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US 20100209517A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0209517 A1 ON (43) Pub. Date: Aug. 19, 2010

(54) AND ANTI-INFLAMMATORY (30) Foreign Application Priority Data COMPOSITIONS COMPRISING DOMPERIDONE AND METHODS OF USING Jun. 26, 1996 (GB) ...... 96.13410.1 SAME Publication Classification (75) Inventor: Ninh ON, London (GB) (51) Int. Cl. A6IR 9/16 (2006.01) Correspondence Address: A63L/454 (2006.01) ROTHWELL FIGG, ERNST & MANBECK, PC. (52) U.S.C. ... 424/490; 514/322 1425 KSTREET, N.W., SUITE 800 WASHINGTON, DC 20005 (US) (57) ABSTRACT The present invention provides a method for eliciting an onset (73) Assignee: The Boots Company, Nottingham hastened analgesic and anti-inflammatory response and com (GB) bating nausea in acute migraine attacks. This method com prises administering a pharmaceutical composition compris (21) Appl. No.: 12/706,252 ing more than one active ingredient, wherein said more than 1-1. one active ingredient consist essentially of (22) Filed: Feb. 16, 2010 (i) domperidone or an analogue thereof in an amount Suf Related U.S. Application Data RWR, invent (63) Continuation of application No. 10/922,828, filed on migraine attack, and Aug. 23, 2004, now abandoned, which is a continua (ii) a NSAID, a pharmaceutically acceptable salt thereofor tion of application No. 09/956,816, filed on Sep. 21, a pure (-) or pure (+) optical isomeric form thereof in an 2001, now abandoned, which is a continuation of analgesically and anti-inflammatory effective amount, application No. 09/492,164, filed on Jan. 27, 2000, wherein said NSAID is selected from the group consist now Pat. No. 6,319,514, which is a continuation of ing of proprionic acid derivatives, deriva application No. 08/859,185, filed on May 20, 1997, tives, derivatives, biphenylcarboxylic acid now abandoned. derivatives and . US 2010/0209517 A1 Aug. 19, 2010

ANALGESCAND ANTI-NFLAMMATORY was demonstrated. The method of making a film coated tablet COMPOSITIONS COMPRISING containing and domperidone is disclosed in DOMPERDONE AND METHODS OF USING WO95/22974. SAME 0007 As far as the inventor knows, the art has never Sug gested that domperidone either be added to selected NSAIDS, CROSS REFERENCE TO RELATED which differ substantially in chemical structure from parac APPLICATION etamol; or be added to selected NSAIDS together with selected narcotic analgesic drugs. Also, the prior art does not 0001. This application is a continuation of U.S. Ser. No. Suggest the use of any two-component composition of a 10/922,828, filed Aug. 23, 2004, which is a continuation of selected NSAID and domperidone; and three-component of a Ser. No. 09/956,816, filed Sep. 21, 2001, which is a continu selected NSAID, a selected narcotic analgesic and domperi ation of Ser. No. 09/492,164, filed Jan. 27, 2000, now U.S. done to hasten the analgesic response and to manage nausea Pat. No. 6,319,514, issued Nov. 20, 2001, which in turn is a symptoms in migraine attacks. continuation of Ser. No. 08/859,185, filed May 20, 1997, now abandoned, which claims priority to U.K. Application No. DETAILED DESCRIPTION OF THE INVENTION 96.13410.1, filed Jun. 26, 1996. 0008. The NSAIDS for use in the compositions and meth ods of the present invention can be selected from the follow BACKGROUND TO THE ART ing categories: 0009 1) the derivatives; 0002 The current means of combating migraine attacks 0.010 2) the acetic acid derivatives; include simple such as or other nonsteroi 0.011 3) the fenamic acid derivatives: dal anti-inflammatory drugs (NSAIDS) and paracetamol, 0012 4) the biphenylcarboxyclic acid derivatives: taken at the earliest signs of an attack 1, 2, 3. Aspirin, 0013 5) the oxicams. paracetamol and have long been among the most 0014 All the contemplated compounds can be used at commonly used members of the NSAIDS class. Amongst the appropriate dosage levels for the purpose in the composition newer NSAIDS are , , , of the present invention. The compounds in groups 1 to 4 , and . The most widely used typically contain a carboxylic acid function; however, those NSAIDS available over the counter that have fewer gastro acids are sometimes administered in the form of their phar intestinal side effects than aspirin are paracetamol and ibu maceutically acceptable salts, e.g. sodium salts. profen. 0015 The propionic acid derivatives for use herein 0003 Combined preparations of paracetamol or aspirin include, but are not limited to, ibuprofen, naproxen, benox with an anti-emetic agent Such as buclizine or metoclopra aprofen, , , , ketoprofen, mide, have been used to alleviate the nausea symptoms that , , , , prapoprofen, often accompanied a migraine attack. Commercially, they are , tioxaprofen, , , tiaprofenic available as Migraleve Duo(R), Paramax(R, Migravess(R). Nar acid, fluprofen, and bucloxic acid. Structurally related propi cotic analgesics Such as codeine have also been employed onic acid derivatives having similar analgesic and anti-in together with NSAIDS to obtain synergistic analgesia, for flammatory properties are also intended to be encompassed example Migraleve Yellow(R), co-codamol. by this group. Presently preferred members of the propionic 0004 Gastric stasis, commonly present in migraine4. acid group include ibuprofen, naproxen, flurbiprofen, feno causes the poor absorption of the analgesics. Dispersible and profen, ketoprofen and fenbufen. effervescent formulations have been used in an attempt to 0016. The acetic acid derivatives for use herein include, overcome this 4. Metoclopramide, an anti-emetic, also but not limited to, indomethacin, , , Zomepi relieves gastric Stasis which has been found useful counter rac, , fenchlofenac, alchlofenac, ibufenac, isox acting the reduced analgesic effects of paracetamol in epac, furofenac, tiopinac, Zidometacin, , fen migraine attacks 1, 4, 5. tiazac, clidanac and OXipinac. Structurally related acetic acid 0005 Attacks who do not respond to analgesics may be derivatives having similar analgesic and anti-inflammatory treated with ergot preparations such as ergotamine tartrate. properties are also intended to be encompassed by this group. Newer alternatives to ergot compounds for acute migraine are Presently, preferred members of the acetic acid group include the selective serotonin 5HT1 agonist, for example Sumatrip tolmetin Sodium, Zomepinac sodium, Sulindac and tan.R. 6,7. Recent trials reported that oral 100 mg Sumatrip indomethacin. tan to be as effective as aspirin 900 mg plus 10 mg metoclo 0017. The fenamic acid derivatives for use herein include, pramide for initial attacks and more effective in Subsequent but are not limited to, mefenamic acid, , attacks 8. , and . Structur 0006. The use of metoclopramide combined with either ally related fenamic acid derivatives having similar analgesic paracetamol, or aspirin has already been disclosed. Domperi and anti-inflammatory properties are also intended to encom done is a dopamine antagonist but is less likely than metoclo passed by this group. Presently, preferred members of the pramide to produce extra pyramidal side effects since it does fenamic acid group include mefenemic acid and meclofe not cross the blood brain barrier. It stimulates gastro-intesti namate sodium (meclofenamic acid, Sodium salt). nal mobility and is used in the management of nausea and 0018. The biphenylcarboxylic acid derivatives for use Vomiting. The activity of domperidone on the gastro intestinal herein include, but are not limited to, diflunisal and flufenisal. mobility could enhance the rate of absorption of the analge Structurally related biphenylcarboxylic acid derivatives hav sics. In Cephalagia 13 (2), 124-7 (1993), the safety and effi ing similar analgesic and anti-inflammatory properties are cacy of separately administered domperidone in combination also intended to be encompassed by this group. Preferred with paracetamol in the treatment of acute attack of migraine members of this group are diflunisal and flufenisal. US 2010/0209517 A1 Aug. 19, 2010

0019. The oxicams for use herein include, but are not which the drug is administered. Generally speaking, the limited to, piroXicam, Sudoxicam, . Structurally selected NSAID or narcotic analgesic can be employed in any related oxicams having similar analgesic and anti-inflamma amount known to be an effective analgesic and anti-inflam tory properties are also intended to be encompassed by this matory amount. group. A preferred member of this group is piroXicam. 0029. Typical effective analgesic amounts of presently 0020. The narcotic analgesics for use in the present inven tion are orally active narcotic agonists. Suitable agonist-an preferred NSAIDs/narcotic analgesic for use in unit dose tagonist for use herein include orally analgesically active compositions of the invention can be found in the British antagonists of the nalorphine type, notably pentazocine; and National Formulary, American Hospital Formulary, Martin orally analgesically active antagonists of the morphine type, dale Extra Pharmacopoeia, e.g. 50-600 mg Ibuprofen. In a notably buprenorphine. Another Suitable agonist-antagonist two component composition of a selected NSAID and dom is meptazinol. Suitable narcotic agonists for use herein peridone and a three component composition of a selected include orally analgesically active members of the morphine NSAID, a selected narcotic analgesic and domperidone, the group, notably codeine, oxycodone, dihydrocodeine, dextro daily analgesic dose for each analgesic will generally not propoxyphene, papaveretum and tramadol. In many exceed their daily analgesic dosages. The ratio of a selected instances, the narcotic analgesics for use herein are adminis NSAID to a selected narcotic analgesic may vary depending tered in the forms of their pharmaceutically acceptable acid on the particular drugs selected and the required analgesic addition salts, e.g. codeine Sulphate, codeine phosphate, response. dihydrocodeine tartrate and tramadol hydrochloride. Struc 0030. While the compositions of the invention are prefer turally related analogues to the aforementioned compounds ably for oral use, they may also be formulated for and admin having similar analgesic property are also intended to be istered by other methods which are known for administering encompassed by this group. analgesics, e.g. Suppositories. Also, the preferred dosage lev 0021 For compounds (NSAIDS or narcotic analgesics) els mentioned earlier are used in adults; pediatric composi which have optically active centre(s), the invention refers to tions would contain proportionally less of the active ingredi the racemate as well as the pure (-) or (+) optical isomeric entS. forms. 0022. The domperidone or its analogues used herein is 0031. The compositions of the present invention can be intended to encompass not only domperidone as the anhy conveniently administered by any route of administration drous powered but any salt or derivatives or any compounded suitable for the selected NSAID and/or selected narcotic anal mixture thereof which is non toxic, pharmaceutically accept gesic component, e.g. oral or rectal. Preferably, the combina able and which has gastric motility stimulating activity to tion is formulated with any Suitable nontoxic pharmaceuti enhance absorption of the co-administered analgesic(s) in cally acceptable-inert carrier material. Such carrier materials gastric Stasis and anti-emetic property. Presently, the pre are well known to those skilled in the art. ferred salt of domperidone is maleate. 0032. In a typical preparation for oral administration, e.g. 0023 The term “selected NSAID' as used herein is tablet or capsule, the selected NSAID in an effective analge intended to mean any non-narcotic analgesic/nonsteroidal sic/anti-inflammatory amount and domperidone in an amount anti-inflammatory compound within one of the five structural Sufficient to hasten its onset and/or to control nausea and categories indicated hereinabove. Similarly, the term vomiting; or the selective NSAID in an effective analgesic/ 'selected narcotic analgesic” as used herein is intended to anti-inflammatory amount together with a selected narcotic mean any orally analgesically active narcotic analgesic, be it analgesic in an amount Sufficient to enhance the analgesic an orally active narcotic agonist having oral analgesic activ response and domperidone in an amount Sufficient to hasten ity. The terms “selected NSAID' and “selected narcotic anal its onset and/or to control nausea and Vomiting; are combined gesic' are used for the sake of simplicity in the discussion with any oral nontoxic pharmaceutically acceptable inert car which follows. rier Such as lactose, starch (pharmaceutical grade), dicalcium 0024. When a selected NSAID or NSAID plus a selected phosphate, calcium Sulphate, kaolin, mannitol and powder narcotic analgesic is combined with domperidone in accord Sugar. with the present invention, the following results may be pro 0033. Additionally, when required, suitable binders, lubri duced: cants, disintegrating agents, colouring agents and coating 0025. The analgesic/anti-inflammatory effect of the agents can also be included. Typical binders include starch, selected NSAID as a single active or NSAID plus a gelatine, Sugars such as Sucrose, molasses and lactose, natural Selected narcotic analgesic can be brought on more and synthetic gums such as acacia, Sodium alginate, car quickly; boxymethylcellulose, methylcellulose, polyvinylpyrroli 0026 the nausea symptom experienced in acute done, polyethylene glycol, ethylcellulose and waxes. Typical migraine attacks can be averted or alleviated. lubricants for use in the dosage forms can include, without 0027. For patients suffering migraine headache, the time limitation, boric acid, Sodium benzoate, Sodium acetate, from administration of to the onset of effective sodium chloride, leucine and polyethylene glycol. Suitable relief is clearly of paramount importance. The hastening of disintegrators can include, without limitation, starch, meth the onset analgesia by combining domperidone with a ylcellulose, agar, bentonite, cellulose, wood products, alginic selected NSAID or a selected NSAID plus a selected narcotic acid, guar gum, citris pulp, carboxymethylcellulose and analgesic according to the present invention is therefore can Sodium lauryl Sulphate. Sweetening and flavouring agents be very significant. and preservatives may be included, particularly when a liquid 0028. The precise amount of NSAID or narcotic analgesic dosage form is formulated, e.g. syrup, Suspension and elixir. drug for use in the present compositions will vary depending, When the dosage form is a capsule, it may contain, in addition for example, on the specific drug chosen, the condition for to the above type, a liquid carrier Such as fatty oil. Various US 2010/0209517 A1 Aug. 19, 2010 other materials may be present as coatings or to otherwise 5. A pharmaceutical composition for treating acute modify the physical form of the dosage unit. migraine attacks by eliciting an onset hastened analgesic and anti-inflammatory response comprising effective amounts of REFERENCES more than one active ingredient, wherein said more than one 0034 1) Atkinson R, Appenzeller O (1984). Headache. active ingredient consist essentially of Postgrad Med J; 60: 841-846. (i) domperidone or an analogue thereof in an amount Suf 0035. 2) Diamond S., Milistein E (1988). Current con ficient to hasten the onset of the analgesic and anti cepts of migraine therapy.J. Clin Pharmacol; 28: 193-199. inflammatory response and to combat nausea in an acute 0036 3) Anonymous (1984). Drugs for migraine. Med migraine attack, and Lett Drugs Ther; 26: 95-96. (ii) a NSAID, a pharmaceutically acceptable salt thereofor 0037 4) Clough C (1989). Treating migraine. Br Med J: a pure (-) or (+) optical isomeric form thereof in an 299: 141-142. analgesically and anti-inflammatory effective amount, 0038 5)Peatfield R (1983). Migraine: Current concepts of wherein said NSAID is selected from the group consist pathogenesis and treatment. Drugs; 26:364-371. ing of ibuprofen, naproxen, , flurbiprofen, 0039 6) Pearce JMS (1991). Sumatriptan in migraine. Br fenoprofen, fenbufen, ketoprofen, indoprofen, pirpro Med J:303: 1941. fen, carprofen, oxaprozin, prapoprofen, miroprofen, 0040 7) Fullerton T. Gengo F M (1992). Sumatriptan: a tioxaprofen, Suprofen, alminoprofen, , Selective 5-hydroxytryptamine receptor agonist for the flurprofen and bucloxic acid. acute treatment of migraine. Ann Pharmacother; 26: 800 6. A pharmaceutical composition according to claim 5. 8O8. wherein the NSAID is ibuprofen. 0041) 8) The oral Sumatriptan and Aspirin plus Metoclo 7. A pharmaceutical composition according to claim 5. pramide Comparative Study Group (1992). A study to wherein the domperidone analogue is domperidone maleate. compare oral Sumatriptan with oral Aspirin plus oral meto 8. A pharmaceutical composition according to claim 5. clopramide in the acute treatment of migraine. EurNeurol;. wherein said more than one active ingredient consist of dom 32:177-184. peridone maleate and ibuprofen. 1. A method for treating acute migraine attacks by eliciting 9. A pharmaceutical composition according to claim 5. an onset hastened analgesic and anti-inflammatory response wherein said composition is formulated for oral administra and combating nausea in a Subject in need of an analgesic, tion. anti-inflammatory and anti-nausea response, comprising 10. A pharmaceutical composition according to claim 5, administering a pharmaceutical composition comprising wherein said composition is formulated as a tablet or capsule effective amounts of more than one active ingredient to said with the addition of a suitable pharmaceutically acceptable Subject, wherein said more than one active ingredient consists carrier. essentially of: 11. A pharmaceutical composition according to claim 10, (i) domperidone or an analogue thereof in an amount Suf wherein said composition is formulated as a dispersible or ficient to hasten the onset of the analgesic and anti effervescent dosage form with the addition of a suitable phar inflammatory response and to combat nausea in an acute maceutically acceptable carrier. migraine attack, and 12. A pharmaceutical composition according to claim 10, (ii) a NSAID, a pharmaceutically acceptable salt thereofor wherein said composition is in a microencapsulated dosage a pure (-) or (+) optical isomeric form thereof in an form with the addition of a suitable pharmaceutically accept analgesically and anti-inflammatory effective amount, able carrier. wherein said NSAID is selected from the group consist 13. A pharmaceutical composition according to claim 5. ing of ibuprofen, naproxen, benoxaprofen, flurbiprofen, said composition is formulated as granules for oral adminis fenoprofen, fenbufen, ketoprofen, indoprofen, pirpro tration with the addition of a suitable pharmaceutically fen, carprofen, oxaprozin, prapoprofen, miroprofen, 20 acceptable carrier tioxaprofen, Suprofen, alminoprofen, tiaprofenic acid, 14. A pharmaceutical composition according to claim 5. flurprofen and bucloxic acid. wherein said composition is formulated for rectal administra 2. A method according to claim 1, wherein the domperi tion. done analogue is domperidone maleate. 15. A pharmaceutical composition according to claim 14, 3. A pharmaceutical composition for treating acute wherein said composition is formulated as a Suppository with migraine attacks which elicits an onset hastened analgesic the addition of a suitable pharmaceutically acceptable carrier. and anti-inflammatory response and combats nausea, com 16. A pharmaceutical composition according to claim 5. prising effective amounts of more than one active ingredient wherein said composition is formulated as an enema or rectal wherein said more than one active ingredient consist essen Solution. tially of: 17. A pharmaceutical composition for treating acute (i) domperidone or an analogue thereof in an amount Suf migraine attacks by eliciting an onset hastened analgesic and ficient to hasten the onset of the analgesic and anti anti-inflammatory response and combating nausea in a Sub inflammatory response and to combat nausea in an acute ject in need of an analgesic, anti-inflammatory and anti-nau migraine attack, and sea response, comprising effective amounts of more than one (ii) ibuprofen, a pharmaceutically acceptable salt thereofor active ingredient, wherein said more than one active ingredi a pure (-) or (+) optical isomeric form thereof in an ent consist essentially of analgesically and anti-inflammatory effective amount. (i) domperidone or an analogue thereof in an amount Suf 4. A method according to claim 1, wherein said more than ficient to hasten the onset of the analgesic and anti one active ingredient consist of domperidone maleate and inflammatory response and to combat nausea in an acute ibuprofen. migraine attack, and US 2010/0209517 A1 Aug. 19, 2010

(ii) a NSAID, a pharmaceutically acceptable salt thereofor 30. A pharmaceutical composition according to claim 29, a pure (-) or (+) optical isomeric form thereof in an wherein the NSAID is ibuprofen. analgesically and anti-inflammatory effective amount, 31. A pharmaceutical composition according to claim 30, wherein said NSAID is selected from the group consist wherein said more than one active ingredient consist of dom ing of ibuprofen, naproxen, benoxaprofen, flurbiprofen, peridone maleate and ibuprofen. fenoprofen, fenbufen, ketoprofen, indoprofen, pirpro 32. A pharmaceutical composition according to claim 29, fen, carprofen, oxaprozin, prapoprofen, miroprofen, further comprising a suitable pharmaceutically acceptable tioxaprofen, Suprofen, alminoprofen, tiaprofenic acid, carrier. 33. A pharmaceutical composition according to claim 29, flurprofen and bucloxic acid. wherein said composition is formulated for oral administra 18. A pharmaceutical composition according to claim 17. tion. wherein the NSAID is ibuprofen. 34. A pharmaceutical composition according to claim 33, 19. A composition according to claim 17, wherein the wherein said composition is formulated as a tablet or capsule domperidone analogue is domperidone maleate. with the addition of a suitable pharmaceutically acceptable 20. A pharmaceutical composition according to claim 17. carrier. wherein said more than one active ingredient consist of dom 35. A pharmaceutical composition according to claim 33, peridone maleate and ibuprofen. wherein said composition is formulated as a dispersible or 21. A composition according to claim 18, wherein said effervescent dosage form with the addition of a suitable phar composition is formulated for oral administration. maceutically acceptable carrier. 22. A composition according to claim 21, wherein said 36. A pharmaceutical composition according to claim 33, composition is formulated as a tablet or capsule with the wherein said composition is in microencapsulated dosage addition of a Suitable pharmaceutically acceptable carrier. form with the addition of a suitable pharmaceutically accept 23. A composition according to claim 21, wherein said able carrier. composition is formulated as a dispersible or effervescent 37. A pharmaceutical composition according to claim 33, dosage form with the addition of a suitable pharmaceutically wherein said composition is formulated as granules for oral acceptable carrier. administration. 24. A composition according to claim 21, wherein said 38. A pharmaceutical composition according to claim 29, composition is in microencapsulated dosage form with the wherein said composition is formulated for rectal administra addition of a Suitable pharmaceutically acceptable carrier. tion. 25. A composition according to claim 21, wherein said 39. A pharmaceutical composition according to claim 29, composition is formulated as granules for oral administra wherein said composition is formulated as a Suppository with tion. the addition of a suitable pharmaceutically acceptable carrier. 26. A composition according to claim 17, wherein said 40. A pharmaceutical composition according to claim 38, composition is formulated for rectal administration. wherein said composition is formulated as an enema or rectal 27. A composition according to claim 17, wherein said solution with the addition of a suitable pharmaceutically composition is formulated as a Suppository with the addition acceptable carrier. of a Suitable pharmaceutically acceptable carrier. 41. A pharmaceutical composition for treating acute 28. A composition according to claim 17, wherein said migraine attacks by eliciting an onset hastened analgesic and composition is formulated as an enema or rectal Solution with anti-inflammatory response comprising effective amounts of the addition of a suitable pharmaceutically acceptable carrier. only two pharmaceutically active ingredients, wherein: 29. A pharmaceutical composition for combating nausea in (i) said first pharmaceutical active ingredient comprises acute migraine attacks comprising more than one active domperidone or an analogue thereof in an amount Suf ingredient, wherein said more than one active ingredient con ficient to hasten the onset of the analgesic and anti sists essentially of inflammatory response and to combat nausea in an acute (i) domperidone or an analogue thereof in an amount Suf migraine attack, and ficient to hasten the onset of the analgesic and anti (ii) said second pharmaceutical active ingredient com inflammatory response and to combat nausea in an acute prises a NSAID, a pharmaceutically acceptable salt migraine attack, and thereof or a pure (-) or (+) optical isomeric form thereof (ii) a NSAID, a pharmaceutically acceptable salt thereofor in an analgesically and anti-inflammatory effective a pure (-) or (+) optical isomeric form thereof in an amount, wherein said NSAID is selected from the group analgesically and anti-inflammatory effective amount, consisting of ibuprofen, naproxen, benoxaprofen, flur wherein said NSAID is selected from the group consist biprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, ing of ibuprofen, naproxen, benoxaprofen, flurbiprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miropro fenoprofen, fenbufen, ketoprofen, indoprofen, pirpro fen, tioxaprofen, Suprofen, alminoprofen, tiaprofenic fen, carprofen, oxaprozin, prapoprofen, miroprofen, acid, flurprofen and bucloxic acid. tioxaprofen, Suprofen, alminoprofen, tiaprofenic acid, flurprofen and bucloxic acid. c c c c c