GB2313309A - Domperidone and NSAIDs for the treatment of migraine - Google Patents

Abstract

Analgesic and anti-inflammatory compositions including domperidone in combination with a non-steroidal anti-inflammatory (NSAID), e.g. ibuprofen, and also a narcotic analgesic, e.g. codeine, are used to treat nausea and vomiting caused by migraine attacks. The compositions may be in the form of tablets, capsules, granules, liquids or suppositories.

Description

ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING DOMPERIDONE AND METHODS OF USING SAME.

BACKGROUND TO THE ART The current means of combating migraine attacks include simple analgesics such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDS) and paracetamol, taken at the earliest signs of an attack 1, 2, 3 Aspirin, paracetamol and phenacetin have long been among the most commonly used members of the NSAIDS class. Amongst the newer NSAIDS are ibuprofen, ketoprofen, mefenamic acid, diflunisal, naproxen and piroxicam. The most widely used NSAIDS available over the counter that have fewer gastro intestinal side effects than aspirin are paracetamol and ibuprofen.

Combined preparations of paracetamol or aspirin with an anti-emetic agent such as buclizine or metoclopramide, have been used to alleviate the nausea symptoms that often accompanied a migraine attack. Commercially, they are available as Migraleve Duo#, Paramax#, Migravess#, Narcotic analgesics such as codeine have also been employed together with NSAIDS to obtain synergistic analgesia, for example Migraleve Yellow#, co-codamol.

Gastric stasis, commonly present in migraine4, causes the poor absorption of the analgesics.

Dlspersible and effervescent formulations have been used in an attempt to overcome this4.

Metoclopramide, an anti-emetic, also relieves gastric stasis which has been found useful counteracting the reduced analgesic effects of paracetamol in migraine attacks ' 4 5.

Attacks who do not respond to analgesic may be treated with ergot preparations such as crgotamlne tartrate. Newer alternatives to ergot compounds for acute migraine are the selective scrotonin 5HT, agonlst, for example Sumatnptan#6, - Recent trials reported that oral 100 mg sumatnptan to be as effective as aspirin 900 mg plus 10 mg metoclopramide for initial attacks and more effective m subsequent attacks 8, The use of metoclopramide combined with either paracetamol, or aspirin has already been disclosed. Dompendone is a dopamine antagonist but is less likely than metoclopramide to produce extra pyramidal side effects smce it does not cross the blood brain barner. It stimulates gastro intestinal mobility and is used in the management of nausea and vomiting. The activity of dompcndone on the gastro intestinal mobility could enhance the rate of absorption of the 1 Athinson R. Appenzeller () (1984). @cadache, Postgrad Med J:60 841-846 2 Diamond S. Millstem E (1988) Current concepts of migraine therapy J Chn Pharmacol, 28. 193-199.

3 Anonvmous (1984) Drugs for migraine Med 1 ctt Drugs Ther, 26. 95-96 4 Clough C (1989) Treating migrame Br Med 1.299 141-142 5 Peatfield R (1983) Migraine: Current concepts of pathogencsis and treatment. Drugs 26 364-371 6 Pearce JMS (1991) Sumatnptan in mugraine. Br Med J, 303: 1941.

7 Fullerton T, Gengo FM (1992). Sumatnptan: a selective 5-hydroxytryptamine receptor agonist for the acutc trcatment of migrame Ann Pharmacother, 26. 800-808 8 The oral Sumatnptan and Aspinn plus Mctoclopramidc Comparative Study Group (1992) A study to compare oral sumatnptan with oral Aspum plus oral metoclopramide in thhe acute trcatment of migrame. liur Neurol; 32: 177-184.

analgesics. In Cephalagia 13 (2), 1247 (1993), the safety and efficacy of separately administered domperidone in combination with paracetamol in the treatment of acute attack of migraine was demonstrated. The method of making a film coated tablet containing paracetamol and dompendone is disclosed in W095/22974.

As far as the inventor knows, the art has never suggested that domperidone either be added to selected NSAIDS, which differ substantially in chemical structure from paracetamol; or be added to selected NSAIDS together with selected narcotic analgesic drugs. Also, the pnor an does not suggest the use of any two-component composition of a selected NSAID and domperidone; and three-component of a selected NSAID, a selected narcotic analgesic and domperidone to hasten the analgesic response and to manage nausea symptoms in migraine attacks.

DETAILED DESCRIPTION OF THE INVENTION The NSAIDS for use m the compositions and methods of the present invention can be selected from the following categones: 1) the propioruc acid derivatives 2) the acetic acid derivatives; 3) the fenanuc acid derivatives; 4) the biphenylcarboxyclic acid denvauves; z) the oxlcams.

All the contemplated compounds can be used at appropnate dosage levels for the purpose In the composition of the present mvenuon. The compounds m groups 1 to 4 typically contain a carboxylic acid function; however, those acids are sometimes adrninistered m the form of their pharmaceutically acceptable salts, e.g. sodium salts.

The propionic acid derivatives for use herem mclude, but are not limited to, ibuprofen, naproxen, benoxaprofen. flurblprofen. fenoprofen, fenbufen, ketoprofen, indoprofen, plrprofen, carprofen, oxaprozin. prapoprofen, muroprofen, uoxaprofen, suprofen, alminoprofen, uaprofenic acid, fluprofen. and bucloxic acid. Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties are also Intended to be encompassed by this group. Presently preferred members of the propionic acid group include ibuprofen. naproxen. flurbiprofen, fenoprofen. ketoprofen and fenbufen.

The acetic acid derivatives for use herein include, but not limited to, indomethacin. sulindac, tolmetin, zomepirac, diclofenac, fenchlofenac, alchlofenac, ibufenac, isoxepac, furofenac, tiopinac, zldometacln. acemetacin, fenuazac, clidanac and oxipinac, Structurally related acetic acid derivatives having similar analgesic and anu-lnflammatorx properues are also intended to be encompassed by this group. Presendy, preferred members of the aceuc acid group Include tolmetin sodium, zomeplnac sodium, sulindac and Indomethacm.

The fenamic acid derivatives for use herem mclude, but are not limited to, mefenamic acid, meclofenanuc acid, flufenamic acid, niflumic acid and tolfenamic acid. Suucturalln related fenamic acid derivatives having similar analgesic and anti-inflammatory properues are also intended to encompassed by this group. Presently, preferred members of the tenamlc acid group include mefenemic acid and meclotenamate sodium (meclofenamic acid, sodium salt).

The biphenylcarboxylic add derivatives for use herein indude, but are not limited to, diflunisal and flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and antiinflammatory properties are also intended to be encompassed by this group. Preferred members of this group are diflunisal and flufenisal.

The oxicams for use herein indude, but are not limited to, piroxicam, sudoxicam, isoxicam.

Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. A preferred member of this group is piroxicam.

The narcotic analgesics for use in the present invention are orally active narcotic agomsts. Suitable agonist-antagonist for use herein indude orally analgesically active antagonists of the nalorphine type, notably pentazocine; and orally analgesically active antagonists of the morphine nope, notably buprenorphine. Another suitable agonist-antagonist is meptazinol. Suitable narcotic agonists for use herein include orally analgesically active members of the morphine group, notably codeine, oxycodone, dihydrocodeine, dextropropoxyphene, papaveretum and trarnadol. In many instances, the narcotic analgesics for use herein are administered in the forms of their pharmaceutically acceptable add addition salts, e.g. codeine sulphate, codeine phosphate. dihydrocodeine tartrate and tramadol hydrochloride. Struturally related analogues to the aforementioned compounds having similar analgesic property are also intended to be encompassed by this group.

For compounds (NSAIDS or narcotic analgesics) which have optically active centre(s), the invention refers to the racemate as well as the pure (-) or (+) optical isomeric forms.

The domperidone or its analogues used herein IS intended to encompass not only domperidone as the an hydros powered but any salt or derivatives or any compounded mixture thereof which is non toxic, pharmaceutically acceptable and which has gasuic motility stimulating activity to enhance absorption of the co-administered analgeslc(s) m gastric stasis and anti-emetic property. Presently, the preferred salt of domperidone is maleate.

The term "selected NSAID" as used herem is intended to mean any non-narcouc analgeslc/nonsteroidal anti-inflammatiory compound within one of the five structural categories indicated hereinabove. Similarly, the term "selected narcotic analgesic" as used herein is intended to mean any orally analgesically active narcouc analgesic, be it an orally active narcotic agonist having oral analgesic activity. The terms "selected NSAID" and "selected narcotic analgesic" are used for the sake of simplicity m the dlscusslon which follows.

Nhen a selected NSAID or NSAID plus a selected narcotic analgesic is combined with dompcndone in accord with the present invention, the following results may be produced: # the analgeslc/anu-lnflammatorr effect of the selected NSAID as a single active or NSA ID plus a selected narcotic analgesic can be brought on more quickly; the nausca symptom experienced m acute migraine attacks can be averted or alleviated.

Itor patients suffenng migraine headache, the ume from administration of medicauon to the onset of effective relief is clearly of paramount importance. The hastening of the onset analgesia by comblnlng domperidone with a selected NSAID or a selected NSAID plus a selected narcotic analgesic according to the present invention is therefore can be ver) slgnificant.

The preclse amount of NSAID or narcotic analgesic drug for use in the present compositions will van,- depending, for example, on the specific drug chosen, the condition for which the drug is adnunistered. Generally speaking, the selected NSA ID or narcotic analgesic can be employed in any amount known to be an effective analgesic and anti-inflammatory amount.

Typical effective analgesic amounts of presently preferred NSAIDs/narcotic analgesic for use m unit dose compositions of the invention can be found in the British National Formulary, Amencan Hospital Formulary, Martindale Extra Pharmacopoeia, e.g. 50 - 600 mg Ibuprofen. In a twocomponent composition of a selected NSAID and domperidone and a three component composition of a selected NSAID, a selected narcotic analgesic and domperidone, the daily analgesic dose for each analgesic will generally not exceed their daily analgesic dosages. The ratio of a selected NSAID to a selected narcotic analgesic may vary depending on the particular drugs selected and the required analgesic response.

While the compositions of the invention are preferably for oral use, they may also be formulated for and administered by other methods which are known for administenng analgesics, e.g.

suppositories. Also, the preferred dosage levels mentioned earlier are used m adults; paediatnc compositions would contain proportionally less of the active ingredients.

The compositions of the present invention can be conveniently administered by any route of administration suitable for the selected NSAID and/or selected narcotic analgesic component, e.g.

oral or rectal. Preferably, the combination is formulated with any suitable non toxic pharmaceutically acceptable mert carrier material. Such carrier materials are well known to those skilled In the art.

in a typical preparation for oral administration, e.g. tablet or capsule, the selected NSAID m an effective analges1c/anti-inflammators amount and dompendone m an amount sufficlent to hasten its onset and/or to control nausea and vomiting; or the selective NSAID m an effective analgesic/anti-infiammatory amount together with a selected narcotic analgesic m an amount sufficient to enhance the analgesic response and dompendone in an amount sufficient to hasten its onset and/or to control nausea and vomiting; are combined with any oral nontoxic pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalclum phosphate. calcium sulphate, kaolin, manitol and powder sugar.

Additionally. when required. suitable binders. lubricants, disintegrating agents. colounng agents and coaung agents can also be included. Typical binders mclude starch, gelatine, sugars such as sucrose.

molasses and lactose, natural and synthetic gums such as acacia. sodium - al nate, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylenc glycol, ethylcellulose and waxes. T!pical lubricants for use In the dosage forms can include, without limitation, boric acid.

sodium benzoate, sodium acetate, sodium chloride, leuclne and polyethylene glycol. Suitable disintegrators can include, without limitation, starch, methylcellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citris pulp, carboxymethylcellulose and sudium lauryl sulphate. Sweetening and flavouring agents and preservatives mar be mcluded, particularly when a liquid dosage form Is formulated, e.g. syrup, suspension and elixir. When the dosage form Is a capsule, it ma! contain, In addiuon to the above type, a liquid carrier such as fatty oil. Various other matenals may be present as coaungs or to otherwise modify the physical form of the dosage unit.

Claims (18)

1. A method for eliciting an onset hastened analgesic and anti-inflammatory response and/or for combating nausea and vomiting in acute migraine attacks, comprising administering a pharmaceutical composition consisting of: (i) an amount of domperidone or its analogues sufficient to hasten the onset of the analgesic and anti-inflammatory response and to combat nausea in acute migraine, and (ii) an analgesically and anti-inflammatory effective amount of a NSAID comprising an acetic acid derivative or a pharmaceutically acceptable salt or an appropriate pure (-) or pure (+) isomeric form thereof from sulindac, diclofenac, fenclofenac, alclofenac, ibuprofen, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac and oxpinac.

2. A method for eliciting an onset hastened analgesic and anti-inflammaton response and/or for combating nausea and vomiting in acute migraine attacks, comprising administering a pharmaceutical composition consisting of: (i) an amount of domperidone or its analogues sufficient to hasten the onset of the analgesic and anti-infiammaton response and to combat nausea in acute migraine, and (ii) an analgesically and anti-mflammaton effective amount of a NSA ID comprising an acetic acid derivative or a pharmaceutically acceptable salt or an appropnate (-) or (+) isomeric form thereof from sulindac, diclofenac, fenclofenac, alclofenac, ibuprofen, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac and oxpinac; together with an analgesically and anti-mflammaton effective amount of a narcotic analgesic, or its pharmaceuucalll acceptable salt or an appropnate pure (-).or (+) pure optical isomer.

3. A pharmaceutical composition of matter for use In eliciting an onset hastened analgesic and anti-inflammatory response and for combating nausea In acute migraine attacks, cpmpnsing administering a pharmaceutical composition conslsung of: (i) an amount of domperidone or its analogues sufficient to hasten the onset of the analgesic and anti-inflammator,' response and to combat nausea in acute migraine, and (ii) an analgesically and anti-inflammatory effective amount of a NSAID comprising an acetic acid derivative or a pharmacetitically acceptable salt or an appropriate (-) or (+) isomeric form thereof from sulindac, diclofenac, fenclofenac, alclofenac, ibuprofen, rsosepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac and oxpinac.

4. A pharmaceutical composition of matter for use In eliciting an onset hastened analgesic and anti-inflammatory response and for combating nausea In acute migraine attacks, comprising administering a pharmaceutical composition conslsung of: (i) an amount of dompendone or its analogues sufficicnt to hasten the onset of the analgesic and anti-inflammatori' response and to combat nausea in acute migraine, and (ii) an analgesically and anu-inflammatory effective amount of a NSAID comprising an acetic acid derivative or a pharmaceutically acceptable salt or an appropnate pure (-) or pure (+) isomeric form thereof from sulindac, diclofenac, fenclofenac, alclofenac, ibuprofen, soxcpac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac and oxpinac; together with an analgesically and ana-lnflammaton effective amount of a narcotic analgesic. or its pharmaceutically acceptable salt or an appropnate pure (-) or pure (-)isomer

5. A pharmaceutical composition according to claims 3 & 4, wherein the NSAID is a propionic acid derivative.

6. A pharmaceutical composition according to claims 3 & 4, wherein the NSAID Is a feriatmic acid derivative.

7. A pharmaceutical composition according to claims 3 & 4, wherein the NSAID is a biphenylcarboxylic acid derivative.

8. A pharmaceutical composition according to clams 3 & 4, wherein the NSAID is an oxicam derivative.

9. A pharmaceutical composition according to claims 3 & 4, said composition being adapted for oral administration.

10. A pharmaceutical composition according to claims 3 & 4, said composition bemg formulated as a tablet or capsule.

11. A pharmaceutical composition according to claim 10, wherein said composition is being formulated as a dispersible or effervescent dosage form.

12. A pharmaceutical composition according to claim 10, wherein said composition is m enteric coated dosage form.

13. A pharmaceutical composition according to claim 10, wherein said composition is in sustained or modified or dme release form.

14. A pharmaceutical composition according to claim 10, wherem said composition is in nucroencapsulated dosage form.

15. A pharmaceutical composition according to claims 3 & 4, said composition being formulated as granules for oral administration.

16. A pharmaceutical composition according to claims 3 & 4, said composition being adapted for rectal administration.

17. A pharmaceutical composition according to claim 17, said composition being formulated as a suppository.

18. A pharmaceutical composition according to claim 17, said composition being formulated as an enema or rectal solution.