WO2009136176A1 - Compositions and methods for the treatment of fibromyalgia - Google Patents

Compositions and methods for the treatment of fibromyalgia Download PDF

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Publication number
WO2009136176A1
WO2009136176A1 PCT/GB2009/001161 GB2009001161W WO2009136176A1 WO 2009136176 A1 WO2009136176 A1 WO 2009136176A1 GB 2009001161 W GB2009001161 W GB 2009001161W WO 2009136176 A1 WO2009136176 A1 WO 2009136176A1
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salt
derivative
mesylate
amantadine
pharmaceutically acceptable
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PCT/GB2009/001161
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French (fr)
Inventor
Malcolm. Philip Young
Olusola Clement Idowu
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E-Therapeutics Plc
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Publication of WO2009136176A1 publication Critical patent/WO2009136176A1/en

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    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides medicaments and methods for the treatment or alleviation of fibromyalgia.
  • the invention relates to the novel use of existing compounds for the treatment or alleviation of fibromyalgia, to methods of treatment related thereto and to novel pharmaceutical compositions. Furthermore, the invention relates to the use of existing compounds for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • Fibromyalgia is one of a number of central pain syndromes characterised by abnormal pain processing.
  • ACR American College of Rheumatology
  • the criteria require that an individual have a history of chronic widespread pain for a minimum of 3 months and at least 11 of 18 possible tender points.
  • Fibromyalgia pain can be accompanied by persistent fatigue, non restorative sleep, generalized morning stiffness, depression and anxiety, poor concentration or memory lapses, paresthesia, occipital headaches and irritable bowel and bladder.
  • the prevalence of fibromyalgia (using the ACR criteria) has been reported to range from 0.5 to 4% in industrialized countries.
  • fibromyalgia The aetiology of fibromyalgia remains unclear, but increasingly pharmacologic management of the disease is based on the premise of a central nervous system malfunction that causes amplification of pain transmission and interpretation. Fibromyalgia sufferers do not detect electrical, pressure or thermal stimuli at lower levels than healthy subjects but the threshold at which these stimuli cause pain or unpleasantness is lower. A number of factors are probably involved in this abnormal pain perception but central sensitization is important. During centralization a cascade of transcriptional and translational events leads to hyperalgesia (increased response to painful stimuli) and/ or allodynia (reduction in pain threshold) of second- and higher-order neurons and expansion of their receptive fields.
  • amantadine (1- aminoadamantane) may have beneficial effects for relieving certain types of chronic pain, including back pain and perioperative pain.
  • Amantadine has been shown to target several of the mechanisms which may give rise to central to central sensitisation in fibromyalgia (amantadine has known dopaminergic, noradrenergic and weak NMDA receptor antagonist activity).
  • amantadine may also target the spinal component of hyperalgesia, by acting as an antagonist of calmodulin.
  • amantadine and its salts hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate salts
  • Amantadine is normally used as hydrochloride.
  • Amantadine hydrochloride is commercially available as Symmetrel® from Endo Pharmaceuticals Inc.
  • a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions include pharmaceutically acceptable salts and amides.
  • Pharmaceutically acceptable salts may be selected from the group consisting of hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate.
  • the composition comprises amantadine hydrochloride.
  • compositions selected from the group consisting of methdilazine, hydroxyzine and one or more ergoloid mesylate may vary depending upon, inter alia, the active ingredient.
  • pharmaceutically acceptable derivatives of methdilazine, hydroxyzine include pharmaceutically acceptable salts, esters and amides of the carboxylic acid group.
  • Suitable salts include ammonium, alkali metal (e.g. sodium, potassium and lithium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with suitable organic bases, e.g.
  • esters include simple lower alkyl esters, e.g. the ethyl ester.
  • the pharmaceutically acceptable acid addition salts include the hydrochloride, e.g. the dihydrochloride.
  • Derivatives shall also, where appropriate include metabolites. Thus, in the case of hydroxyzine, derivatives shall include the active metabolite, cetirizine.
  • a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of methdilazine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a preferred salt of methdilazine is methdilazine hydrochloride.
  • Methdilazine is 10-[(l-methylpyrrolidin-3-yl) methyl]- lOH-phenothiazine.
  • a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of hydroxyzine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a preferred salt of hydroxyzine is hydroxyzine hydrochloride.
  • Hydroxyzine is 2-(2- ⁇ 4-[(4-chlorophenyl)(phenyl)methyl]piperazin-l-yl ⁇ ethoxy) ethanol.
  • a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Examples of ergoloid mesylates include, but shall not be limited to, dihydroergocornine mesylate (MW 659.80), dihydroergocristine mesylate (MW 707.84), dihydro-alpha-ergocryptine mesylate (MW 673.82) and dihydro-beta- ergocryptine mesylate (MW 673.82).
  • the term "derivative" used herein shall include any conventionally known derivatives of amantadine, methdilazine, hydroxyzine or ergoloid mesylates, such as, inter alia, solvates.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
  • amantadine, hydroxyzine, methdilazine and ergoloid mesylates, or a salt or a derivative and/or combinations thereof are known per se and may be prepared using methods known to the person skilled in the art or may be obtained commercially.
  • amantadine and its salts is known from UK Patent No. 1006885.
  • Hydroxyzine is known from US Patent No. 3,965,257.
  • Methdilazine is known from UK Patent No. 894049.
  • Ergoloid mesylates are known from US Patent No. 3,733,423.
  • composition of the invention is advantageous in that, inter alia, it is useful for the treatment or alleviation of fibromyalgia pain.
  • the composition of the invention is useful for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • amantadine or a pharmaceutically acceptable salt or a derivative thereof, in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain.
  • the use is in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • methdilazine or a salt or a derivative thereof
  • hydroxyzine or a salt or a derivative thereof
  • one or more ergoloid mesylate in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain.
  • the use is in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • amantadine or a salt or a derivative thereof in the combination with methdilazine or a salt or a derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • Amantadine and methdilazine can be administered sequentially or concurrently. When administered concurrently, amantadine and methdilazine can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and methdilazine.
  • Another objective of the present invention is the use of amantadine or a salt or a derivative thereof in the combination with hydroxyzine or a salt or a derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • Amantadine and hydroxyzine can be administered sequentially or concurrently. When administered concurrently, amantadine and hydroxyzine can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and hydroxyzine.
  • amantadine or a salt or a derivative thereof in the combination with ergoloid mesylates or a salt or derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • Amantadine and ergoloid mesylates can be administered sequentially or concurrently. When administered concurrently, amantadine and ergoloid mesylates can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and ergoloid mesylates.
  • the invention also provides amantadine, or a pharmaceutically acceptable salt or a derivative thereof, for the treatment or alleviation fibromyalgia pain.
  • the invention provides amantadine, or a pharmaceutically acceptable salt or a derivative thereof for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • the invention also provides rnethdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate, for the treatment or alleviation fibromyalgia pain.
  • the invention provides methdilazine, hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
  • the present invention provides a method of treatment of a patient suffering from fibromyalgia pain, said method comprising the administration of a therapeutically effective amount of a combination therapy comprising amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; simultaneously, sequentially or separately.
  • a combination therapy comprising amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; simultaneously, sequentially or separately.
  • the method of the invention comprises the simultaneous administration of amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine, hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate
  • the method preferably comprises the administration of a composition as hereinbefore described.
  • the compounds comprising of amantadine, or a salt or a derivative thereof, in combination with either methdilazine, hydroxyzine, or ergoloid mesylates, or salts or derivatives thereof may be administered orally.
  • compositions of the invention may be suitable for oral administration and may include tablets, capsules, dragees, liquid suspensions, solutions and syrups; examples of such adjuvants, diluents or carriers are: for tablets and dragees - fillers, e.g. lactose, starch, microcrystalline cellulose, talc and stearic acid; lubricants/glidants, e.g. magnesium stearate and colloidal silicon dioxide; disintegrants, e.g. sodium starch glycolate and sodium carboxymethylcellulose; for capsules - pregelatinised starch or lactose.
  • adjuvants, diluents or carriers are: for tablets and dragees - fillers, e.g. lactose, starch, microcrystalline cellulose, talc and stearic acid; lubricants/glidants, e.g. magnesium stearate and colloidal silicon dioxide; disintegrants, e.g. sodium starch glycolate and sodium carboxy
  • compositions and methods described herein may be used prophylactically as a means to prevent the development and/or onset of fibromyalgia and optionally associated symptoms of one or more of fatigue, depression and sleep disturbances.

Abstract

There is described a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, in and a therapeutically effective amount of one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF FIBROMYALGIA
FIELD OF THE INVENTION
The present invention provides medicaments and methods for the treatment or alleviation of fibromyalgia.
More particularly the invention relates to the novel use of existing compounds for the treatment or alleviation of fibromyalgia, to methods of treatment related thereto and to novel pharmaceutical compositions. Furthermore, the invention relates to the use of existing compounds for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
BACKGROUND
Fibromyalgia is one of a number of central pain syndromes characterised by abnormal pain processing. In 1990 the American College of Rheumatology (ACR) standardised the definition of fibromyalgia. The criteria require that an individual have a history of chronic widespread pain for a minimum of 3 months and at least 11 of 18 possible tender points. Fibromyalgia pain can be accompanied by persistent fatigue, non restorative sleep, generalized morning stiffness, depression and anxiety, poor concentration or memory lapses, paresthesia, occipital headaches and irritable bowel and bladder. The prevalence of fibromyalgia (using the ACR criteria) has been reported to range from 0.5 to 4% in industrialized countries. The aetiology of fibromyalgia remains unclear, but increasingly pharmacologic management of the disease is based on the premise of a central nervous system malfunction that causes amplification of pain transmission and interpretation. Fibromyalgia sufferers do not detect electrical, pressure or thermal stimuli at lower levels than healthy subjects but the threshold at which these stimuli cause pain or unpleasantness is lower. A number of factors are probably involved in this abnormal pain perception but central sensitization is important. During centralization a cascade of transcriptional and translational events leads to hyperalgesia (increased response to painful stimuli) and/ or allodynia (reduction in pain threshold) of second- and higher-order neurons and expansion of their receptive fields.
An analysis of current pharmacotherapies for fibromyalgia strongly indicates that targeting somatosensory imbalances is an effective therapeutic strategy for treating fibromyalgia pain. Hence, there is a demand for single pharmacological agents or combination agents which can reduce peripheral and central sensitivity and rebalance supraspinal mechanisms in fibromyalgia sufferers.
It has been reported that the antiviral and antiparkinsonian agent, amantadine (1- aminoadamantane) may have beneficial effects for relieving certain types of chronic pain, including back pain and perioperative pain. Amantadine has been shown to target several of the mechanisms which may give rise to central to central sensitisation in fibromyalgia (amantadine has known dopaminergic, noradrenergic and weak NMDA receptor antagonist activity). Furthermore, we have evidence that amantadine may also target the spinal component of hyperalgesia, by acting as an antagonist of calmodulin.
The preparation of amantadine and its salts (hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate salts) is described in UK Patent No. GB 1,006,885. Amantadine is normally used as hydrochloride. Amantadine hydrochloride is commercially available as Symmetrel® from Endo Pharmaceuticals Inc.
We have now found certain combination therapies comprising amantadine in combination with certain other medicaments which act synergistically in the relief of fibromyalgia pain. In addition, these combinations also have the benefit of targeting key secondary symptoms of fibromyalgia (fatigue, depression and sleep disturbances).
SUMMARY OF THE INVENTION
According to a first aspect of the invention we provide a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Pharmaceutically acceptable derivatives of the compounds of amantadine include pharmaceutically acceptable salts and amides. Pharmaceutically acceptable salts may be selected from the group consisting of hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate. Preferably, the composition comprises amantadine hydrochloride.
Pharmaceutically acceptable derivatives of the compounds selected from the group consisting of methdilazine, hydroxyzine and one or more ergoloid mesylate may vary depending upon, inter alia, the active ingredient. Thus, for example, pharmaceutically acceptable derivatives of methdilazine, hydroxyzine include pharmaceutically acceptable salts, esters and amides of the carboxylic acid group. Suitable salts include ammonium, alkali metal (e.g. sodium, potassium and lithium) and alkaline earth metal (e.g. calcium or magnesium) salts, and salts with suitable organic bases, e.g. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine, with substituted lower alkylamines, e.g. hydroxy substituted alkylamines such as tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine. Suitable esters include simple lower alkyl esters, e.g. the ethyl ester. The pharmaceutically acceptable acid addition salts include the hydrochloride, e.g. the dihydrochloride. Derivatives shall also, where appropriate include metabolites. Thus, in the case of hydroxyzine, derivatives shall include the active metabolite, cetirizine.
Thus, according to another aspect of the present invention we provide a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of methdilazine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. A preferred salt of methdilazine is methdilazine hydrochloride. Methdilazine is 10-[(l-methylpyrrolidin-3-yl) methyl]- lOH-phenothiazine.
According to another aspect of the present invention we provide a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of hydroxyzine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. A preferred salt of hydroxyzine is hydroxyzine hydrochloride.
Hydroxyzine is 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-l-yl}ethoxy) ethanol.
According to another aspect of the present invention we provide a pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
Examples of ergoloid mesylates include, but shall not be limited to, dihydroergocornine mesylate (MW 659.80), dihydroergocristine mesylate (MW 707.84), dihydro-alpha-ergocryptine mesylate (MW 673.82) and dihydro-beta- ergocryptine mesylate (MW 673.82). The term "derivative" used herein shall include any conventionally known derivatives of amantadine, methdilazine, hydroxyzine or ergoloid mesylates, such as, inter alia, solvates. It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compounds described herein, which may be used in any one of the uses/methods described. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
The exact dosages for the given combinations described above for the treatment of fibromyalgia pain and associated symptoms will depend on factors including dosage form, severity of fibromyalgia symptoms, age and physical condition of the patient, and other medications being taken.
The compounds selected from the group amantadine, hydroxyzine, methdilazine and ergoloid mesylates, or a salt or a derivative and/or combinations thereof, are known per se and may be prepared using methods known to the person skilled in the art or may be obtained commercially. Thus, as hereinbefore described, amantadine and its salts is known from UK Patent No. 1006885. Hydroxyzine, is known from US Patent No. 3,965,257. Methdilazine is known from UK Patent No. 894049. Ergoloid mesylates are known from US Patent No. 3,733,423.
The composition of the invention is advantageous in that, inter alia, it is useful for the treatment or alleviation of fibromyalgia pain. Preferentially, the composition of the invention is useful for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
Thus, according to a further aspect of the invention we provide the use of amantadine, or a pharmaceutically acceptable salt or a derivative thereof, in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain. Preferentially, the use is in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
According to a yet further aspect of the invention we provide the use of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate, in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain. Preferentially, the use is in the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
One objective of the present invention is the use of amantadine or a salt or a derivative thereof in the combination with methdilazine or a salt or a derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances. Amantadine and methdilazine can be administered sequentially or concurrently. When administered concurrently, amantadine and methdilazine can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and methdilazine.
Another objective of the present invention is the use of amantadine or a salt or a derivative thereof in the combination with hydroxyzine or a salt or a derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
Amantadine and hydroxyzine can be administered sequentially or concurrently. When administered concurrently, amantadine and hydroxyzine can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and hydroxyzine.
Another objective of the present invention is the use of amantadine or a salt or a derivative thereof in the combination with ergoloid mesylates or a salt or derivative thereof for the manufacture of a medicament for the treatment of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances. Amantadine and ergoloid mesylates can be administered sequentially or concurrently. When administered concurrently, amantadine and ergoloid mesylates can be used in two different compositions, or in a single pharmaceutical composition containing an effective amount of amantadine and ergoloid mesylates.
Thus, the invention also provides amantadine, or a pharmaceutically acceptable salt or a derivative thereof, for the treatment or alleviation fibromyalgia pain. Preferentially, the invention provides amantadine, or a pharmaceutically acceptable salt or a derivative thereof for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
Thus, the invention also provides rnethdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate, for the treatment or alleviation fibromyalgia pain. Preferentially, the invention provides methdilazine, hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
Furthermore, in a further aspect, the present invention provides a method of treatment of a patient suffering from fibromyalgia pain, said method comprising the administration of a therapeutically effective amount of a combination therapy comprising amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; simultaneously, sequentially or separately.
When the method of the invention comprises the simultaneous administration of amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine, hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate, the method preferably comprises the administration of a composition as hereinbefore described. Advantageously, in the use and or method of the invention the compounds comprising of amantadine, or a salt or a derivative thereof, in combination with either methdilazine, hydroxyzine, or ergoloid mesylates, or salts or derivatives thereof, may be administered orally.
The compositions of the invention may be suitable for oral administration and may include tablets, capsules, dragees, liquid suspensions, solutions and syrups; examples of such adjuvants, diluents or carriers are: for tablets and dragees - fillers, e.g. lactose, starch, microcrystalline cellulose, talc and stearic acid; lubricants/glidants, e.g. magnesium stearate and colloidal silicon dioxide; disintegrants, e.g. sodium starch glycolate and sodium carboxymethylcellulose; for capsules - pregelatinised starch or lactose.
In a further embodiment, the compositions and methods described herein may be used prophylactically as a means to prevent the development and/or onset of fibromyalgia and optionally associated symptoms of one or more of fatigue, depression and sleep disturbances.
1563P.WO.Speo

Claims

Claims
1. A pharmaceutical composition comprising a therapeutically effective amount of amantadine, or a salt or a derivative thereof, in and a therapeutically effective amount of one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
2. A pharmaceutical composition according to claim 1 wherein the pharmaceutically acceptable derivatives of the compound of amantadine is a pharmaceutically acceptable salt or an amide.
3. A pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable salt of amantadine is selected from the group consisting of hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate.
4. A pharmaceutical composition according to claim 3 wherein the composition comprises amantadine hydrochloride.
5. A pharmaceutical composition according to claim 1 wherein the pharmaceutically acceptable derivative of methdilazine or hydroxyzine is selected from one or more of pharmaceutically acceptable salts, esters and amides of the carboxylic acid group.
6. A pharmaceutical composition according to claim 1 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of methdilazine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
7. A pharmaceutical composition according to claim 1 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of hydroxyzine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A pharmaceutical composition according to claim 1 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A pharmaceutical composition according to claim 8 wherein the ergoloid mesylate is selected from one or more of dihydroergocornine mesylate, dihydroergocristine mesylate, dihydro-alpha-ergocryptine mesylate and dihydro-beta- ergocryptine mesylate.
10. A pharmaceutical composition according to claim 1 wherein the composition is suitable for enteral administration.
11. A pharmaceutical composition according to claim 10 wherein the composition is suitable for oral administration.
12. A pharmaceutical composition according to claim 11 wherein the composition is in tablet form.
13. A pharmaceutical composition according to claim 1 wherein the composition is administrable on a once or a twice daily dose regime.
14. A pharmaceutical composition according to claim 1 for the treatment or alleviation of fibromyalgia pain.
15. A pharmaceutical composition according to claim 14 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
16. The use of amantadine, or a pharmaceutically acceptable salt or a derivative thereof, in the manufacture of a combination therapy for the treatment or alleviation fibromyalgia pain.
17. The use according to claim 16 wherein the use comprises the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
18. The use according to claim 16 wherein the pharmaceutically acceptable derivatives of the compound of amantadine is a pharmaceutically acceptable salt or an amide.
19. The use according to claim 18 wherein the pharmaceutically acceptable salt of amantadine is selected from the group consisting of hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate.
20. The use according to claim 19 wherein the composition comprises amantadine hydrochloride.
21. The use of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate, in the manufacture of a combination therapy for the treatment or alleviation fibromyalgia pain.
22. The use according to claim 21 which comprises the use of methdilazine.
23. The use according to claim 21 which comprises the use of hydroxyzine
24. The use according to claim 21 which comprises the use of one or more ergoloid mesylate.
25. The use according to claim 24 wherein the ergoloid mesylate is selected from one or more of dihydroergocornine mesylate, dihydroergocristine mesylate, dihydro- alpha-ergocryptine mesylate and dihydro-beta-ergocryptine mesylate.
26. The use according to claim 16 or 21 wherein the use comprises the manufacture of a combination therapy for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
27. Amantadine, or a pharmaceutically acceptable salt or a derivative thereof, for the treatment or alleviation fibromyalgia pain.
28. Amantadine according to claim 27 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
29. Methdilazine, or a salt or a derivative thereof, for the treatment or alleviation fibromyalgia pain.
30. Methdilazine according to claim 29 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
31. Hydroxyzine, or a salt or a derivative thereof, for the treatment or alleviation fibromyalgia pain.
32. Hydroxyzine according to claim 31 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
33. One or more ergoloid mesylate for the treatment or alleviation fibromyalgia pain.
34. One or more ergoloid mesylate according to claim 33 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
35. One or more ergoloid mesylate according to claim 33 or 34 wherein the ergoloid mesylate is selected from one or more of dihydroergocornine mesylate, dihydroergocristine mesylate, dihydro-alpha-ergocryptine mesylate and dihydro-beta- ergocryptine mesylate.
36. A method of treatment of a patient suffering from fibromyalgia pain, said method comprising the administration of a therapeutically effective amount of a combination therapy comprising amantadine or a salt or a derivative thereof in and one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; simultaneously, sequentially or separately.
37. A method according to claim 36 which comprises the simultaneous administration of amantadine or a salt or a derivative thereof and one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate.
38. A method according to claim 37 which comprises the administration of a pharmaceutical composition comprising a therapeutically effective amount of amantadine or a salt or a derivative thereof in and a therapeutically effective amount of one or more compounds selected from the group consisting of methdilazine (or a salt or a derivative thereof), hydroxyzine (or a salt or a derivative thereof) and one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
39. A method according to claim 36 wherein the pharmaceutically acceptable derivatives of the compound of amantadine is a pharmaceutically acceptable salt or an amide.
40. A method according to claim 39 wherein the pharmaceutically acceptable salt of amantadine is selected from the group consisting of hydrochloride, phosphate, sulphate, adipate, acetate, succinate, propionate, tartrate, citrate, bicarbonate and lactate.
41. A method according to claim 40 wherein the composition comprises amantadine hydrochloride.
42. A method according to claim 36 wherein the pharmaceutically acceptable derivative of methdilazine or hydroxyzine is selected from one or more of pharmaceutically acceptable salts, esters and amides of the carboxylic acid group.
43. A method according to claim 36 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of methdilazine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
44. A method according to claim 36 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of hydroxyzine, or a salt or a derivative thereof; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
45. A method according to claim 36 wherein the composition comprises a therapeutically effective amount of amantadine, or a salt or a derivative thereof, and a therapeutically effective amount of one or more ergoloid mesylate; in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
46. A method according to claim 45 wherein the ergoloid mesylate is selected from one or more of dihydroergocomine mesylate, dihydroergocristine mesylate, dihydro-alpha-ergocryptine mesylate and dihydro-beta-ergocryptine mesylate.
47. A method according to claim 36 wherein the composition is suitable for enteral administration.
48. A method according to claim 47 wherein the composition is suitable for oral administration.
49. A method according to claim 48 wherein the composition is in tablet form.
50. A method according to claim 36 wherein the composition is administrable on a once or a twice daily dose regime.
51. A method according to claim 36 for the treatment or alleviation of fibromyalgia pain and associated symptoms of one or more of fatigue, depression and sleep disturbances.
52. The composition, use or method substantially as hereinbefore described with reference to the accompanying examples.
1563P.WO.Spec
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