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WO2016190638A1 - Médicament comprenant du carisbamate, et son utilisation pour la prévention, le soulagement ou le traitement de la douleur ou de l'épilepsie - Google Patents

Médicament comprenant du carisbamate, et son utilisation pour la prévention, le soulagement ou le traitement de la douleur ou de l'épilepsie Download PDF

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WO2016190638A1
WO2016190638A1 PCT/KR2016/005441 KR2016005441W WO2016190638A1 WO 2016190638 A1 WO2016190638 A1 WO 2016190638A1 KR 2016005441 W KR2016005441 W KR 2016005441W WO 2016190638 A1 WO2016190638 A1 WO 2016190638A1
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Prior art keywords
pain
component
gabapentin
pregabalin
charisbamate
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Korean (ko)
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이한주
황선관
조민재
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SK Biopharmaceuticals Co Ltd
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SK Biopharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors

Definitions

  • the present invention relates to a medicament comprising charisbamate, and to its use for treating pain or epilepsy, and more particularly, to charisbamate; And one or more selected from gabapentin and pregabalin; and to their use for treating pain or epilepsy.
  • Pain is defined as the uncomfortable sensory and emotional experience associated with actual or potential tissue injury (Pain, 1979 June; 6 (3): 247-8).
  • Acute pain is a physical response to negative chemical, thermal or mechanical stimuli that may be associated with surgery, trauma, or acute disease. These conditions include postoperative pain, sports medicine injuries, carpal tunnel syndrome, burns, musculoskeletal and sprains, tendon sprains, cervical spine pain syndrome, indigestion, stomach ulcers, duodenal ulcers, kidney stones pain, gallbladder pain, gallstones Pain, dysmenorrhea, endometriosis, rheumatism pain or dental pain.
  • Chronic pain refers to a pain condition that goes beyond the normal progression of an injury or disease and may be the result of an inflammatory or severe, progressive, painful disease stage.
  • Various types of chronic pain include headache, migraine, trigeminal neuropathy, jaw joint syndrome, fibromyalgia, osteoarthritis, rheumatoid arthritis, bone pain due to osteoarthritis, osteoporosis, pain due to bone metastasis or unknown reasons, gout, connective tissue, muscle Fascia pain, thoracic outlet syndrome, upper or lower back pain, pelvic pain, cardiothoracic pain, non-cardiothoracic pain, spinal injury-related pain, stiff pain after stroke, cancer pain, AIDS pain, sickle cell pain, senile Including but not limited to pain.
  • analgesics narcotic or nonsteroidal anti-inflammatory agents
  • Conventional analgesics have limited therapeutic value in the management of chronic pain. This necessitates the use of supplemental analgesics.
  • the treatment of chronic pain requires careful attention to side effects, combination contraindications and drug interactions.
  • drugs and combination therapies that can treat pain without unwanted side effects.
  • Epilepsy is also a serious neurological condition characterized by seizures. Epilepsy is common, but more than 2.5 million people suffer from hopelessness in the United States alone. Epilepsy is the condition of a person with a chronically recurrent attack that underlies the process. Epilepsy is a clinical phenomenon rather than a single disease state, so the causes and forms of epilepsy vary. If epilepsy is defined as two or more unexplained seizures, 5 to 10 people per 1000 are diagnosed with epilepsy and are measured at about 0.3 to 0.5 percent in other communities throughout the world.
  • epilepsy Based on clinical and cerebral imaging phenomena, four types of epilepsy are recognized: grand mal epilepsy (subgroup: whole body, focal point, jacksonian), petit mal epilepsy, Psychomotor or temporal lobe epilepsy (subgroup: moderate or stiff psychomotor with adversive or torsional movements, automatic with hallucinations, or hallucinations or dream states Sensory seizures associated with) and autonomic nervous system epilepsy or hepatic cerebral epilepsy (flushing, paleness, tachycardia, high blood pressure, sweating or other visceral symptoms). Since epilepsy has similar problems as described above, a combination therapy for treating epilepsy with fewer side effects is required.
  • the present invention provides pharmaceuticals and pharmaceutical compositions that provide for the prevention, alleviation or treatment of enhanced pain or epilepsy without increasing side effects.
  • Agents for the prevention, alleviation or treatment of pain or epilepsy provided according to the present invention, as an active ingredient, (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof; And (b) one or more selected from gabapentin, pregabalin and pharmaceutically acceptable salts and hydrates thereof.
  • compositions for the prevention, alleviation, or treatment of pain or epilepsy include, as an active ingredient, (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof; And (b) at least one selected from gabapentin, pregabalin and pharmaceutically acceptable salts and hydrates thereof, and further comprises at least one pharmaceutically acceptable carrier.
  • compositions of the present invention provide an effect of preventing, alleviating or treating enhanced pain or epilepsy without increasing side effects.
  • the compositions of the present invention exhibit a synergistic effect in the prevention, alleviation or treatment of pain or epilepsy.
  • Figure 1 shows the correlation coefficient according to the mixing ratio of the carisbamate and gabapentin in the spinal nerve ligation model. The description of each symbol in FIG. 1 is as follows:
  • a ', B', C ', D' ED 50 standard, the Charis the carbamate and gabapentin respectively, 3: 1, 1: 1, 1: 3, 1: additive ED 50 when combined in a ratio of 6 Calculation
  • A, B, C, D ED 50 measured value of the combination of carisbamate and gabapentin in the ratio of 3: 1, 1: 1, 1: 3, 1: 6, respectively, based on ED 50
  • Figure 2 illustrates the pain suppression effect according to the combination ratio of the carisbamate and gabapentin in the spinal nerve ligation model.
  • Figure 3 shows the correlation coefficient according to the combination ratio of the charisbamate and pregabalin in the spinal nerve ligation model.
  • the description of each symbol in FIG. 3 is as follows:
  • Figure 4 illustrates the pain inhibition effect according to the combination ratio of the charisbamate and pregabalin in the spinal nerve ligation model.
  • Figure 5 shows the results of toxicity experiments on motility.
  • MES epilepsy
  • Charisbamate has the trade name Comfyde® and the chemical formula is (S) -2-O-carbamoyl-1-o-chlorophenyl-ethanol.
  • the structure is as follows:
  • Gabafetin is marketed under the name Neurontin®.
  • the chemical formula is 1- (aminomethyl) -cyclohexane acetic acid, whose structure is:
  • Pregabalin is marketed under the trade name Lyrica®.
  • the chemical formula is (S) -3- (aminomethyl) -5-methylhexanoic acid, and its structure is as follows:
  • charisbamate gabapentin and pregabalin, their free forms, or pharmaceutically acceptable salts or hydrates thereof can be used, respectively.
  • the pharmaceutically acceptable salts of the charisbamate, gabapentin and pregabalin are, independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, sheet Elate, edetate, edysylate, estoleate, ecylate, fumarate, gluceptate, gluconate, glutamate, glycoloylarsanylate, hexylresorcinate, hydravamine, hydrobromide, hydrochloride, Hydrogencarbonate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate, methylsulfate, catenate, Latex, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygal Lacturon
  • Salicylates stearates, subacetates, succinates or hemi-succinates, sulfates or hemi-sulfates, tannates, tartrates, oxalates or hemi-tartrates, the thiolates, triethiodes , Benzatin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium and zinc and the like.
  • the composition may comprise a charisbamate (free form) in the range of 50 to 1200 mg, 50 to 500 mg, 10 to 300 mg, 25 to 300 mg.
  • the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention comprises at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg of at least one (free form) selected from gabapentin and pregabalin. Or in an amount of at least 100 mg, and at least one (free form) selected from gabapentin and pregabalin at most 3000 mg, at most 2800 mg, at most 2600 mg, at most 2400 mg, at most 2200 mg, at 2000 mg. Or less, 1800 mg or less, 1600 mg or less, 1400 mg or less, 1200 mg or less, 1000 mg or less, 800 mg or less, 600 mg or less, 400 mg or less, or 200 mg or less.
  • the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may include gabapentin (free form) in an amount of 50 mg or more, 60 mg or more, 70 mg or more, 80 mg or more, 90 mg or more or 100 mg or more.
  • gabapentin (glass type) is 3000 mg or less, 2800 mg or less, 2600 mg or less, 2400 mg or less, 2200 mg or less, 2000 mg or less, 1800 mg or less, 1600 mg or less, 1400 mg or less, 1200 mg or less, And up to 1000 mg, up to 800 mg, or up to 600 mg.
  • the composition may comprise gabapentin (free form) at 100 to 3000 mg, 100 to 2000 mg, 100 to 600 mg.
  • a medicament or pharmaceutical composition according to one embodiment of the invention comprises pregabalin (free form) in an amount of at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg or at least 100 mg. May also comprise pregabalin (free form) in an amount of up to 800 mg, up to 600 mg, up to 400 mg or up to 200 mg. In one embodiment, the composition may comprise 50 to 800 mg, 50 to 400 mg, 50 to 200 mg of pregabalin.
  • the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention comprises 50 to 1200 mg of carrisbamate and 100 to 3000 mg of gabapentin on a free basis.
  • the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention comprises 50 to 500 mg of carrisbamate and 100 to 2000 mg of gabapentin on a free basis.
  • the pharmaceutical or pharmaceutical composition according to one embodiment of the present invention comprises, on a free basis, 10 to 300 mg of carrisbamate and 100 to 600 mg of gabapentin.
  • a pharmaceutical or pharmaceutical composition according to one embodiment of the invention comprises 50 to 1200 mg of carrisbamate and 50 to 800 mg of pregabalin on a free basis.
  • a pharmaceutical or pharmaceutical composition according to one embodiment of the invention comprises 50 to 500 mg of charisbamate and 50 to 400 mg of pregabalin on a free basis.
  • a pharmaceutical or pharmaceutical composition according to one embodiment of the invention comprises, on a free basis, 25 to 300 mg of charisbamate and 50 to 200 mg of pregabalin.
  • component (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof versus component (b) gabapentin, pregabalin and pharmaceutically acceptable compounds thereof in said pharmaceutical or pharmaceutical composition One or more blending ratios selected from possible salts and hydrates (a) :( b) (based on ED 50 ) are independently 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1 , 4: 1, 3: 1, 2: 1 or 1: 1 to independently 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9 , 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20.
  • the blending ratio of component (a) to component (b) is based on the ED 50 (median effective dose) value of each component.
  • the expression “the ratio of component (a) to component (b) (based on ED 50 )” means “the amount of component (a) / ED 50 of the component (a) (the amount showing 50% of drug efficacy) versus ( b) it means the ratio of ED 50 "of amount / (b) component.
  • the compounding ratio (a) :( b) (based on ED 50 ) is 1: 1, and when 10 mg of component (a) and 100 mg of component (b) are combined, the mixing ratio (a) :( b) (based on ED 50 ) is 1: 2, (a When 20 mg of component and 50 mg of component (b) are mix
  • ED 50 for pain or epilepsy can be measured by known methods.
  • ED 50 for pain is Pain. 1992; 50 (3): 355-63
  • ED 50 for epilepsy can use the method disclosed in Luszczki et al., 2009 (Eur J Pharmacol. 2009 Jan 14; 602 (2-3): 298-305) have.
  • the compounding ratio of (a) :( b) (based on ED 50 ) is independently 6: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1 to independently 1: 2, 1 : 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15 , 1:16, 1:17, 1:18, 1:19, or 1:20.
  • the blending ratio (a) :( b) (based on ED 50 ) may be 5: 1 to 1:16 in one embodiment, 3: 1 to 1:12 in another embodiment, and another In embodiments, 3: 1 to 1: 3.
  • the compounding ratio of hydrate (a) :( b) (based on ED 50 ) is independently 7: 1, 6: 1, 5: 1, 4: 1, 3: 1, 2: 1 or 1: 1 to independent As 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1:10, 1:11, 1:12, 1:13, 1 It may be: 14 or 1:15.
  • the blending ratio (a) :( b) (based on ED 50 ) may be 6: 1 to 1: 9 in one embodiment, and 3: 1 to 1: 6 in other embodiments.
  • compositions of the present invention may be prepared in various forms oral or parenteral formulations, for example intravenous, intramuscular, intracutaneous, subcutaneous injection, intraduodenal It can be administered by injection or intraperitoneal, intrathecal injection, or by transdermal route.
  • the pharmaceutical composition of the present invention further comprises at least one pharmaceutically acceptable carrier in addition to the above-mentioned effective ingredients (a) and (b).
  • Pharmaceutically acceptable carriers may be solid or liquid, excipients, antioxidants, buffers, bactericides, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release controlling agents, wetting agents, It may be at least one selected from stabilizers, suspending agents and lubricants.
  • the pharmaceutically acceptable carrier may be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and mixtures thereof.
  • suitable excipients include sugars (eg dextrose, sucrose, maltose and lactose), starch (eg corn starch), sugar-alcohols (eg mannitol, sorbitol, maltitol, erythritol and Xylitol), starch hydrolysates (such as dextrin and maltodextrin), cellulose or cellulose derivatives (such as microcrystalline cellulose), or mixtures thereof, may be used.
  • sugars eg dextrose, sucrose, maltose and lactose
  • starch eg corn starch
  • sugar-alcohols eg mannitol, sorbitol, maltitol, erythritol and Xylitol
  • starch hydrolysates such as dextrin and maltodextrin
  • cellulose or cellulose derivatives such as microcrystalline cellulose
  • suitable antioxidants include, but are not limited to, tocopherol, ascorbic acid, gallate, and the like.
  • a suitable buffer may be citric acid monohydrate.
  • suitable surfactants include anionic, cationic or nonionic surfactants such as sodium laurate, sodium lauryl sulfate, sodium dodecanesulfonate, sodium oleyl sulfate, benzalkonium chloride, Alkyltrimethyl ammonium bromide, glyceryl monooleate, polyoxyethylene dried sorbitan fatty acid esters, polyvinyl alcohol and dried sorbitan S or mixtures thereof may be used, but is not limited thereto.
  • anionic, cationic or nonionic surfactants such as sodium laurate, sodium lauryl sulfate, sodium dodecanesulfonate, sodium oleyl sulfate, benzalkonium chloride, Alkyltrimethyl ammonium bromide, glyceryl monooleate, polyoxyethylene dried sorbitan fatty acid esters, polyvinyl alcohol and dried sorbitan S or mixtures thereof may be used, but is not limited thereto.
  • suitable binders include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch or Mixtures thereof may be used, but are not limited thereto.
  • suitable preservatives include benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, or mixtures thereof. May be used, but is not limited thereto.
  • starch glycolate sodium salt crosslinked polyvinyl pyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose or mixtures thereof may be used.
  • the present invention is not limited thereto.
  • suitable sweeteners may include sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose or mixtures thereof, but It is not limited.
  • suitable glidants may include, but are not limited to, colloidal silicon dioxide.
  • suitable release-modifying excipients include, but are not limited to, pH-independent polymers such as hydroxypropylmethylcellulose, polyethylene oxide, carbomer, alginic acid, pH-dependent polymers, or mixtures thereof. May be used, but is not limited thereto.
  • suitable wetting agents are hypromellose (HPMC), polyoxyethylene derivatives of sorbitan esters such as polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, Sodium deoxycholate or mixtures thereof may be used, but is not limited thereto.
  • HPMC hypromellose
  • polyoxyethylene derivatives of sorbitan esters such as polysorbate 20 and polysorbate 80
  • lecithin polyoxyethylene- and polyoxypropylene ethers
  • Sodium deoxycholate or mixtures thereof may be used, but is not limited thereto.
  • suitable suspending agents include cellulose derivatives such as microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginate, chitosan, dex Tran, gelatin, polyethylene glycol, polyoxyethylene- and polyoxypropylene ether or mixtures thereof may be used, but is not limited thereto.
  • suitable lubricants may include, but are not limited to, long chain fatty acids and salts thereof such as magnesium stearate and stearic acid, talc, glyceride wax or mixtures thereof.
  • compositions of the present invention may be formulated into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • the carrier is a fine solid that is mixed in the form of a mixture with the active ingredient, and in tablets the active ingredient may have binding properties that can be mixed with the carrier and compressed into suitable proportions and desired shapes and sizes.
  • the pharmaceutical composition of the present invention may be prepared in capsule form.
  • the pharmaceutical composition of the present invention on a free form, may comprise a) 100 mg, 200 mg, 300 mg or 400 mg of carrisbamate; b) 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1000 mg of gabapentin; And a capsule containing gelatin and titanium dioxide as the capsule base. The amount can be adjusted as needed.
  • the pharmaceutical composition of the present invention on a free form, may comprise a) 100 mg, 200 mg, 300 mg or 400 mg of charisbamate; b) pregabalin 75 mg, 100 mg, 150 mg, 200 mg, 300 mg; And a capsule containing gelatin and titanium dioxide as the capsule base. The amount can be adjusted as needed.
  • compositions of the present invention have medicinal uses for the prevention, alleviation or treatment of pain or epilepsy.
  • a pharmaceutical composition comprising (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof; And (b) at least one selected from gabapentin, pregabalin, and pharmaceutically acceptable salts and hydrates thereof, in a therapeutically effective amount to prevent, alleviate, or treat pain or epilepsy.
  • a method is provided.
  • one or more of the agents and compositions of the invention described above can be used in a method of preventing, alleviating or treating pain or epilepsy.
  • the components (a) and (b) may be administered to the treatment subject simultaneously, sequentially or separately.
  • a pharmaceutical composition comprising (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof; And (b) one or more selected from gabapentin, pregabalin, and pharmaceutically acceptable salts and hydrates thereof, for use in preventing, alleviating, or treating pain or epilepsy.
  • one or more of the agents and compositions of the invention described above may have use for preventing, alleviating or treating pain or epilepsy.
  • the pain may include, but is not limited to, acute pain or chronic pain.
  • the pain may include, but is not limited to, nociceptive pain, neuropathic pain, or nociceptive-neuropathy complex pain.
  • the pain may be neuropathic pain.
  • the neurodegenerative pain may be central or peripheral neuropathic pain.
  • the pain may include, but is not limited to, spontaneous pain, allodynia, hyperalgesia, abnormalities, discomfort, hyperalgesia syndrome, or inflammatory pain.
  • the pain may include, but is not limited to, trauma, infection, metabolic disease, nutritional deficiency, immunity, tumor, vascular disease, compression or ischemia, or pain of unknown cause.
  • the pain is upper back pain, lower back pain, bone pain, pelvic pain, pain after spinal cord injury ), Cardiothoracic pain, non-cardiac chest pain, stiff pain after stroke, myofascial pain, cancer pain, AIDS pain , Sickle cell pain, senile pain, headache, migraine, trigeminal neuralgia, jaw pain, fibromyalgia, degenerative arthritis pain osteoarthritic pain, rheumatoid arthritis pain, fibrositis pain or thoracic outlet syndrome pain, but is not limited thereto.
  • the pain is postherpetic neuralgia, diabetic neuropathy, complex site pain syndrome (CRPS), drug induced neuropathy (chemotherapy induced peripheral neuropathy), tumors Cancer pain, Pain from brain tumor, Pain from stroke, Pain from spinal cord injury, Pain from AIDS, Pain from multiple sclerosis, Phantom limb pain, Trigeminal neuralgia, Lower back Pain, or fibromyalgia, but is not limited thereto.
  • CRPS complex site pain syndrome
  • drug induced neuropathy chemotherapy induced peripheral neuropathy
  • tumors Cancer pain Pain from brain tumor
  • Pain from stroke Pain from stroke
  • Pain from spinal cord injury Pain from AIDS
  • Pain from multiple sclerosis Pain from multiple sclerosis
  • Phantom limb pain Trigeminal neuralgia
  • Lower back Pain or fibromyalgia
  • the pain may include, but is not limited to, headache, migraine, jaw joint pain, degenerative arthritis pain, rheumatoid arthritis pain, connective tissue pain, or thoracic outlet syndrome pain.
  • the pain is somatic pain, visceral pain, pain due to central nervous system damage, pain due to brain tumor, pain due to cerebral hemorrhage, syringomyelia Pain, pain caused by AIDS, peripheral pain, post shingles neuralgia, diabetic neuropathy pain, complex site pain, low back pain, or cancer pain.
  • the pain is complex regional pain syndrome (CRPS), reflex sympathetic dystrophy (RSD), causalgia, surgical pain, phantom limb pain , Pain from spinal cord injury, neuralgia after shingles, pain from AIDS, leprosy pain, diabetic neuropathic pain, porphyria pain, pain from uremia, pain from alcoholism, pain from vitamin deficiency, multiple sclerosis Pain caused by cancer, invasion, metastasis or treatment of cancer (surgery, chemotherapy, radiation therapy), central post-stroke pain (CPSP), lupus pain, rheumatoid arthritis pain, neuronal tunnel syndrome Pain, pain due to syringomyelia, pain due to multiple sclerosis or pain due to amyotrophic lateral sclerosis (ALS) It may include, but is not limited to this.
  • CRPS complex regional pain syndrome
  • RSD reflex sympathetic dystrophy
  • causalgia surgical pain
  • phantom limb pain Pain from spinal cord injury, neuralgia after shingles,
  • the pain is peripheral neuropathic pain, central neuropathic pain, mixed neuropathic pain, phantom pain, fibromyalgia ), Allodynia, neuralgia, migraine, diabetic neuropathy or cancer pain, but are not limited thereto.
  • mice Male rats (Sprague-Dawley, 150-200 g, 6 weeks old, Orient Bio Co., Ltd.) were purchased and acclimated to animal chambers for at least one week. The experimental animals were maintained at a light and dark cycle of 12 hours, a temperature of 22 to 25 ° C, and a relative humidity of 40 to 60%, and water and food were freely accessible.
  • the next higher bending force filament was applied, or when the avoidance reaction was shown, the next lower bending force filament was applied.
  • Application of the filament was carried out four more times after changing the avoidance reaction to obtain at least six reaction results. Starting at 2.0 g, 0.2 g for the reaction for 4 consecutive filaments and 15.0 g for the 5 consecutive reactions were designated.
  • ED 50 for intraperitoneal administration of each compound namely, carrisbamate, gabapentin and pregabalin
  • charisbamate, gabapentin, and charisbamate and pregabalin are each formulated at a ratio of 6: 1, 3: 1, 1: 1, 1: 3, 1: 6, 1: 9.
  • the ED 50 value was obtained.
  • ED 50 was obtained by measuring the efficacy at at least three doses for each compounding ratio.
  • ED 50 was calculated by non-linear regression method using PRISM 5.0 program based on the% MPE values of three doses.
  • Intraperitoneal administration ED 50 of carrisbamate, gabapentin, and pregabalin was obtained in the spinal nerve ligation model, which was estimated as 32.1, 28.3, 9.7, 53.2 mg / kg, and ip, respectively.
  • the mixture of charisbamate and gabapentin in a ratio of 5: 1, 3: 1, 1: 1, 1: 3, 1: 6, 1: 8 was obtained to obtain ED 50 at each compounding ratio. It was compared with the red ED 50 calculation. As a result, when the charisbamate and gabapentin were blended in a ratio of 3: 1, 1: 1, 1: 3, it was confirmed that the correlation coefficient showed synergy to 0.7 or less (Table 1, Fig. 1). In addition, the compounding ratio of 3: 1, 1: 1, and 1: 3 showed a much better effect than that at the ED 50 analogous dose of carisbamate or gabapentin at doses similar to the additive ED 50 calculations (FIG. 2). .
  • charisbamate and pregabalin are blended at a ratio of 6: 1, 3: 1, 1: 1, 1: 3, 1: 6, 1: 9, and ED 50 at each compounding ratio is obtained.
  • the correlation coefficient is synergistic to 0.7 or less when charisbamate and pregabalin are combined in ratios of 3: 1, 1: 1, 1: 3, and 1: 6. It confirmed that it shows (Table 2, FIG. 3).
  • the compounding ratio of 3: 1, 1: 1, 1: 3 and 1: 6 shows a much better effect than that of the charisbamate or pregabalin ED 50 similar dose at doses similar to the additive ED 50 calculations. ( Figure 4).
  • ED50 (mg / kg), which protects 50% of mice against MES-induced seizures.
  • Electroconvulsions were generated by current through a standard auricular electrode (50 mA, 500 V, 50 Hz, 0.2 s stimulus duration) by a Hugo Shock generator (Rodent Shocker, Type 221, Freiburg, Germany). The criterion for the development of seizure activity was the tonic hindlimb extension. Experimental animals were administered at different doses to obtain varying percentages of protection against MES-induced seizures. This was used to generate dose-response relationship curves (DRRCs) according to Litchfield and Wilcoxon (J Pharmacol Exp Ther. 1949 Jun; 96 (2): 99-113) for each of the administered charisbamate and gabapentin.
  • DRRCs dose-response relationship curves
  • MES epilepsy
  • the ratio showing synergy can be confirmed through the correlation coefficient calculated through the additive ED 50 calculation value and the measured value ED 50 .
  • the ratio of charisbamate to gabapentin showed a significant synergistic effect in the range of 1: 1 to 1:12.
  • the rotarod test was performed on rats to examine whether an increase in side effects due to the synergistic effect of the combination of the present invention was observed (Curr. Protoc. Neurosci. 2001; Chapter 8: Unit8.12). Rats were trained twice for 10 minutes (30 minutes rest) to balance on a rotating rod (7.5 cm diameter, 7 revolutions per minute), followed by charisbamate alone (25, 50, 100, mg / kg, ip) and gabapentin and Charismamate co-administration (+ gabapentin 30 mg / kg, ip). 30% PEG was used as the vehicle. Behavior on rotarod was measured at 0.5, 1, 2, 4 and 16 hours after drug administration. The results are shown in Table 4 below. The rats were walked for 1 minute on a rod that rotates 7 minutes per minute at a constant speed for each hour. Each rat attempted up to three times. If the rat fell 1 minute before on 3 trials, it was determined to fail.

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Abstract

La présente invention concerne un médicament comprenant du carisbamate, et son utilisation pour la prévention, le soulagement ou le traitement de la douleur ou de l'épilepsie. Plus spécifiquement, l'invention porte sur un médicament et une composition pharmaceutique comprenant : du carisbamate ; et au moins un élément choisi parmi la gabapentine et la prégabaline. L'invention a également trait à son utilisation pour le traitement de la douleur ou de l'épilepsie.
PCT/KR2016/005441 2015-05-22 2016-05-23 Médicament comprenant du carisbamate, et son utilisation pour la prévention, le soulagement ou le traitement de la douleur ou de l'épilepsie Ceased WO2016190638A1 (fr)

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CN115974799A (zh) * 2021-10-14 2023-04-18 成都百裕制药股份有限公司 氨基甲酸酯取代的醇衍生物及其在医药上的应用
US11896593B2 (en) 2020-09-10 2024-02-13 Bio-Pharm Solutions Co., Ltd. Sulfamate derivative compounds for use in treating or alleviating a psychiatric disorder

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WO2022045824A1 (fr) * 2020-08-31 2022-03-03 Bio-Pharm Solutions Co., Ltd. Composés carbamate de phényle alkyle destinés à être utilisés dans la prévention ou le traitement d'une maladie neurodégénérative
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US11896593B2 (en) 2020-09-10 2024-02-13 Bio-Pharm Solutions Co., Ltd. Sulfamate derivative compounds for use in treating or alleviating a psychiatric disorder
CN115974799A (zh) * 2021-10-14 2023-04-18 成都百裕制药股份有限公司 氨基甲酸酯取代的醇衍生物及其在医药上的应用

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