WO2016190638A1 - Medicament comprising carisbamate, and use thereof for prevention, alleviation or treatment of pain or epilepsy - Google Patents

Abstract

The present invention relates to a medicament comprising carisbamate, and use thereof for prevention, alleviation or treatment of pain or epilepsy and, more specifically, relates to a medicament and a pharmaceutical composition comprising: carisbamate; and at least one selected from among gabapentin and pregabalin, and use thereof for treating pain or epilepsy.

Description

Medicaments comprising charisbamate, and uses thereof for preventing, alleviating or treating pain or epilepsy

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.

Conventional analgesics (narcotic or nonsteroidal anti-inflammatory agents) have limited therapeutic value in the management of chronic pain. This necessitates the use of supplemental analgesics. However, the treatment of chronic pain requires careful attention to side effects, combination contraindications and drug interactions. There is a need for 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.

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.

Pharmaceutical compositions for the prevention, alleviation, or treatment of pain or epilepsy provided according to the present invention 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.

The pharmaceuticals and pharmaceutical compositions of the present invention provide an effect of preventing, alleviating or treating enhanced pain or epilepsy without increasing side effects. In one embodiment, 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

α (correlation coefficient) = ED ₅₀ found / additive ED ₅₀ calculated

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:

A ', B', C ', D', E ', F': On the basis of ED ₅₀ , charisbamate and pregabalin were determined as 6: 1, 3: 1, 1: 1, 1: 3, 1: 6, additive ED ₅₀ calculated at the ratio of 1: 9

A, B, C, D, E, F: On the basis of ED ₅₀ , the charisbamate and pregabalin were determined as 6: 1, 3: 1, 1: 1, 1: 3, 1: 6, 1: 9 ED ₅₀ actual value when we mixed in ratio

α (correlation coefficient) = ED ₅₀ found / additive ED ₅₀ calculated

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.

6 and 7 show the results of epilepsy (MES) experiments of gabapentin and charisbamate.

Hereinafter, the present invention will be described in detail.

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:

In the present invention, as the charisbamate, gabapentin and pregabalin, their free forms, or pharmaceutically acceptable salts or hydrates thereof can be used, respectively.

According to one embodiment of the invention, as the charisbamate, gabapentin and pregabalin, their free forms are used, respectively.

For example, 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 Lacturonate. 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.

Pharmaceutical or pharmaceutical composition according to an embodiment of the present invention, the charisbamate (free form) of 10 mg or more, 15 mg or more, 20 mg or more, 25 mg or more, 30 mg or more, 35 mg or more, 40 mg Or more, 45 mg or more, or 50 mg or more, and also contains charisbamate (free form) at most 1200 mg, at most 1100 mg, at most 1000 mg, at most 900 mg, at most 800 mg, at most 700 mg, And up to 600 mg, up to 500 mg, up to 400 mg or up to 300 mg. In one embodiment, 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. And 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. In one embodiment, 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.

In one embodiment of the invention, 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.

In the present specification, the blending ratio of component (a) to component (b) is based on the ED ₅₀ (median effective dose) value of each component. In other words, 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. For example, when the ED ₅₀ of the (a) component drug is 10 mg and the ED ₅₀ of the (b) component drug is ₅₀ mg, 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 | blended, the compounding ratio (a) :( b) (based on ED ₅₀ ) is 2: 1.

ED ₅₀ for pain or epilepsy can be measured by known methods. For example, 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.

In one embodiment of the present invention, component (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof in the pharmaceutical or pharmaceutical composition versus gabapentin or a pharmaceutically acceptable salt or hydrate thereof as component (b) 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. Alternatively, 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.

In one embodiment of the present invention, the component (a) charisbamate or a pharmaceutically acceptable salt or hydrate thereof in the pharmaceutical or pharmaceutical composition vs. pregabalin or a pharmaceutically acceptable salt thereof as component (b) Or 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. Alternatively, 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.

The pharmaceutical and pharmaceutical 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. In addition, 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.

In one embodiment, 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.

In one embodiment, suitable antioxidants include, but are not limited to, tocopherol, ascorbic acid, gallate, and the like.

In one embodiment, a suitable buffer may be citric acid monohydrate.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, as a suitable disintegrant, starch glycolate sodium salt, crosslinked polyvinyl pyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose or mixtures thereof may be used. However, the present invention is not limited thereto.

In one embodiment, 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.

In one embodiment, suitable glidants may include, but are not limited to, colloidal silicon dioxide.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

The pharmaceutical 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. In powders, 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.

For example, 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.

In another example, 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.

Pharmaceuticals and pharmaceutical compositions of the present invention have medicinal uses for the prevention, alleviation or treatment of pain or epilepsy.

In addition, according to the present invention, there is provided 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. In one embodiment, 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. In addition, in one embodiment, the components (a) and (b) may be administered to the treatment subject simultaneously, sequentially or separately.

In addition, according to the present invention, there is provided 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. In one embodiment, one or more of the agents and compositions of the invention described above may have use for preventing, alleviating or treating pain or epilepsy.

In one embodiment, the pain may include, but is not limited to, acute pain or chronic pain.

In one embodiment, the pain may include, but is not limited to, nociceptive pain, neuropathic pain, or nociceptive-neuropathy complex pain.

In one embodiment, the pain may be neuropathic pain. The neurodegenerative pain may be central or peripheral neuropathic pain.

In one embodiment, the pain may include, but is not limited to, spontaneous pain, allodynia, hyperalgesia, abnormalities, discomfort, hyperalgesia syndrome, or inflammatory pain.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

In one embodiment, 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.

Hereinafter, the present invention will be described in more detail with reference to the following examples. The objects, features and advantages of the present invention will be readily understood through the following examples. The invention is not limited to the embodiments described herein, but may be embodied in other forms. The embodiments introduced herein are provided so that the disclosure may be made thorough and complete, and the spirit of the present invention may be sufficiently delivered to those skilled in the art. Therefore, the present invention should not be limited by the following examples.

[ Example ]

Example  One: Spinal nerve Ligation  Combination Study in the Model

Laboratory animals

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.

Mechanical Allodynia  Measure

Mechanical allodynia was evaluated by measuring the paw withdrawal threshold of the rat right hind paw using Dixon's 'up-down method' (J Neurosci Methods. 1994; 53 (1)). : 55-63, Annu Rev Pharmacol Toxicol. 1980; 20: 441-62). First, the rats are placed in an acrylic box (13 x 25 x 13 cm ³ ) placed on a wire mesh installed about 35 cm from the floor and allowed to stabilize for at least 20 minutes. Eight von Frey filaments (0.2, 0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g) with varying flexural forces were used. Flexural force was applied starting with 2.0 g of filament perpendicular to the plantar surface. When the avoidance reaction was not shown, 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.

Spinal nerve Ligation  Induced neuropathic pain

In order to screen rats with normal pain, the "50% foot avoidance threshold" of the left hind paw of the normal rat without surgery was measured, and spinal nerve ligation surgery to rats with an avoidance threshold of 10 g or more. Was performed. During all stages before surgery, anesthesia was performed under a gas mixture containing 2-3% enflurane and 95% oxygen. In order to induce neuropathic pain, the fifth urinary nerve was tightly ligated using a 5-0 silk suture and the muscles and skin were sutured. After 10 days after spinal nerve ligation surgery, rats with a 50% paw avoidance threshold of 4.0 g or less were selected and tested for efficacy. (Pain. 1992; 50 (3): 355-63)

Combination Research

ED ₅₀ for intraperitoneal administration of each compound, namely, carrisbamate, gabapentin and pregabalin, was determined. Based on the ED ₅₀ of each compound, 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. When obtained, 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  And correlation coefficients

First, the Maximum Possible Effect (%) was determined using the average value of the paw avoidance response threshold.

[% MPE = (foot avoidance threshold after drug treatment-threshold at 0 hours) / (foot avoidance threshold at Naive group-threshold at 0 hours) × 100]

ED ₅₀ was calculated by non-linear regression method using PRISM 5.0 program based on the% MPE values of three doses.

In the combination study, synergy was judged using the correlation coefficient (α), and the correlation coefficient (α) was calculated as 'ED ₅₀ measured value / additive ED ₅₀ calculated value', and if α≤0.7, synergy, 0.7 <α≤ 1.3 is an additive action, α> 1.3 is an antagonism. (Pharmacol Rev. 1989; 41 (2): 93-141)

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.

Based on the ED ₅₀ value, 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). .

Table 1 Results of neuropathic pain model test of charisbamate and gabapentin

¹⁾ Correlation coefficient (α) = ED ₅₀ found / additive ED ₅₀ calculated

²⁾ α≤0.7: synergy, 0.7 <α≤1.3: additive, α> 1.3: antagonism

In addition, the spontaneous locomotor activity test in rats was used to evaluate the degree of adverse effects on the central nervous system when the combination of charisbamate and gabapentin was administered ( Neuroscience Letters , 58 (1985) 97-100). Charisbamate (10 mg / kg) and a combination of charisbamate (10 mg / kg) and gabapentin (100 mg / kg) were orally administered to rats at 3 mL / kg, respectively. After 60 minutes each rat was placed in an active chamber and the total ambulatory locomotor counts were recorded for 10 minutes. Total gait shift values were measured using an automated light beam Opto-Varimax® which records photobeam breaks with the Auto-track system version 4.10. 30% PEG400 was used as the vehicle.

There was no increase in CNS-related side effects even at doses that were synergistic with the combination of charisbamate and gabapentin (FIG. 5).

Based on the ED ₅₀ value, 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. As a result of comparison with the additive ED ₅₀ calculations, 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). In addition, 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).

Table 2 Results of neuropathic pain model test of charisbamate and pregabalin

¹⁾ Correlation coefficient (α) = ED ₅₀ found / additive ED ₅₀ calculated

²⁾ α≤0.7: synergy, 0.7 <α≤1.3: additive, α> 1.3: antagonism

Example  2: MES  Combination Studies in Testing

Mouse best electric shock attack Maximal Electroshock Seizure : MES A) induced seizure test

Protective activity according to the combination of gabapentin and charisbamate was evaluated and expressed as 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. The anticonvulsant effect of the mixture of gabapentin and carrisbamate in the 1: 9 to 16: 1 ratio was evaluated and expressed as the median effective dose (ED50 mix value) for MES-induced seizures. For a detailed experimental method refer to the study of Luszczki et al., 2009 (Eur J Pharmacol. 2009 Jan 14; 602 (2-3): 298-305).

Combination research

Dose dependent data for both compounds is described in Berenbaum M.C., "What is synergy?" It was used to measure theoretical additive lines using the method described in Pharmacological Reviews, Vol. 41, pp. 93-141 (1989). The combination of gabapentin or pregabalin and charisbamate was specified according to a fixed ratio design, with a dose ratio of 9: 1 to 16: 1 for the two components.

As a result of the epilepsy (MES) pharmacological test alone, ED ₅₀ had gabapentin 73.82 mg / kg and carrisbamate 9.94 mg / kg upon ip administration. On the other hand, MES test results according to the combination of gabapentin and charisbamate in various ratios are shown in Table 3 below.

Table 3 MES test results according to the combination of gabapentin and charisbamate

¹⁾ Correlation coefficient (α) = ED ₅₀ found / additive ED ₅₀ calculated

²⁾ α≤0.7: synergy, 0.7 <α≤1.3: additive, α> 1.3: antagonism

In Table 3, 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.

It can be observed from the results in FIG. 6 that the synergistic effect through the combination is maintained longer over time. In addition, as shown in FIG. 7, a combination of 30 mg / kg of gabapentin and 5 mg / kg of carisbamate was found to be intraperitoneally, resulting in an antiepileptic effect of 62.5%. This is a significant and significantly greater value than the 15% anti-epileptic effect of Gabapentin alone at 40 mg / kg, which is greater than / kg. From this, the synergistic effect on the combination of the two drugs can be directly observed.

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.

[Table 4] Rotarod test results according to the charisbamate alone and the combination of the charisbamate and gabapentin

As a result of using a combination of gabapentin and charisbamate, it was confirmed that there was no toxicity increase unlike the synergistic increase of the effect.

Claims (42)

1.  (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 a medicament for preventing, alleviating, or treating pain or epilepsy.
2. The medicament according to claim 1, comprising charisbamate (free form) in an amount of 10 mg to 1200 mg.
3. The medicament according to claim 1, comprising one or more (free form) selected from gabapentin and pregabalin in an amount of 50 mg to 3000 mg.
4. The agent according to claim 1, which comprises gabapentin (free form) in an amount of 50 mg to 3000 mg.
5. The agent according to claim 1, which comprises pregabalin (free form) in an amount of 50 mg to 800 mg.
6. The medicament according to claim 1, comprising 50 to 1200 mg of carrisbamate and 100 to 3000 mg of gabapentin on a free basis.
7. The medicament according to claim 1, comprising 50 to 500 mg of carrisbamate and 100 to 2000 mg of gabapentin on a free basis.
8. The medicament according to claim 1, comprising 10 to 300 mg of charisbamate and 100 to 600 mg of gabapentin on a free basis.
9. The medicament according to claim 1, comprising 50 to 1200 mg of carrisbamate and 50 to 800 mg of pregabalin on a free basis.
10. The medicament according to claim 1, comprising 50 to 500 mg of carrisbamate and 50 to 400 mg of pregabalin on a free basis.
11. The medicament according to claim 1, comprising 25 to 300 mg of charisbamate and 50 to 200 mg of pregabalin on a free basis.
12. The agent according to claim 1, wherein the compounding ratio (a) :( b) (based on an ED ₅₀ ) of component (a) to component (b) is 10: 1 to 1:20.
13. The method of claim 1, wherein component (a) for the component (b) as a blend ratio (a) :( b) (ED ₅₀ standard), six of gabapentin: 1 to 1:20 in a medicament.
14. The agent according to claim 1, wherein the compounding ratio of gabapentin as component (a) to component (b) is (a) :( b) (based on an ED ₅₀ ) of 5: 1 to 1:16.
15. The method of claim 1, wherein component (a) for the component (b) as the third mixing ratio (a) of gabapentin :( b) (ED _50): The 1 to 1:12 in a medicament.
16. The method of claim 1, wherein component (a) for the component (b) blending ratio of pregabalin (a) :( b) (ED ₅₀ standard) as a 7: 1 to 1:15 in a medicament.
17. The method of claim 1, wherein component (a) for the component (b) blending ratio of pregabalin (a) :( b) (ED ₅₀ standard) of 6 as a: 1 to 1: 9 drug.
18. The method of claim 1, wherein component (a) for the component (b) blending ratio of pregabalin (a) :( b) (ED ₅₀ standard) of 3 as a 1 to 1: 6 in a medicament.
19. The agent according to claim 1, wherein the pain is acute pain or chronic pain.
20. The agent according to claim 1, wherein the pain is nociceptive pain, neuropathic pain or nociceptive-neuropathy complex pain.
21. The agent of claim 1, wherein the pain is neuropathic pain.
22. The agent according to claim 1, wherein the pain is spontaneous pain, allodynia, hyperalgesia, abnormality, discomfort, hyperalgesia syndrome or inflammatory pain.
23. The agent of claim 1, wherein the pain is due to trauma, infection, metabolic disease, nutritional deficiency, immunity, tumor, vascular disease, compression or ischemia, or an unknown cause pain.
24. The method of claim 1, wherein the pain is caused by postherpetic neuralgia, diabetic neuropathy, complex site pain syndrome, peripheral neuropathy caused by drugs, pain caused by tumor, pain caused by brain tumor, pain caused by stroke, spinal cord injury A drug that is pain, pain caused by AIDS, pain caused by multiple sclerosis, limb pain, trigeminal neuralgia, lower back pain or fibromyalgia.
25. The agent according to claim 1, wherein the pain is headache, migraine, jaw joint pain, degenerative arthritis pain, rheumatoid arthritis pain, connective tissue pain or thoracic outlet syndrome pain.
26. (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 comprising at least one pharmaceutically acceptable carrier. Pharmaceutical compositions for prophylaxis, alleviation or treatment.
27. (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. How to.
28. (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; for use in preventing, alleviating, or treating pain or epilepsy.
29. The method of claim 27, wherein said pain is acute or chronic pain.
30. The method of claim 27, wherein the pain is nociceptive pain, neuropathic pain or nociceptive-neuropathy complex pain.
31. The method of claim 27, wherein said pain is neuropathic pain.
32. The method of claim 27, wherein the pain is spontaneous pain, allodynia, hyperalgesia, abnormalities, discomfort, hyperalgesia syndrome or inflammatory pain.
33. The method of claim 27, wherein the pain is due to trauma, infection, metabolic disease, nutritional deficiency, immunity, tumor, vascular disease, pressure or ischemia, or unexplained pain.
34. 28. The method of claim 27, wherein the pain is due to postherpetic neuralgia, diabetic neuropathy, complex site pain syndrome, peripheral neuropathy caused by drugs, pain caused by tumor, pain caused by brain tumor, pain caused by stroke, spinal cord injury Pain, pain caused by AIDS, pain due to multiple sclerosis, limb pain, trigeminal neuralgia, back pain or fibromyalgia.
35. The method of claim 27, wherein the pain is headache, migraine, jaw joint pain, degenerative arthritis pain, rheumatoid arthritis pain, connective tissue pain or thoracic outlet syndrome pain.
36. The method of claim 27, wherein said components (a) and (b) are administered to the treated subject simultaneously or sequentially.
37. The method of claim 27, wherein said components (a) and (b) are administered to the subject separately.
38. The method of claim 27, wherein the charisbamate (free form) is used in an amount of 10 mg to 1200 mg.
39. The method of claim 27, wherein at least one (free form) selected from gabapentin and pregabalin is used in an amount of 50 mg to 3000 mg.
40. 28. The method of claim 27, wherein the ratio of usage (a) :( b) (based on ED ₅₀ ) of component (a) to component (b) is from 10: 1 to 1:20.
41. 28. The method of claim 27 wherein the ratio of usage of gabapentin as component (a) to component (b) is from 6: 1 to 1:20 (a) :( b) (based on ED ₅₀ ).
42. 28. The method of claim 27 wherein the ratio (a) :( b) (based on ED ₅₀ ) of pregabalin as component (a) to component (b) is 7: 1 to 1:15.

Images