butorphanol (10) memantine 18 butorphanol (10) memantine acetaminophen (325) 7. The analgesic composition of claim 6 wherein the 19 buprenorphine (3) dextromethorphan non-narcotic analgesic is Selected from the group consisting hydrobromide (30) of acetaminophen, aspirin, diclofenac, difluSinal, etodolac, 20 buprenorphine (1) dextromethorphan acetaminophen (325) fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, hydrobromide (30) 55 21 buprenorphine (2) dextrorphan indomethacin, ketoprofen, ketorolac, meclofenamic acid, hydrobromide (30) mefenamic acid, nabu metone, naproxen, oxaprozin, 22 buprenorphine (1) amantadine (30) phenylbutaZone, piroXicam, Sulindac, tolmetin, tramadol 23 buprenorphine (1) memantine (30) and Zomepirac. 24 buprenorphine (1) memantine (30) ibuprofen (325) 25 meptazinol (30) dextromethorphan 8. The analgesic composition of claim 7 wherein the hydrobromide (30) 60 nontoxic NMDA receptor antagonist is selected from the 26 meptazinol (35) dextromethorphan acetaminophen (325) group consisting of dextromethorphan, dextrorphan, hydrobromide (30) amantadine, memantine and pharmaceutically acceptable 27 meptazinol (30) dextrorphan salts thereof. hydrobromide (30) 28 dezocine (30) dextromethorphan 9. The analgesic composition of claim 1 containing at hydrobromide (30) 65 least 15 mg (b). 29 dezocine (25) dextromethorphan acetaminophen (325) 10. The analgesic composition of claim 1 containing at least 20 mg (b). 6,007,841 7 8 11. A method of alleviating pain which comprises admin 16. The method of claim 11 containing a therapeutically istering to a mammal exhibiting pain (a) an analgesia effective amount of at least one other pharmacologically effective amount of at least one narcotic agonist-antagonist active Substance (c). analgesic and (b) a narcotic agonist-antagonist analgesic 17. The method of claim 16 wherein the pharmacologi potentiating amount of at least one nontoxic N-methyl-D- aspartate receptor antagonist. cally active Substance (c) is a non-narcotic analgesic. 12. The method of claim 11 wherein the narcotic agonist 18. The method of claim 17 wherein the non-narcotic antagonist analgesic is Selected from the group consisting of analgesic is Selected from the group consisting of pentazocine, nalbuphine, butorphanol, buprenophine, acetaminophen, aspirin, diclofenac, difluSinal, etodolac, meptazinol, dezocine, nalorphine, cyclazocine and pharma fenbufen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ceutically acceptable Salts thereof. ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, 13. The method of claim 11 wherein the nontoxic NMDA nabu metone, naproxen, oxapro Zin, phenylbutaZone, receptor antagonist is at least one member Selected from the piroXicam, Sulindac, tolmetin, tramadol and Zomepirac. group consisting of dextromethorphan, dextrorphan, 19. The method of claim 18 wherein the nontoxic NMDA amantadine, memantine and pharmaceutically acceptable 15 receptor antagonist is Selected from the group consisting of salts thereof. dextromethorphan, dextrorphan, amantadine, memantine 14. The method of claim 11 wherein (a) and (b) are and pharmaceutically acceptable Salts thereof. coadministered. 15. The method of claim 11 wherein (a) and (b) are coadministered as a Sustained release dosage form.