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

Definitions

• 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 17% 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
• 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.
• 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 for local applications.
• Clinical experience suggests that, amongst all the available modes of administration, patients find that orally administered medicaments are the simplest to use.
• 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.
• 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.
• 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 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.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising ibuprofen lysinate in association with domperidone or a pharmaceutically acceptable salt thereof.
• 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.
• 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 overindulge ce .
• 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.
• ibuprofen is a racemic mixture.
• the active enantiomer of ibuprofen is the S(+) enantiomer.
• 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.
• 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 laevo (L) form), may be used in the same manner.
• the pharmaceutical composition according to the present invention majr conveniently be adapted for administration orally, rectally or parenterally.
• 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.
• 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.
• 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.
• 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.
• the molar ratio of ibuprofen lysinate to domperidone or its pharmaceutically acceptable salt will suitably be approximately 1 to 1.
• this ratio will be between 0.001 to 1 and 1000 to 1, and especially from 0.01:1 to 100:1.
• 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.
• domperidone or a pharmaceutically acceptable salt thereof 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.
• 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 g 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.
• 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 final mix is compressed to obtain round, flat tablets of 13 mm diameter and 409 mg weight, using a Korsch KO excenter tablet press.
• 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
• 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.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Pain & Pain Management (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 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 WO PCT/GB1999/003398 patent/WO2000021534A1/en not_active Ceased
  • 1999-10-13 EP EP99949222A patent/EP1121124A1/de not_active Withdrawn
  • 1999-10-13 AU AU62197/99A patent/AU6219799A/en not_active Abandoned

Non-Patent Citations (1)

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