CA2347192A1 - Pharmaceutical combination of ibuprofen-lysine and domperidone for treating migraine - Google Patents
Pharmaceutical combination of ibuprofen-lysine and domperidone for treating migraine Download PDFInfo
- Publication number
- CA2347192A1 CA2347192A1 CA002347192A CA2347192A CA2347192A1 CA 2347192 A1 CA2347192 A1 CA 2347192A1 CA 002347192 A CA002347192 A CA 002347192A CA 2347192 A CA2347192 A CA 2347192A CA 2347192 A1 CA2347192 A1 CA 2347192A1
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- Canada
- Prior art keywords
- domperidone
- migraine
- ibuprofen
- treatment
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 36
- 208000019695 Migraine disease Diseases 0.000 title claims abstract description 29
- 206010027599 migraine Diseases 0.000 title claims abstract description 29
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960001253 domperidone Drugs 0.000 title claims abstract description 28
- IHHXIUAEPKVVII-APFIOPMWSA-N (2s)-2,6-diaminohexanoic acid;(2r)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-APFIOPMWSA-N 0.000 title abstract description 4
- 206010047700 Vomiting Diseases 0.000 claims abstract description 13
- 206010028813 Nausea Diseases 0.000 claims abstract description 11
- 230000008693 nausea Effects 0.000 claims abstract description 11
- 206010019233 Headaches Diseases 0.000 claims abstract description 10
- 231100000869 headache Toxicity 0.000 claims abstract description 10
- IHHXIUAEPKVVII-ZSCHJXSPSA-N [(1s)-5-amino-1-carboxypentyl]azanium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound OC(=O)[C@@H](N)CCCC[NH3+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 IHHXIUAEPKVVII-ZSCHJXSPSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 20
- 230000002265 prevention Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000011260 co-administration Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 206010021518 Impaired gastric emptying Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000001288 gastroparesis Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 208000001407 Vascular Headaches Diseases 0.000 description 1
- IHHXIUAEPKVVII-PTKYJSHISA-N [(5s)-5-amino-5-carboxypentyl]azanium;(2s)-2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-PTKYJSHISA-N 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002579 antinauseant Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 108091008690 chemoreceptors Proteins 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a combination of ibuprofen lysine and domperidone for treating and/or preventing migraine, migraine-associated nausea and vomiting and headache with nausea following overindulgence.</SDOA B>
Description
PHARMACEUTICAL COMBINATION OF IBUPROFEN-LYSINE
AND DOMPERIDONE FOR TREATING MIGRAINE
The present invention relates to a pharmaceutical composition comprising a combination of active ingredients. More particularly, the invention concerns a pharmaceutical formulation comprising ibuprofen lysinate in combination with domperidone or a salt thereof, for use in the control of migraine, and in particular migraine-associated nausea and vomiting, and of headache with nausea following overindulgence.
Migraine is a recurrent, often familial, symptom complex of periodic attacks of vascular headache,, which is frequently associated with nausea and vomiting. Migraine affects approximately I7% of adult women and 6% of adult men (Stewart et al., Neurology, 1994, 44 (suppl. 4), 517-523).
Ibuprofen, or (~)-2-(p-isobutylphenyl)propionic acid, is a well-known non-steroidal anti-inflammatory drug (NSAID) of the formula Hs H3C ~
/CH-CHZ O CH-COOH
The compound is widely prescribed for its analgesic and anti-pyretic activity. It is also available as a low dose over-the-counter product to be used orally for the treatment of minor aches and pains, and as. a topically applied gel for the treatment of muscular sprains and strains.
The lysine salt of ibuprofen has been developed in order to confer water solubility upon the compound, primarily to assist in the development of an injectable form of ibuprofen. Thus, for example, UK
Patent Specification No. 1,471,910 (published 27th April 1977) describes the lysine salt of ibuprofen and its formulation as injectable solutions, tabloids, freeze-dried in vials on a mannitol support, ampoules, capsules, suppositories and ointments far local applications.
AND DOMPERIDONE FOR TREATING MIGRAINE
The present invention relates to a pharmaceutical composition comprising a combination of active ingredients. More particularly, the invention concerns a pharmaceutical formulation comprising ibuprofen lysinate in combination with domperidone or a salt thereof, for use in the control of migraine, and in particular migraine-associated nausea and vomiting, and of headache with nausea following overindulgence.
Migraine is a recurrent, often familial, symptom complex of periodic attacks of vascular headache,, which is frequently associated with nausea and vomiting. Migraine affects approximately I7% of adult women and 6% of adult men (Stewart et al., Neurology, 1994, 44 (suppl. 4), 517-523).
Ibuprofen, or (~)-2-(p-isobutylphenyl)propionic acid, is a well-known non-steroidal anti-inflammatory drug (NSAID) of the formula Hs H3C ~
/CH-CHZ O CH-COOH
The compound is widely prescribed for its analgesic and anti-pyretic activity. It is also available as a low dose over-the-counter product to be used orally for the treatment of minor aches and pains, and as. a topically applied gel for the treatment of muscular sprains and strains.
The lysine salt of ibuprofen has been developed in order to confer water solubility upon the compound, primarily to assist in the development of an injectable form of ibuprofen. Thus, for example, UK
Patent Specification No. 1,471,910 (published 27th April 1977) describes the lysine salt of ibuprofen and its formulation as injectable solutions, tabloids, freeze-dried in vials on a mannitol support, ampoules, capsules, suppositories and ointments far local applications.
- 2 - PCTlGB99/0339$
Clinical experience suggests that, amongst all the available modes of administration, patients find that orally administered medicaments are the simplest to use. However, the efficacy of drugs given orally to relieve migraine attacks is not always reliable as gastrointestinal motility is inhibited even in the earliest stages of an attack, and there is always a risk of nausea during the attack culminating in vomiting.
It has now been found that these disadvantages can be overcome by the co-administration of a ibuprofen lysinate in conjunction with domperidone or a pharmaceutically acceptable salt thereof, the resulting combined formulation displaying beneficial effects in controlling migraine-associated nausea and vomiting and in headache and nausea associated with overindulgence.
Domperidone has an antinauseant effect through an action at the chemoreceptor trigger zone. It also has a gastric prokinetic effect through an action on gut dopaminergic receptors. Gastric stasis is a feature of migraine attacks and can also contribute to nausea experienced after an excess of alcohol consumption. It is also possible that domperidone will increase the absorption of the ibuprofen lysine through counteracting gastric stasis.
Ibuprofen lysinate provides rapid absorption of racemic ibuprofen because the lysine salt is very soluble. Thus this compound is particularly well suited to treatment of headache in migraine and overindulgence where drug absorption may be compromised.
Despite the above-mentioned advantageous properties of the compounds used in the present invention, their combination has been nowhere suggested in the prior art. Further the combination is surprisingly effective in providing a fast-acting anti-nauseam medication for the treatment of migraine-associated nausea and vomiting and of headache with nausea following overindulgence.
Furthermore, as both compounds are well known the combination has the advantage of being unexpectedly efficacious and safe for self medication without medical supervision. This overcomes the long standing problem of the lack of effective self administered migraine and overindulgence medications which usually consist of an analgesic alone and thus suffer from the above-mentioned drawbacks.
The present invention accordingly provides a method for the treatment and/or prevention of migraine which comprises administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence, which comprises administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of a combination of I5 ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine.
The present invention further provides the use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence.
In another aspect, the present invention provides a pharmaceutical composition comprising ibuprofen lysinate in association with domperidone or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides a product comprising ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraine.
In a yet further aspect, the present invention provides a product comprising ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence.
In the normal practice of the invention, ibuprofen lysinate and domperidone or its pharmaceutically acceptable salt will usually be administered to a patient within a reasonable period of time, which will typically be up to about one hour apart. The compounds may be in the same pharmaceutical carrier and therefore administered simultaneously.
They may be in separate pharmaceutical carriers and administered simultaneously, by mixing the materials just prior to administration.
They may alternatively be in different dosage forms which can be taken simultaneously, or adminstered sequentially.
As is evident from its chemical name, ibuprofen is a racemic mixture. The active enantiomer of ibuprofen is the S(+) enantiomer.
Whilst the present invention refers in general to the racemate it will be appreciated that the S(+} enantiomer of ibuprofen in the form of its lysine salt may be used in the same manner. A particularly convenient method for the formation and resolution of (S}-ibuprofen-(S)-lysine is described in US Patent No. 4,994,604 (published 19th February 1991).
It will also be appreciated that the lysine may exist in its racemic form or as single enantiomers. Whilst the present invention refers in general to the racemate it will be appreciated that either enantiomer, such as the naturally occurring S(+} enantiomer (i.e. the laeuo (L) form), may be used in the same manner.
The pharmaceutical composition according to the present invention may conveniently be adapted for administration orally, rectally or - 5 _ PCT/GB99/03398 parenterally. For oral administration, the formulation may be presented in the form of tablets, pills, capsules, powders or granules; for parenteral administration, sterile parenteral solutions or suspensions may conveniently be utilised; and for rectal administration, the formulation may conveniently be in the form of suppositories. Suitably, the pharmaceutical compositions in accordance with the invention may be presented in the form of a kit of parts adapted for simultaneous, separate or sequential administration.
The compositions may be formulated by conventional methods well known in the pharmaceutical art, for example as described in Remington:
The Science and Practice of Pharmacy, Mack Publishing Company, 19th Edition, 1995.
For administration in combination, the ibuprofen lysinate and the domperidone or its pharmaceutically acceptable salt may be presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the molar ratio of ibuprofen lysinate to domperidone or its pharmaceutically acceptable salt will suitably be approximately 1 to 1.
Preferably, this ratio will be between 0.001 to 1 and 1000 to 1, and especially from 0.01:1 to 100:1.
For co-administration with domperidone or a pharmaceutically acceptable salt thereof in the treatment of migraine, and in particular migraine-associated nausea and vomiting or overindulgence, ibuprofen lysinate may suitably be administered at a daily dosage of about 0.001 to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg, and especially about 0.05 to 10 mg/kg. For co-administration with ibuprofen lysinate in the treatment of migraine, and in particular migraine-associated nausea and vomiting or overindulgence, domperidone or a pharmaceutically acceptable salt thereof may suitably be administered at a daily dosage of about O.OOI to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg and WO 00/21534 - s - PCT/GB99/03398 especially about 0.05 to 10 mg/kg. The active ingredients will typically be co-administered on a regimen of 1 to 4 times per day.
A sample treatment regime based upon a tablet containing 10 mg of domperidone and 342 mg of ibuprofen lysinate (equivalent to 200 mg of ibuprofen) is as follows:
for migraine - two tablets at the beginning of an attack with a dosage repeat after four hours if necessary up to a maximum of four dosages in twenty-four hours;
for overindulgence - one or two tablets at the beginning of an attack repeated after four hours if necessary up to a maximum of eight tablets in one day.
The following non-limiting Example serves to illustrate the present invention.
1,000 tablets were prepared as follows:
Blending:
Ibuprofen lysinate, compacted and Domperidone are pre-blended by hand in a pan.
Polyvidon K 29/32 and microcrystalline cellulose are added and hand-blended.
Magnesium stearate is then added and hand-blended.
The mix is finally blended in a 3,51-cubemixer for 30 minutes to obtain the final mix.
WO 00/21534 _ 7 _ PCT/GB99/03398 Compressing:
The final mix is compressed to obtain round, flat tablets of 13 mm diameter and 409 mg weight, using a Korsch KO excenter tablet press.
Formula per tablet:
Ibuprofen lysinate, compacted 342.0 mg Domperidone 10.0 mg Polyvidon K 29/32 17.0 mg Microcrystalline Cellulose 36.0 mg Magnesium Stearate 4.0 mg 409.0 mg The microcrystalline cellulose may be Avicel PH102. The magnesium stearate is generally from a vegetal source. In addition to the above ingredients about 4mg talc may be added to the mixture. Lactose fast flow may also be added.
The tablets may be supplied with a film coating comprising hypromellose, hydroxypropylcellulose, titanium dioxide and water.
Clinical experience suggests that, amongst all the available modes of administration, patients find that orally administered medicaments are the simplest to use. However, the efficacy of drugs given orally to relieve migraine attacks is not always reliable as gastrointestinal motility is inhibited even in the earliest stages of an attack, and there is always a risk of nausea during the attack culminating in vomiting.
It has now been found that these disadvantages can be overcome by the co-administration of a ibuprofen lysinate in conjunction with domperidone or a pharmaceutically acceptable salt thereof, the resulting combined formulation displaying beneficial effects in controlling migraine-associated nausea and vomiting and in headache and nausea associated with overindulgence.
Domperidone has an antinauseant effect through an action at the chemoreceptor trigger zone. It also has a gastric prokinetic effect through an action on gut dopaminergic receptors. Gastric stasis is a feature of migraine attacks and can also contribute to nausea experienced after an excess of alcohol consumption. It is also possible that domperidone will increase the absorption of the ibuprofen lysine through counteracting gastric stasis.
Ibuprofen lysinate provides rapid absorption of racemic ibuprofen because the lysine salt is very soluble. Thus this compound is particularly well suited to treatment of headache in migraine and overindulgence where drug absorption may be compromised.
Despite the above-mentioned advantageous properties of the compounds used in the present invention, their combination has been nowhere suggested in the prior art. Further the combination is surprisingly effective in providing a fast-acting anti-nauseam medication for the treatment of migraine-associated nausea and vomiting and of headache with nausea following overindulgence.
Furthermore, as both compounds are well known the combination has the advantage of being unexpectedly efficacious and safe for self medication without medical supervision. This overcomes the long standing problem of the lack of effective self administered migraine and overindulgence medications which usually consist of an analgesic alone and thus suffer from the above-mentioned drawbacks.
The present invention accordingly provides a method for the treatment and/or prevention of migraine which comprises administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
The present invention also provides a method for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence, which comprises administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of a combination of I5 ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine.
The present invention further provides the use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence.
In another aspect, the present invention provides a pharmaceutical composition comprising ibuprofen lysinate in association with domperidone or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides a product comprising ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraine.
In a yet further aspect, the present invention provides a product comprising ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential use in the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence.
In the normal practice of the invention, ibuprofen lysinate and domperidone or its pharmaceutically acceptable salt will usually be administered to a patient within a reasonable period of time, which will typically be up to about one hour apart. The compounds may be in the same pharmaceutical carrier and therefore administered simultaneously.
They may be in separate pharmaceutical carriers and administered simultaneously, by mixing the materials just prior to administration.
They may alternatively be in different dosage forms which can be taken simultaneously, or adminstered sequentially.
As is evident from its chemical name, ibuprofen is a racemic mixture. The active enantiomer of ibuprofen is the S(+) enantiomer.
Whilst the present invention refers in general to the racemate it will be appreciated that the S(+} enantiomer of ibuprofen in the form of its lysine salt may be used in the same manner. A particularly convenient method for the formation and resolution of (S}-ibuprofen-(S)-lysine is described in US Patent No. 4,994,604 (published 19th February 1991).
It will also be appreciated that the lysine may exist in its racemic form or as single enantiomers. Whilst the present invention refers in general to the racemate it will be appreciated that either enantiomer, such as the naturally occurring S(+} enantiomer (i.e. the laeuo (L) form), may be used in the same manner.
The pharmaceutical composition according to the present invention may conveniently be adapted for administration orally, rectally or - 5 _ PCT/GB99/03398 parenterally. For oral administration, the formulation may be presented in the form of tablets, pills, capsules, powders or granules; for parenteral administration, sterile parenteral solutions or suspensions may conveniently be utilised; and for rectal administration, the formulation may conveniently be in the form of suppositories. Suitably, the pharmaceutical compositions in accordance with the invention may be presented in the form of a kit of parts adapted for simultaneous, separate or sequential administration.
The compositions may be formulated by conventional methods well known in the pharmaceutical art, for example as described in Remington:
The Science and Practice of Pharmacy, Mack Publishing Company, 19th Edition, 1995.
For administration in combination, the ibuprofen lysinate and the domperidone or its pharmaceutically acceptable salt may be presented in a ratio which is consistent with the manifestation of the desired effect. In particular, the molar ratio of ibuprofen lysinate to domperidone or its pharmaceutically acceptable salt will suitably be approximately 1 to 1.
Preferably, this ratio will be between 0.001 to 1 and 1000 to 1, and especially from 0.01:1 to 100:1.
For co-administration with domperidone or a pharmaceutically acceptable salt thereof in the treatment of migraine, and in particular migraine-associated nausea and vomiting or overindulgence, ibuprofen lysinate may suitably be administered at a daily dosage of about 0.001 to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg, and especially about 0.05 to 10 mg/kg. For co-administration with ibuprofen lysinate in the treatment of migraine, and in particular migraine-associated nausea and vomiting or overindulgence, domperidone or a pharmaceutically acceptable salt thereof may suitably be administered at a daily dosage of about O.OOI to 250 mg/kg, typically about 0.005 to 100 mg/kg, more particularly about 0.01 to 50 mg/kg and WO 00/21534 - s - PCT/GB99/03398 especially about 0.05 to 10 mg/kg. The active ingredients will typically be co-administered on a regimen of 1 to 4 times per day.
A sample treatment regime based upon a tablet containing 10 mg of domperidone and 342 mg of ibuprofen lysinate (equivalent to 200 mg of ibuprofen) is as follows:
for migraine - two tablets at the beginning of an attack with a dosage repeat after four hours if necessary up to a maximum of four dosages in twenty-four hours;
for overindulgence - one or two tablets at the beginning of an attack repeated after four hours if necessary up to a maximum of eight tablets in one day.
The following non-limiting Example serves to illustrate the present invention.
1,000 tablets were prepared as follows:
Blending:
Ibuprofen lysinate, compacted and Domperidone are pre-blended by hand in a pan.
Polyvidon K 29/32 and microcrystalline cellulose are added and hand-blended.
Magnesium stearate is then added and hand-blended.
The mix is finally blended in a 3,51-cubemixer for 30 minutes to obtain the final mix.
WO 00/21534 _ 7 _ PCT/GB99/03398 Compressing:
The final mix is compressed to obtain round, flat tablets of 13 mm diameter and 409 mg weight, using a Korsch KO excenter tablet press.
Formula per tablet:
Ibuprofen lysinate, compacted 342.0 mg Domperidone 10.0 mg Polyvidon K 29/32 17.0 mg Microcrystalline Cellulose 36.0 mg Magnesium Stearate 4.0 mg 409.0 mg The microcrystalline cellulose may be Avicel PH102. The magnesium stearate is generally from a vegetal source. In addition to the above ingredients about 4mg talc may be added to the mixture. Lactose fast flow may also be added.
The tablets may be supplied with a film coating comprising hypromellose, hydroxypropylcellulose, titanium dioxide and water.
Claims (6)
1. A pharmaceutical composition comprising ibuprofen lysinate in association with domperidone or a pharmaceutically acceptable salt thereof.
2. A product comprising ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof as a combined preparation for simultaneous, separate or sequential administration.
3. The use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine.
4. The use of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence.
5. A method for the treatment and/or prevention of migraine which comprises administering to a patient in need of such treatment simultaneously, separately or sequentially, an effective amount of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
6. A method for the treatment and/or prevention of migraine-associated nausea and vomiting or of headache with nausea following overindulgence, which comprises administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of a combination of ibuprofen lysinate and domperidone or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9822333.2 | 1998-10-13 | ||
GBGB9822333.2A GB9822333D0 (en) | 1998-10-13 | 1998-10-13 | Pharmaceutical formulation |
PCT/GB1999/003398 WO2000021534A1 (en) | 1998-10-13 | 1999-10-13 | Pharmaceutical combination of ibuprofen-lysine and domperidone for treating migraine |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2347192A1 true CA2347192A1 (en) | 2000-04-20 |
Family
ID=10840497
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002347192A Abandoned CA2347192A1 (en) | 1998-10-13 | 1999-10-13 | Pharmaceutical combination of ibuprofen-lysine and domperidone for treating migraine |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1121124A1 (en) |
AU (1) | AU6219799A (en) |
CA (1) | CA2347192A1 (en) |
GB (1) | GB9822333D0 (en) |
WO (1) | WO2000021534A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9816899D0 (en) | 1998-08-05 | 1998-09-30 | Boots Co Plc | Therapeutic agents |
GB0108930D0 (en) * | 2001-04-10 | 2001-05-30 | Boots Co Plc | Therapeutic agents |
US9198889B2 (en) * | 2012-09-19 | 2015-12-01 | Quality IP Holdings, LLC | Methods for treating post-traumatic stress disorder |
US8715752B2 (en) | 2012-09-20 | 2014-05-06 | Quality Ip Holdings, Inc. | Compositions for increasing human growth hormone levels |
US9066953B2 (en) | 2012-09-20 | 2015-06-30 | Quality IP Holdings, LLC | Methods for increasing endurance and fat metabolism in humans |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9702392D0 (en) * | 1997-02-06 | 1997-03-26 | Boots Co Plc | Therapeutic agents |
-
1998
- 1998-10-13 GB GBGB9822333.2A patent/GB9822333D0/en not_active Ceased
-
1999
- 1999-10-13 CA CA002347192A patent/CA2347192A1/en not_active Abandoned
- 1999-10-13 AU AU62197/99A patent/AU6219799A/en not_active Abandoned
- 1999-10-13 WO PCT/GB1999/003398 patent/WO2000021534A1/en not_active Application Discontinuation
- 1999-10-13 EP EP99949222A patent/EP1121124A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
AU6219799A (en) | 2000-05-01 |
EP1121124A1 (en) | 2001-08-08 |
GB9822333D0 (en) | 1998-12-09 |
WO2000021534A1 (en) | 2000-04-20 |
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