WO2022097764A1 - Pharmaceutical composition comprising pregabalin and tianeptine for treating neuropathic pain - Google Patents

Pharmaceutical composition comprising pregabalin and tianeptine for treating neuropathic pain Download PDF

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WO2022097764A1
WO2022097764A1 PCT/KR2020/015280 KR2020015280W WO2022097764A1 WO 2022097764 A1 WO2022097764 A1 WO 2022097764A1 KR 2020015280 W KR2020015280 W KR 2020015280W WO 2022097764 A1 WO2022097764 A1 WO 2022097764A1
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neuropathic pain
pain
tianeptine
neuropathic
induced
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PCT/KR2020/015280
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French (fr)
Korean (ko)
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윤명하
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전남대학교병원
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to a pharmaceutical composition for the treatment of neuropathic pain.
  • Neuropathic pain is defined by the International Association for the Study of Pain as "pain due to lesions or diseases of the somatosensory nervous system". It is associated with a reduced quality of life in 7-8% of adults. Nevertheless, many patients do not receive adequate treatment for neuropathic pain due to various mechanisms, difficulties in diagnosis, ineffective treatment, and side effects associated with these treatments. Although there is no definitive classification for combination therapy, combination therapy with an anticonvulsant and an antidepressant (both first-line drugs for neuropathic pain) may be an option for physicians expecting a synergistic effect. This approach improves efficacy and reduces side effects. In addition, there is considerable interest in the identification of novel targets to enable appropriate drug selection based on neuropathic pain pathophysiology.
  • Pregabalin an anticonvulsant drug that acts on calcium channels, inhibits neurotransmitter release. Efficacy has been demonstrated in postherpetic neuralgia, diabetic peripheral neuropathy, and spinal cord injury. Tianeptine, an antidepressant with distinct neurochemical properties, selectively enhances serotonin reuptake. However, there are few published studies on the analgesic effect.
  • the antithrombotic drug, clopidogrel is activated by hepatic metabolism and targets the purinergic P2Y12 receptor on platelets. In particular, P2Y12 receptor antagonists have recently received attention due to their relationship with pathological pain (eg, neuropathic or inflammatory pain).
  • An object of the present invention is to provide a pharmaceutical composition for the treatment of neuropathic pain.
  • tianeptine tianeptine
  • a pharmaceutical composition for treating neuropathic pain comprising a pharmaceutically acceptable salt thereof.
  • neuropathic pain is postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure
  • Neuropathic pain due to, sciatica, carpal tunnel syndrome neuropathic pain due to infection, neuropathic pain after infection, neuropathic pain due to impaired organ function, neuropathic pain due to vascular disease, neuropathic pain due to metabolic disease
  • a pharmaceutical composition for the treatment of neuropathic pain which is neuropathic pain caused by autoimmune disease, neuropathic back pain, neuropathic pain caused by fibromyalgia or unknown (idiopathic
  • neuropathic pain is postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure
  • Figure 2 shows an isobologram of the interaction between pregabalin and tianeptine's anti-nociceptive effect.
  • 3 is a graph showing the hind paw avoidance response to von Frey filaments over time when pregabalin alone is administered.
  • FIG. 4 is a graph showing the hindpaw avoidance response to von Frey filaments over time when tianeptine alone is administered.
  • 5 is a graph showing the hindpaw avoidance response to von Frey filaments over time when administered in combination with pregabalin and tianeptine.
  • the present invention relates to pregabalin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for the treatment of neuropathic pain (neuropathic pain) comprising a tianeptine (tianeptine) or a pharmaceutically acceptable salt thereof.
  • pregabalin and tianeptine are administered in combination, there is a significant therapeutic effect on neuropathic pain even with a small amount compared to when administered alone.
  • Pregabalin is a drug used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome and generalized anxiety disorder am.
  • Tianeptine is an atypical antidepressant primarily used to treat major depressive disorder, and is also used to treat anxiety, asthma and irritable bowel syndrome.
  • Neuropathic pain is caused by a disease in the somatosensory system after damage to the peripheral and central nerves. it means.
  • causes of neuropathic pain include trauma or injury, metabolic (ex. diabetic neuropathy, etc.), ischemic or vascular (ex. central pain after stroke, etc.), toxicity (ex. heavy metal poisoning, chemotherapy, etc.), nerve compression (ex. spinal stenosis, carpal tunnel syndrome, etc.), immune-mediated (ex. multiple sclerosis, etc.), inflammation (ex. post-herpetic neuralgia) and congenital problems, but are not limited thereto.
  • neuropathic pain The characteristic symptoms of neuropathic pain include hyperalgesia (a pain response that occurs when a response to a noxious stimulus is strengthened) and allodynia (a pain response induced even by a harmless stimulus). Symptoms of neuropathic pain include intermittent sharp pain, tingling pain like electricity, numbness, and paraesthesia.
  • the neuropathic pain includes postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure-induced neuropathic pain, diabetes sexual peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain due to chronic disease (multiple sclerosis, HIV, etc.), neuropathic pain due to trauma (burning pain), collision Neuropathic pain caused by (sciatica, carpal tunnel syndrome, etc.), neuropathic pain caused by infection, neuropathic pain after infection, neuropathic pain caused by impaired organ function, neuropathic pain caused by vascular disease, nerve caused by metabolic disease It may be pathological pain, neuropathic pain caused by an autoimmune disease, neuropathic back pain, neuropathic pain caused by fibromyalgia, or neuropathic pain of unknown cause (idiopathic),
  • pharmaceutically acceptable means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
  • pharmaceutically acceptable salt refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and the pharmaceutically acceptable salt is, for example, an acid addition salt or a metal salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda.
  • the metal salt may be a sodium, potassium or calcium salt.
  • Metal salts can be prepared using a base, for example an alkali metal or alkaline earth metal salt by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating the filtrate and/or Or it can be obtained by drying
  • treatment refers to treatment that results in a beneficial effect in a subject or patient suffering from the condition being treated, including not only cure, but also any degree of remission, including mild remission, substantial remission, major remission, the degree of remission being At least it's a slight relief.
  • the pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can, but is not limited thereto.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • it is prepared using usually used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
  • Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc., but these solid preparations include at least one or more excipients in the compound, for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc. are mixed and prepared.
  • excipients for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • various excipients for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of disease in the patient; Sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art.
  • the effective amount in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 6000 mg per kg of body weight, preferably 60 to 600 mg per kg of body weight, may be administered once or divided into three doses. there is. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the present invention relates to pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or it provides a functional food for improving neuropathic pain, including a pharmaceutically acceptable salt thereof.
  • Pregabalin, tianeptine and neuropathic pain may be within the ranges described above.
  • food acceptable means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
  • food acceptable salt refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and may be within the range described above for "salt”.
  • the health functional food of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of improving neuropathic pain.
  • the health functional food of the present invention refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
  • the health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
  • Examples of the items listed in the Food Additives Code include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations such as sodium L-glutamate preparation, noodles added alkali agent, preservative agent, tar color agent, etc. are not limited thereto.
  • a health functional food in the form of a tablet is granulated in a conventional manner by mixing the composition with an excipient, a binder, a disintegrant and other additives, followed by compression molding by adding a lubricant, or the mixture directly. Compression molding is possible.
  • the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
  • hard capsules can be prepared by filling a mixture of the composition and additives such as excipients in ordinary hard capsules, and soft capsules are gelatin obtained by mixing the composition with additives such as excipients. It can be prepared by filling in a capsule base such as The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
  • a health functional food in the form of a ring can be prepared by molding a mixture of the composition and an excipient, a binder, a disintegrant, etc. by a known method, and if necessary, it can be coated with sucrose or other skinning agent, or starch , it is also possible to coat the surface with a material such as talc.
  • a health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing the composition with an excipient, a binder, a disintegrant, etc., and may contain a flavoring agent, a corrosive agent, etc. as necessary.
  • Health functional foods include beverages, meat, chocolate, foods, and sweets. It may be pizza, ramen, other noodles, gums, candies, ice cream, alcoholic beverages, vitamin complexes, health supplements, and the like.
  • Health functional foods may be orally applied for the purpose of nutritional supplements, and the application form is not particularly limited.
  • the daily intake is preferably 5000 mg or less, more preferably 2000 mg or less, and most preferably 500 to 1500 mg or 650 mg daily.
  • 1 tablet may be administered with water once a day.
  • Rats Male Spraque-Dawley rats (weight 130-150 g) were used. Rats were maintained at a well-controlled temperature of 24° C. on a light-dark cycle of 12 hours. Food and water were provided freely. The experimental protocol was approved by the Animal Care Committee of Chonnam National University Animal Hospital (CNU IACUC-H-2014-11).
  • the drugs used were pregabalin (Pfizer Inc, New York, NY, USA), tianeptine (JEIL Pharm.Co., Ltd., Seoul, Korea) and clopidogrel hydrogen sulfate (Tocris Bioscience). , Bristol, UK), and all drugs were dissolved in saline.
  • the drug was injected intrathecally in a volume of 10 ⁇ l of the solution using a hand-driven, gear-actuated syringe pump. An additional 10 ⁇ l of normal saline was injected into the catheter.
  • Rats were acclimated for 30 min in a separate transparent container with a wire mesh bottom, and testing was performed with calibrated von Frey filaments from under the cage to the hind paws.
  • Eight von Frey filaments (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 15 g) were sequentially pressed vertically on the plantar surface of the hind paw for 5 s and the filaments were bent.
  • a rapid paw withdrawal response after mechanical stimulation with von Frey filaments was considered a positive result.
  • a light filament was used after a positive reaction and a heavier filament was used after a negative reaction.
  • a series of 5-6 experiments were performed after the first positive test. The lightest filament exhibiting a withdrawal reaction was defined as the paw withdrawal threshold. The maximum value was recorded as 15 g when rats responded negatively without withdrawal reaction at 15 g pressure of Frey filament.
  • Rats that underwent an adaptation time of 30 minutes on the day of the experiment (7 days after intrathecal tube insertion) were assigned to two groups: experimental and control. Experimental drugs were delivered randomly. In the control group, intrathecal saline was delivered in the same volume as the experimental group. In the experiment, rats were used only once, and the researcher proceeded with the experiment without knowing what drug was used. The effects of intrathecal tianeptine (30, 100, 300 ⁇ g), clopidogrel (300 ⁇ g) and pregabalin (0.3, 1, 3 ⁇ g) on neuropathic pain were evaluated (5-7 rats per group). . A baseline mechanical withdrawal threshold was identified prior to drug infusion. Paw withdrawal thresholds were assessed at 15, 30, 60, 90, 120, 150 and 180 minutes after intrathecal drug injection. The maximum drug dose was determined based on a preliminary study in the absence of neurological deficits. The anti-nociceptive effect of the drug was evaluated as a percentage of the maximal possible effect (% MPE).
  • % MPE ([post drug threshold - post injured baseline threshold] / [cutoff threshold - post injured baseline threshold]) X 100.
  • Isobolographic analysis and fixed-dose analysis were performed to evaluate drug interactions between pregabalin and tianeptine or clopidogrel (Fig. 2). Isobolographic analysis determines the equivalent dose of the drug.
  • a 50% effective dose (ED 50 ) value was estimated from the dose response curves of both drugs (pregabalin and tianeptine), which resulted in a 50% reduction in MPE. Then, a dose response curve was obtained for the combined administration of the two drugs at a constant dose ratio based on the ED 50 of the individual drugs.
  • tianeptine ED 50 + pregabalin ED 50 (tianeptine ED 50 + pregabalin ED 50 )/2, (tianeptine ED 50 + pregabalin ED 50 )/4 and (tianeptine ED 50 + pregabalin ED 50 )/4 and (tianeptine ED 50 + pregabalin ED 50 ) Gabalin ED 50 )/8 was injected. Then, the ED 50 value of each drug in the case of combined administration was calculated, which means the dose of each drug included in the mixture showing 50% MPE in the dose response curve for the combined administration of the two drugs.
  • Isobolograms were expressed by plotting the ED 50 values of each drug on the x and y axes, respectively (Fig. 2).
  • the line connecting the two points represents the theoretical additive action line.
  • Isobologram analysis is a method that can infer the interaction between two drugs. When the ED 50 of mixed administration is on the additive action line, it is an additive action between the two drugs. It can be said that there is an antagonistic action relationship.
  • total dose fraction value was also used to describe the magnitude of the interaction. When the total amount fraction value approaches 1, it can be said that there is an additive effect between the two drugs, when it is less than 1, there is a synergistic effect, and when it is larger than 1, it can be said that there is an antagonistic effect.
  • Total dose fraction value (Drug 1 + ED 50 of Drug 2) / (ED 50 of Drug 1 alone) + (ED 50 of Drug 2 + Drug 1 alone) / (ED 50 of Drug 2 alone).
  • clopidogrel alone had no anti-allodynic effect a fixed-dose assay was used to investigate the correlation between pregabalin and clopidogrel.
  • Dose-response results were analyzed by one-way analysis of variance through Bonferroni comparison for post-hoc analysis. Dose-response lines were fitted by least-squares linear regression. ED 50 and 95% confidence intervals (CI) were calculated according to the method described by Tallarida and Murray. Differences in theoretical and experimental ED 50 values were investigated using t-test. P ⁇ 0.05 was considered statistically significant.
  • Tactile allodynia was induced after ligation of L5-L6 spinal nerves in experimental mice.
  • the paw avoidance threshold was ⁇ 4 g. No behavioral changes were observed even at the highest dose of each drug (ie, 3 ⁇ g for pregabalin, 300 ⁇ g for tianeptine, and 300 ⁇ g for clopidogrel). Both pregabalin and tianeptine increased the mechanical avoidance threshold values in a dose-dependent manner ( FIGS. 3 and 4 ).
  • the ED 50 of tianeptine was 108.80 ⁇ g (CI, 87.46 ⁇ 135.35 ⁇ g), and the ED 50 of pregabalin was 0.78 ⁇ g (CI, 0.56 ⁇ 1.10 ⁇ g), and when administered in combination, thia
  • the ED 50 of neptine was 34.33 ⁇ g (CI, 26.83 ⁇ 43.92 ⁇ g), and the ED 50 of pregabalin was 0.24 ⁇ g (CI, 0.19 ⁇ 0.31 ⁇ g) when administered in combination.
  • the total dose fraction value obtained using this number is 0.63, which is less than 1, indicating that there is a synergistic effect between the two drugs.

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Abstract

The present invention relates to a pharmaceutical composition for treating neuropathic pain which, by comprising pregabalin or pharmaceutically acceptable salt thereof, and tianeptine or pharmaceutically acceptable salt thereof, is superbly effective in treating neuropathic pain even in low doses in comparison with administration of each medicine alone.

Description

프레가발린 및 티아넵틴을 포함하는 신경병성 통증 치료용 약학적 조성물Pharmaceutical composition for treating neuropathic pain comprising pregabalin and tianeptine
본 발명은 신경병성 통증 치료용 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the treatment of neuropathic pain.
신경병성 통증(neuropathic pain)은 국제 통증 연구 협회(International Association for the Study of Pain)에 의해 "체성 감각 신경계의 병변 또는 질병으로 인한 통증"으로 정의된다. 성인의 7~8%의 삶의 질을 저하시키는 것과 관련이 있다. 그럼에도 불구하고 많은 환자들은 다양한 기전, 진단의 어려움, 비효과적인 치료 및 이러한 치료와 관련된 부작용으로 인해 신경병성 통증에 대한 적절한 치료를 받지 못하고 있다. 병용 요법에는 결정적인 등급 분류가 없지만 항경련제와 항우울제(신경병성 통증에 대한 1차 약물 모두)와의 병용 치료는 시너지 효과를 기대하는 의사에게 선택지가 될 수 있다. 이 접근법은 효능을 향상시키고 부작용을 감소시킨다. 또한, 신경병성 통증 병태 생리학에 기반한 적절한 약물 선택을 가능하게 하기 위해 새로운 표적의 식별에 상당한 관심이 있다.Neuropathic pain is defined by the International Association for the Study of Pain as "pain due to lesions or diseases of the somatosensory nervous system". It is associated with a reduced quality of life in 7-8% of adults. Nevertheless, many patients do not receive adequate treatment for neuropathic pain due to various mechanisms, difficulties in diagnosis, ineffective treatment, and side effects associated with these treatments. Although there is no definitive classification for combination therapy, combination therapy with an anticonvulsant and an antidepressant (both first-line drugs for neuropathic pain) may be an option for physicians expecting a synergistic effect. This approach improves efficacy and reduces side effects. In addition, there is considerable interest in the identification of novel targets to enable appropriate drug selection based on neuropathic pain pathophysiology.
칼슘 채널에 작용하는 항경련제인 프레가발린은 신경 전달 물질 방출을 억제한다. 포진 후 신경통, 당뇨병성 말초 신경병증, 척수 손상에서 효능이 입증되었다. 뚜렷한 신경화학적 특성을 가진 항우울제인 티아넵틴은 세로토닌 재흡수를 선택적으로 향상시킨다. 그러나 진통 효과에 관한 발표된 연구는 거의 없다. 항혈전제인 클로피도그렐은 간 대사에 의해 활성화되며 혈소판에서 퓨린성 P2Y12 수용체를 표적으로 삼는다. 특히 P2Y12 수용체 길항제는 병리학적 통증(예를 들어, 신경병성 또는 염증성 통증)과의 관계로 인해 최근 주목을 받고 있다.Pregabalin, an anticonvulsant drug that acts on calcium channels, inhibits neurotransmitter release. Efficacy has been demonstrated in postherpetic neuralgia, diabetic peripheral neuropathy, and spinal cord injury. Tianeptine, an antidepressant with distinct neurochemical properties, selectively enhances serotonin reuptake. However, there are few published studies on the analgesic effect. The antithrombotic drug, clopidogrel, is activated by hepatic metabolism and targets the purinergic P2Y12 receptor on platelets. In particular, P2Y12 receptor antagonists have recently received attention due to their relationship with pathological pain (eg, neuropathic or inflammatory pain).
본 발명은 신경병성 통증 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a pharmaceutical composition for the treatment of neuropathic pain.
1. 프레가발린(pregabalin) 또는 이의 약학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 약학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 치료용 약학 조성물.1. Pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or a pharmaceutical composition for treating neuropathic pain comprising a pharmaceutically acceptable salt thereof.
2. 위 1에 있어서, 상기 신경병성 통증은 대상포진 후 신경통, 수술 후 신경병성 통증, 암에 의한 신경병성 통증, 암 치료에 의한 신경병성 통증, 약물 노출에 의한 신경병성 통증, 독성 화학물질 노출에 의한 신경병성 통증, 당뇨병성 말초 신경병증, 3차 신경통, 복합 부위 통증 증후군, 반사 교감신경 이영양증, 편두통, 환상지통, 다발성 경화증에 의한 신경병성 통증, HIV에 의한 신경병성 통증, 외상(작열통)에 의한 신경병성 통증, 좌골신경통, 손목 터널 증후군, 감염에 의한 신경병성 통증, 감염 후 신경병성 통증, 손상된 장기 기능에 의한 신경병성 통증, 혈관 질환에 의한 신경병성 통증, 대사 질환에 의한 신경병성 통증, 자가면역 질환에 의한 신경병성 통증, 신경병성 요통, 섬유근육통에 의한 신경병성 통증 또는 원인 미상(특발성) 신경병성 통증인, 신경병성 통증 치료용 약학 조성물.2. The method of 1 above, wherein the neuropathic pain is postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure Neuropathic pain due to, diabetic peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain due to multiple sclerosis, neuropathic pain due to HIV, trauma (burning pain) Neuropathic pain due to, sciatica, carpal tunnel syndrome, neuropathic pain due to infection, neuropathic pain after infection, neuropathic pain due to impaired organ function, neuropathic pain due to vascular disease, neuropathic pain due to metabolic disease , A pharmaceutical composition for the treatment of neuropathic pain, which is neuropathic pain caused by autoimmune disease, neuropathic back pain, neuropathic pain caused by fibromyalgia or unknown (idiopathic) neuropathic pain.
3. 프레가발린(pregabalin) 또는 이의 식품학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 식품학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 개선용 건강기능식품.3. Pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or a functional food for improving neuropathic pain comprising a pharmaceutically acceptable salt thereof.
4. 위 3에 있어서, 상기 신경병성 통증은 대상포진 후 신경통, 수술 후 신경병성 통증, 암에 의한 신경병성 통증, 암 치료에 의한 신경병성 통증, 약물 노출에 의한 신경병성 통증, 독성 화학물질 노출에 의한 신경병성 통증, 당뇨병성 말초 신경병증, 3차 신경통, 복합 부위 통증 증후군, 반사 교감신경 이영양증, 편두통, 환상지통, 다발성에 경화증에 의한 신경병성 통증, HIV에 의한 신경병성 통증, 외상(작열통)에 의한 신경병성 통증, 좌골신경통, 손목 터널 증후군, 감염에 의한 신경병성 통증, 감염 후 신경병성 통증, 손상된 장기 기능에 의한 신경병성 통증, 혈관 질환에 의한 신경병성 통증, 대사 질환에 의한 신경병성 통증, 자가면역 질환에 의한 신경병성 통증, 신경병성 요통, 섬유근육통에 의한 신경병성 통증 또는 원인 미상(특발성) 신경병성 통증인, 신경병성 통증 개선용 건강기능식품4. The method of 3 above, wherein the neuropathic pain is postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure Neuropathic pain caused by neuropathic pain, diabetic peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain caused by multiple sclerosis, neuropathic pain caused by HIV, trauma (burning pain) ) caused by neuropathic pain, sciatica, carpal tunnel syndrome, neuropathic pain caused by infection, neuropathic pain after infection, neuropathic pain caused by impaired organ function, neuropathic pain caused by vascular disease, neuropathic caused by metabolic disease Health functional food for improving neuropathic pain, which is pain, neuropathic pain caused by autoimmune disease, neuropathic back pain, neuropathic pain caused by fibromyalgia or unknown (idiopathic) neuropathic pain
본 발명은 프레가발린 및 티아넵틴을 포함하는 신경병성 통증 치료용 약학 조성물에 관한 것으로, 프레가발린 및 티아넵틴을 병용 투여하는 경우, 각각을 단독 투여하는 경우와 비교하여 소량으로도 우수한 신경병성 통증 치료 효과를 갖는다.The present invention relates to a pharmaceutical composition for treating neuropathic pain comprising pregabalin and tianeptine. It has a pain-relieving effect.
도 1은 프레가발린 및 티아넵틴의 척수강내 단독 투여 시 항통각 효과를 maximal possible effect(% MPE)의 백분율로 나타낸 것이다.1 shows the anti-nociceptive effect as a percentage of the maximal possible effect (% MPE) when pregabalin and tianeptine are administered alone intrathecally.
도 2는 프레가발린 및 티아넵틴의 항통각 효과의 상호 작용에 대한 isobologram을 나타낸 것이다.Figure 2 shows an isobologram of the interaction between pregabalin and tianeptine's anti-nociceptive effect.
도 3은 프레가발린 단독 투여 시 von Frey 필라멘트에 대한 뒷발 회피 반응을 시간에 따라 나타낸 것이다.3 is a graph showing the hind paw avoidance response to von Frey filaments over time when pregabalin alone is administered.
도 4는 티아넵틴 단독 투여 시 von Frey 필라멘트에 대한 뒷발 회피 반응을 시간에 따라 나타낸 것이다.4 is a graph showing the hindpaw avoidance response to von Frey filaments over time when tianeptine alone is administered.
도 5는 프레가발린 및 티아넵틴 병용 투여 시 von Frey 필라멘트에 대한 뒷발 회피 반응을 시간에 따라 나타낸 것이다.5 is a graph showing the hindpaw avoidance response to von Frey filaments over time when administered in combination with pregabalin and tianeptine.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 프레가발린(pregabalin) 또는 이의 약학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 약학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 치료용 약학 조성물을 제공한다.The present invention relates to pregabalin or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for the treatment of neuropathic pain (neuropathic pain) comprising a tianeptine (tianeptine) or a pharmaceutically acceptable salt thereof.
프레가발린 및 티아넵틴을 병용 투여하는 경우, 단독 투여하는 경우와 비교하여 소량으로도 현저한 신경병성 통증 치료 효과가 있다.When pregabalin and tianeptine are administered in combination, there is a significant therapeutic effect on neuropathic pain even with a small amount compared to when administered alone.
프레가발린(pregabalin)은 간질(epilepsy), 신경병성 통증(neuropathic pain), 섬유 근육통(fibromyalgia), 하지 불안 증후군(restless leg syndrome) 및 범 불안 장애(gemeralized anxiety disorder)를 치료하는 데 사용되는 약물이다.Pregabalin is a drug used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome and generalized anxiety disorder am.
티아넵틴(tianeptine)은 주로 주요 우울 장애(major depressive disorder) 치료에 사용되는 비정형 항우울제로, 불안(anxiety), 천식(asthma) 및 과민성 대장 증후군(irritable bowel syndrome) 치료에도 사용되는 약물이다.Tianeptine is an atypical antidepressant primarily used to treat major depressive disorder, and is also used to treat anxiety, asthma and irritable bowel syndrome.
신경병성 통증(neuropathic pain)은 말초 및 중추 신경 손상 후에 몸감각(somatosensory) 체계에 병을 일으켜 발생하며, 신경병성 통증 질환이란 신경계통 손상 등의 일차적 병변 또는 신경기능 변화에 의해 초래되는 통증 질환을 의미한다. 신경병성 통증의 원인으로는 외상 또는 손상, 대사성(ex. 당뇨병성 신경병증 등), 허혈성 또는 혈관성(ex. 뇌졸중 후 중추성 통증 등), 독성(ex. 중금속 중독, 화학요법 등), 신경압박(ex. 척추협착증, 손목터널증후군 등), 면역매개성(ex. 다발성경화증 등), 염증(ex. 대상포진 후 신경통) 및 선천적인 문제 등이 있으나, 이에 제한되는 것은 아니다. 신경병성 통증의 특징적인 증상으로는 통각 과민(hyperalgesia, 유해자극에 대한 반응이 더 강화되어서 나타나는 통증반응)과 이질통(allodynia, 무해한 자극에도 유발되는 통증반응)이 있고, 이 외에 지속적인 화끈거리는 통증, 간헐적인 날카로운 통증, 전기가 오는 것처럼 저린 통증, 감각저하, 이상감각 등이 신경병성 통증의 증상에 해당한다.Neuropathic pain is caused by a disease in the somatosensory system after damage to the peripheral and central nerves. it means. Causes of neuropathic pain include trauma or injury, metabolic (ex. diabetic neuropathy, etc.), ischemic or vascular (ex. central pain after stroke, etc.), toxicity (ex. heavy metal poisoning, chemotherapy, etc.), nerve compression (ex. spinal stenosis, carpal tunnel syndrome, etc.), immune-mediated (ex. multiple sclerosis, etc.), inflammation (ex. post-herpetic neuralgia) and congenital problems, but are not limited thereto. The characteristic symptoms of neuropathic pain include hyperalgesia (a pain response that occurs when a response to a noxious stimulus is strengthened) and allodynia (a pain response induced even by a harmless stimulus). Symptoms of neuropathic pain include intermittent sharp pain, tingling pain like electricity, numbness, and paraesthesia.
상기 신경병성 통증은 대상포진 후 신경통, 수술 후 신경병성 통증, 암에 의한 신경병성 통증, 암 치료에 의한 신경병성 통증, 약물 노출에 의한 신경병성 통증, 독성 화학물질 노출에 의한 신경병성 통증, 당뇨병성 말초 신경병증, 3차 신경통, 복합 부위 통증 증후군, 반사 교감신경 이영양증, 편두통, 환상지통, 만성 질환(다발성 경화증, HIV 등)에 의한 신경병성　통증, 외상(작열통)에 의한 신경병성　통증, 충돌에 의한 신경병성　통증(좌골신경통, 손목 터널 증후군 등), 감염에 의한 신경병성 통증, 감염 후 신경병성 통증, 손상된 장기 기능에 의한 신경병성 통증, 혈관 질환에 의한 신경병성 통증, 대사 질환에 의한 신경병성 통증, 자가면역 질환에 의한 신경병성 통증, 신경병성 요통, 섬유근육통에 의한 신경병성 통증 또는 원인 미상(특발성) 신경병성 통증일 수 있으나, 이에 제한되는 것은 아니다.The neuropathic pain includes postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure-induced neuropathic pain, diabetes Sexual peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain due to chronic disease (multiple sclerosis, HIV, etc.), neuropathic pain due to trauma (burning pain), collision Neuropathic pain caused by (sciatica, carpal tunnel syndrome, etc.), neuropathic pain caused by infection, neuropathic pain after infection, neuropathic pain caused by impaired organ function, neuropathic pain caused by vascular disease, nerve caused by metabolic disease It may be pathological pain, neuropathic pain caused by an autoimmune disease, neuropathic back pain, neuropathic pain caused by fibromyalgia, or neuropathic pain of unknown cause (idiopathic), but is not limited thereto.
용어 "약학적으로 허용 가능한"은 화합물 또는 조성물이 투여되는 개체, 세포, 조직 등에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 특성을 나타내는 것을 의미한다.The term "pharmaceutically acceptable" means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
용어 "약학적으로 허용 가능한 염"은, 본 발명에 따른 특정 화합물과 비교적 무독성인 산 또는 염기를 이용해서 조제되는 염을 의미하며, 약학적으로 허용 가능한 염은 예를 들어 산 부가염 또는 금속염일 수 있다.The term "pharmaceutically acceptable salt" refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and the pharmaceutically acceptable salt is, for example, an acid addition salt or a metal salt. can
산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 형성될 수 있다. 이러한 약학적으로 무독한 염은 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트, 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피을레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴- 1,4-디오에이트, 핵산-1，6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 를투엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β_하이드톡시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함할 수 있다.Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propylate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, etuenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycol lactate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
금속염은 나트륨, 칼륨 또는 칼슘염일 수 있다. 금속염은 염기를 사용하여 제조할 수 있으며, 예를 들어, 알칼리 금속 또는 알칼리 토금속 염은 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고 여액을 증발 및/또는 건조시켜 수득할 수 있다The metal salt may be a sodium, potassium or calcium salt. Metal salts can be prepared using a base, for example an alkali metal or alkaline earth metal salt by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating the filtrate and/or Or it can be obtained by drying
용어 "치료"는 치유뿐만 아니라 경미한 완화, 실질적인 완화, 주요 완화를 포함하는 임의의 정도의 완화를 포함하여 치료될 병태를 앓고 있는 대상체 또는 환자에게 유리한 효과를 초래하는 처치를 지칭하고, 완화 정도는 적어도 경미한 완화이다.The term “treatment” refers to treatment that results in a beneficial effect in a subject or patient suffering from the condition being treated, including not only cure, but also any degree of remission, including mild remission, substantial remission, major remission, the degree of remission being At least it's a slight relief.
본 발명의 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can, but is not limited thereto.
조성물에 함유될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로즈, 수크로스, 덱스트린, 말토덱스트린, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으나, 이에 제한되지 않는다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면 활성제 등의 희석제 또는 부형제를 사용하여 조제되나, 이에 제한되지 않는다.Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using usually used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며 이에 제한되지는 않으나, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다.Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc., but these solid preparations include at least one or more excipients in the compound, for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of disease in the patient; Sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물에서 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 1 내지 6000 ㎎, 바람직하게는 60 내지 600 ㎎을 1회 또는 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The effective amount in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 6000 mg per kg of body weight, preferably 60 to 600 mg per kg of body weight, may be administered once or divided into three doses. there is. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
본 발명은 프레가발린(pregabalin) 또는 이의 식품학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 식품학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 개선용 건강기능식품을 제공한다.The present invention relates to pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or it provides a functional food for improving neuropathic pain, including a pharmaceutically acceptable salt thereof.
프레가발린, 티아넵틴 및 신경병성 통증은 상기 전술한 범위 내의 것일 수 있다.Pregabalin, tianeptine and neuropathic pain may be within the ranges described above.
용어 "식품학적으로 허용 가능한"은 화합물 또는 조성물이 투여되는 개체, 세포, 조직 등에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 특성을 나타내는 것을 의미한다.The term “food acceptable” means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
용어 "식품학적으로 허용 가능한 염"은, 본 발명에 따른 특정 화합물과 비교적 무독성인 산 또는 염기를 이용해서 조제되는 염을 의미하며, "염"에 관한 전술한 범위 내일 수 있다.The term "food acceptable salt" refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and may be within the range described above for "salt".
본 발명의 건강기능식품은 신경병성 통증(neuropathic pain) 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of improving neuropathic pain.
본 발명의 건강기능식품이라 함은, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The health functional food of the present invention refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류 첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 포함하나, 이에 제한되지 않는다.Examples of the items listed in the Food Additives Code include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations such as sodium L-glutamate preparation, noodles added alkali agent, preservative agent, tar color agent, etc. are not limited thereto.
예를 들어, 정제 형태의 건강기능식품은 상기 조성물을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다.For example, a health functional food in the form of a tablet is granulated in a conventional manner by mixing the composition with an excipient, a binder, a disintegrant and other additives, followed by compression molding by adding a lubricant, or the mixture directly. Compression molding is possible. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 상기 조성물을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 상기 조성물을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Among health functional foods in the form of capsules, hard capsules can be prepared by filling a mixture of the composition and additives such as excipients in ordinary hard capsules, and soft capsules are gelatin obtained by mixing the composition with additives such as excipients. It can be prepared by filling in a capsule base such as The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
환 형태의 건강기능식품은 상기 조성물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.A health functional food in the form of a ring can be prepared by molding a mixture of the composition and an excipient, a binder, a disintegrant, etc. by a known method, and if necessary, it can be coated with sucrose or other skinning agent, or starch , it is also possible to coat the surface with a material such as talc.
과립 형태의 건강기능식품은 상기 조성물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.A health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing the composition with an excipient, a binder, a disintegrant, etc., and may contain a flavoring agent, a corrosive agent, etc. as necessary.
건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류. 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.Health functional foods include beverages, meat, chocolate, foods, and sweets. It may be pizza, ramen, other noodles, gums, candies, ice cream, alcoholic beverages, vitamin complexes, health supplements, and the like.
건강기능식품은 영양제의 용도로 경구 적용될 수 있으며, 적용 형태는 특별히 제한되지 않는다. 예를 들면 경구 투여되는 경우, 하루 섭취량은 5000mg 이하인 것이 바람직하고, 하루 섭취량이 2000mg 이하인 것이 보다 바람직하며, 하루 섭취량이 500 내지 1500mg, 또는 650mg인 것이 가장 바람직하다. 캡슐제 또는 정제로 제제화하는 경우, 1일 1회 1정을 물과 함께 투여할 수 있다.Health functional foods may be orally applied for the purpose of nutritional supplements, and the application form is not particularly limited. For example, in the case of oral administration, the daily intake is preferably 5000 mg or less, more preferably 2000 mg or less, and most preferably 500 to 1500 mg or 650 mg daily. When formulated as a capsule or tablet, 1 tablet may be administered with water once a day.
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, examples will be given to describe the present invention in detail.
실시예Example
실험재료 및 방법Experimental materials and methods
1. 시험 동물 준비1. Test Animal Preparation
본 실험에서 수컷 Spraque-Dawley 쥐(무게 130~150 g)가 사용되었다. 쥐를 잘 조절된 24 ℃의 온도에서 12시간의 명암 주기로 유지했다. 음식과 물은 자유롭게 제공되었다. 전남대학교 동물병원 동물 관리위원회가 실험 프로토콜을 승인했다(CNU IACUC-H-2014-11).In this experiment, male Spraque-Dawley rats (weight 130-150 g) were used. Rats were maintained at a well-controlled temperature of 24° C. on a light-dark cycle of 12 hours. Food and water were provided freely. The experimental protocol was approved by the Animal Care Committee of Chonnam National University Animal Hospital (CNU IACUC-H-2014-11).
2. 신경병성 통증(neuropathic pain) 동물 모델2. Neuropathic pain animal model
신경병성 통증을 유도하기 위해 척수 신경 결찰법이 사용되었다. 세보플루란(sevoflurane) 마취 하에 쥐를 사용하여 척추 근처의 왼쪽 L5 및 L6 척수 신경을 분리하고 6-0 실크를 사용하여 단단히 연결했다. 쥐는 기계적 이질통(mechanical allodynia, 4 g 미만의 굽힘력 적용에 대한 반응으로 발을 움찔거리는 행동)을 보일 때, 신경병성 통증을 나타내는 것으로 간주되었다. 시술 후 운동 장애가 유발된 경우, 쥐는 세보플루란의 과다 복용으로 안락사되었다.Spinal nerve ligation was used to induce neuropathic pain. Using mice under sevoflurane anesthesia, the left L5 and L6 spinal nerves near the spine were isolated and tightly connected using 6-0 silk. Rats were considered to exhibit neuropathic pain when they exhibited mechanical allodynia (flickering of the paw in response to application of a flexion force of less than 4 g). If movement impairment was induced after the procedure, the mice were euthanized due to an overdose of sevoflurane.
3. 척수강내 카테터 삽입(intrathecal catheterization)3. Intrathecal catheterization
척수 신경 결찰 후 5일째에 쥐를 세보플루란 마취 하에, 환추후두막(atlantooccipital membrane)을 요추 확장 부(lumbar enlargement) 수준까지 절개하여 폴리에틸렌 튜브(PE-10)를 척수강내로 이식했다. 카테터 이식 후, 쥐에게 7일의 회복 기간을 제공했다. 신경학적 결손을 보이는 경우 면밀히 모니터링되고 제외되었다.On day 5 after spinal nerve ligation, rats were under sevoflurane anesthesia, the atlantooccipital membrane was incised to the level of the lumbar enlargement, and a polyethylene tube (PE-10) was intrathecally implanted. After catheter implantation, mice were given a recovery period of 7 days. Neurological deficits were closely monitored and excluded.
4. 약제4. Pharmaceuticals
사용된 약물은 프레가발린(pregabalin, Pfizer Inc, New York, NY, USA), 티아넵틴(tianeptine, JEIL Pharm.Co., Ltd., Seoul, Korea) 및 클로피도그렐 황산수소염(clopidogrel hydrogen sulfate, Tocris Bioscience, Bristol, UK)이고, 모든 약물은 식염수에 용해되었다. 손으로 구동되는 기어 작동식 주사기 펌프를 사용하여 약물을 척수강내에 10 ㎕ 부피의 용액으로 주입했다. 10 ㎕ 추가 정상 식염수를 카테터로 주입하였다.The drugs used were pregabalin (Pfizer Inc, New York, NY, USA), tianeptine (JEIL Pharm.Co., Ltd., Seoul, Korea) and clopidogrel hydrogen sulfate (Tocris Bioscience). , Bristol, UK), and all drugs were dissolved in saline. The drug was injected intrathecally in a volume of 10 μl of the solution using a hand-driven, gear-actuated syringe pump. An additional 10 μl of normal saline was injected into the catheter.
5. 기계적 이질통(mechanical allodynia)의 평가5. Evaluation of mechanical allodynia
쥐를 철망 바닥이 있는 별도의 투명 용기에서 30분 동안 순응시키고, 케이지 아래에서 뒷발까지 calibrated von Frey 필라멘트로 테스트를 수행하였다. 8개의 von Frey 필라멘트(0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 15 g)를 뒷발의 발바닥 표면에 5초 동안 수직으로 순차적으로 누르고 필라멘트를 구부렸다. von Frey 필라멘트를 사용한 기계적 자극 후 빠른 발 회피 반응이 양성 결과(positive result)로 간주되었다. up and down 방법에 따라 양성 반응(positive reaction) 후에는 가벼운 필라멘트를 사용하고 음성 반응(negative reaction) 후에는 더 무거운 필라멘트를 사용했다. 첫 번째 양성 반응 후 일련의 5~6개의 실험이 수행되었다. 회피 반응(withdrawal reaction)을 나타내는 가장 가벼운 필라멘트는 발 회피 임계 값(paw withdrawal threshold)으로 정의되었다. 쥐가 Frey 필라멘트의 15 g 압력에서 철수 반응 없이 음성 반응하면 최대 값은 15 g으로 기록되었다.Rats were acclimated for 30 min in a separate transparent container with a wire mesh bottom, and testing was performed with calibrated von Frey filaments from under the cage to the hind paws. Eight von Frey filaments (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, 15 g) were sequentially pressed vertically on the plantar surface of the hind paw for 5 s and the filaments were bent. A rapid paw withdrawal response after mechanical stimulation with von Frey filaments was considered a positive result. According to the up and down method, a light filament was used after a positive reaction and a heavier filament was used after a negative reaction. A series of 5-6 experiments were performed after the first positive test. The lightest filament exhibiting a withdrawal reaction was defined as the paw withdrawal threshold. The maximum value was recorded as 15 g when rats responded negatively without withdrawal reaction at 15 g pressure of Frey filament.
6. 실험적 패러다임6. Experimental Paradigm
실험 당일(척수강내 배관 삽입 7일 후) 30분의 적응 시간을 겪은 쥐를 실험 및 대조군의 두 그룹으로 할당했다. 실험 약물은 무작위로 전달되었다. 대조군에서는 척수강내 식염수를 실험군과 동일한 부피로 전달하였다. 실험에 쥐는 한 번만 사용되었고 연구자는 사용된 약물이 무엇인지 모른 상태로 실험을 진행하였다. 신경병성 통증에 대한 척수강내 티아넵틴(30, 100, 300 ㎍), 클로피도그렐(300㎍) 및 프레가발린(0.3, 1, 3 ㎍)의 효과를 평가했다(그룹 당 5~7 마리의 쥐). 약물 주입 전에 기준 기계적 회피 임계 값(baseline mechanical withdrawal threshold)을 확인했다. 척수강내 약물 주입 후 15, 30, 60, 90, 120, 150 및 180 분에 발 회피 역치를 평가하였다. 최대 약물 용량은 신경학적 결함이 없던 예비 연구를 기반으로 결정되었다. 약물의 항통각 효과를 maximal possible effect(% MPE)의 백분율로 평가하였다.Rats that underwent an adaptation time of 30 minutes on the day of the experiment (7 days after intrathecal tube insertion) were assigned to two groups: experimental and control. Experimental drugs were delivered randomly. In the control group, intrathecal saline was delivered in the same volume as the experimental group. In the experiment, rats were used only once, and the researcher proceeded with the experiment without knowing what drug was used. The effects of intrathecal tianeptine (30, 100, 300 μg), clopidogrel (300 μg) and pregabalin (0.3, 1, 3 μg) on neuropathic pain were evaluated (5-7 rats per group). . A baseline mechanical withdrawal threshold was identified prior to drug infusion. Paw withdrawal thresholds were assessed at 15, 30, 60, 90, 120, 150 and 180 minutes after intrathecal drug injection. The maximum drug dose was determined based on a preliminary study in the absence of neurological deficits. The anti-nociceptive effect of the drug was evaluated as a percentage of the maximal possible effect (% MPE).
[수학식 1][Equation 1]
% MPE= ([post drug threshold - post injured baseline threshold] / [cutoff threshold - post injured baseline threshold]) X 100.% MPE= ([post drug threshold - post injured baseline threshold] / [cutoff threshold - post injured baseline threshold]) X 100.
7. 약물 상호작용7. Drug Interactions
프레가발린과 티아넵틴 또는 클로피도그렐 사이의 약물 상호 작용을 평가하기 위해 Isobolographic 분석 및 고정 용량 분석을 수행했다(도 2). Isobolographic 분석은 약물의 등가 용량을 결정한다. 두 약물(프레가발린 및 티아넵틴)의 용량 반응 곡선에서 50 % 유효 용량(ED 50) 값이 추정되었는데, 이는 MPE를 50% 감소시킨 것이다. 그 후, 개별 약물의 ED 50을 기준으로 일정한 용량 비율로 두 약물의 조합 투여에 대한 용량 반응 곡선을 얻었다. 따라서, 티아넵틴 ED 50 + 프레가발린 ED 50, (티아넵틴 ED 50 + 프레가발린 ED 50)/2, (티아넵틴 ED 50 + 프레가발린 ED 50)/4 및 (티아넵틴 ED 50 + 프레가발린 ED 50)/8이 주입되었다. 그 후, 혼합 투여하는 경우의 각 약물의 ED 50 값을 계산하였는데, 이는 두 약물 병용 투여에 대한 용량 반응 곡선에서 50% MPE를 나타내는 혼합물에 포함된 각 약물의 용량을 의미한다.Isobolographic analysis and fixed-dose analysis were performed to evaluate drug interactions between pregabalin and tianeptine or clopidogrel (Fig. 2). Isobolographic analysis determines the equivalent dose of the drug. A 50% effective dose (ED 50 ) value was estimated from the dose response curves of both drugs (pregabalin and tianeptine), which resulted in a 50% reduction in MPE. Then, a dose response curve was obtained for the combined administration of the two drugs at a constant dose ratio based on the ED 50 of the individual drugs. Thus, tianeptine ED 50 + pregabalin ED 50 , (tianeptine ED 50 + pregabalin ED 50 )/2, (tianeptine ED 50 + pregabalin ED 50 )/4 and (tianeptine ED 50 + pregabalin ED 50 )/4 and (tianeptine ED 50 + pregabalin ED 50 ) Gabalin ED 50 )/8 was injected. Then, the ED 50 value of each drug in the case of combined administration was calculated, which means the dose of each drug included in the mixture showing 50% MPE in the dose response curve for the combined administration of the two drugs.
Isobolograms는 각 약물의 ED 50 값을 x 및 y 축에 각각 표시하여 표현했다(도 2). 두 점을 연결하는 선은 이론적인 부가적 작용 직선을 나타낸다. Isobologram 분석은 두 약물의 상호작용을 추론할 수 있는 방법으로, 혼합 투여시의 ED 50가 부가적 작용 직선상에 위치하면 두 약물 간에 부가적 작용, 아래쪽에 위치하면 상승적 작용, 그리고 위쪽에 위치하면 길항적 작용 관계를 보인다고 말할 수 있다.Isobolograms were expressed by plotting the ED 50 values of each drug on the x and y axes, respectively (Fig. 2). The line connecting the two points represents the theoretical additive action line. Isobologram analysis is a method that can infer the interaction between two drugs. When the ED 50 of mixed administration is on the additive action line, it is an additive action between the two drugs. It can be said that there is an antagonistic action relationship.
또한 상호작용의 크기를 설명하기 위해 "총 량 분율 값(total dose fraction value)"이 사용되었다. 총 량 분율 값이 1에 근접하면 두 약물 간 부가 효과(additive effect), 1보다 작으면 상승 효과(synergistic effect), 그리고 1보다 크면 길항 효과(antagonistic effect)가 있다고 말할 수 있다.The “total dose fraction value” was also used to describe the magnitude of the interaction. When the total amount fraction value approaches 1, it can be said that there is an additive effect between the two drugs, when it is less than 1, there is a synergistic effect, and when it is larger than 1, it can be said that there is an antagonistic effect.
[수학식 2][Equation 2]
총 량 분율 값 = (약물 1 + 약물 2의 ED 50) / (약물 1 단독의 ED 50) + (약물 2 + 약물 1의 ED 50) / (약물 2 단독의 ED 50).Total dose fraction value = (Drug 1 + ED 50 of Drug 2) / (ED 50 of Drug 1 alone) + (ED 50 of Drug 2 + Drug 1 alone) / (ED 50 of Drug 2 alone).
클로피도그렐만으로는 항이질통 효과가 없었기 때문에 프레가발린과 클로피도그렐의 상관 관계를 조사하기 위해 고정 용량 분석을 사용했다. 고정된 클로피도그렐 용량(300 ㎍)을 다양한 프레가발린 용량으로 척수강내에 주사했다.Because clopidogrel alone had no anti-allodynic effect, a fixed-dose assay was used to investigate the correlation between pregabalin and clopidogrel. A fixed dose of clopidogrel (300 μg) was injected intrathecally at various pregabalin doses.
8. 일반적인 행동8. General Behavior
프레가발린(3 ㎍), 티아넵틴(300 ㎍) 및 클로피도그렐(300 ㎍)의 최고 용량에서 행동 변화를 평가하기 위해 다른 쥐를 대상으로 추가 실험을 수행했다. 운동 기능에 대해 위치 반사(placing reflex), 내딛기 반사(stepping reflex) 및 정향 반사(righting reflex)를 평가했다. 각막 및 귓바퀴 반사는 각막 또는 외이도의 끈 자극에 의해 유도되었다. 행동 변화는 존재 또는 부재로 표시되었다.Additional experiments were performed in other mice to assess behavioral changes at the highest doses of pregabalin (3 μg), tianeptine (300 μg) and clopidogrel (300 μg). The placing reflex, stepping reflex, and righting reflex were evaluated for motor function. Corneal and pinna reflexes were induced by string stimulation of the cornea or external auditory meatus. Changes in behavior were indicated by presence or absence.
9. 통계 분석9. Statistical Analysis
모든 데이터는 평균 ± 표준편차로 표현된다. 용량-반응 결과는 사후 분석을 위해 Bonferroni comparison를 통한 one-way analysis of variance으로 분석되었다. 용량-반응 라인은 least-squares linear regression에 의해 맞춰졌다. ED 50 및 95 % 신뢰 구간(CI)은 Tallarida와 Murray가 설명한 방법에 따라 계산되었다. 이론적 및 실험적 ED 50 값의 차이는 t-test를 사용하여 조사되었다. P < 0.05는 통계적으로 유의한 것으로 간주되었다.All data are expressed as mean ± standard deviation. Dose-response results were analyzed by one-way analysis of variance through Bonferroni comparison for post-hoc analysis. Dose-response lines were fitted by least-squares linear regression. ED 50 and 95% confidence intervals (CI) were calculated according to the method described by Tallarida and Murray. Differences in theoretical and experimental ED 50 values were investigated using t-test. P < 0.05 was considered statistically significant.
결과result
촉각 이질통은 실험 쥐에서 L5-L6 척수 신경의 결찰 후에 유도되었다. 발 회피 역치는 < 4 g이었다. 각 약물의 최고 용량에서도 행동 변화가 관찰되지 않았다(즉, 프레가발린의 경우 3 ㎍, 티아넵틴의 경우 300 ㎍, 클로피도그렐의 경우 300 ㎍). 프레가발린과 티아넵틴은 둘 다 용량 의존적인 방식으로 기계적 회피 역치 값을 증가시켰다(도 3 및 도 4).Tactile allodynia was induced after ligation of L5-L6 spinal nerves in experimental mice. The paw avoidance threshold was <4 g. No behavioral changes were observed even at the highest dose of each drug (ie, 3 μg for pregabalin, 300 μg for tianeptine, and 300 μg for clopidogrel). Both pregabalin and tianeptine increased the mechanical avoidance threshold values in a dose-dependent manner ( FIGS. 3 and 4 ).
프레가발린과 티아넵틴의 1:1 비율은 isobolographic 분석에서 시너지 효과를 나타냈다. 실험 ED 50 및 총 분율 값은 표 1에 나와있다. 고정 클로피도그렐 용량(300 ㎍)과 프레가발린을 함께 투여한 척수강내 병용은 프레가발린 단독의 발 회피 역치 값에 영향을 미치지 않았다. 하기 표 1은 척수 신경 결찰 쥐 모델에서 둘을 병용 투여한 경우의, 티아넵틴 및 프레가발린 각각을 척수강내에 투여한 경우에 비해 감소된 ED 50 값과 이를 이용해 총 분율 값을 구한 것이다.A 1:1 ratio of pregabalin and tianeptine showed a synergistic effect in isobolographic analysis. Experimental ED 50 and total fraction values are given in Table 1. The combined intrathecal combination of a fixed dose of clopidogrel (300 μg) and pregabalin did not affect the paw avoidance threshold value of pregabalin alone. Table 1 below shows the reduced ED 50 value compared to the intrathecal administration of tianeptine and pregabalin, respectively, when the two were administered in combination in a rat model of spinal nerve ligation, and the total fraction value was obtained using the same.
약물drug ED 50 (95% CI): ㎍ED 50 (95% CI): μg 총 분율 값total fraction value
티아넵틴Tianeptine 108.80 (87.46 ~ 135.35)108.80 (87.46 to 135.35) --
프레가발린pregabalin 0.78 (0.56 ~ 1.10)0.78 (0.56 to 1.10) --
티아넵틴 *:프레가발린Tianeptine * : Pregabalin 34.33 (26.83 ~ 43.92)34.33 (26.83 ~ 43.92) 0.630.63
프레가발린 *:티아넵틴Pregabalin * : Tianeptine 0.24 (0.19 ~ 0.31)0.24 (0.19 to 0.31)
*혼합 투여 시 각 약물의 ED 50 값* ED50 value of each drug when administered in combination
두 약물의 척수강내 단독 투여 시, 티아넵틴의 ED 50은 108.80 ㎍ (CI, 87.46 ~ 135.35 ㎍)이었고, 프레가발린의 ED 50은 0.78 ㎍ (CI, 0.56 ~ 1.10 ㎍)이었고, 혼합 투여 시 티아넵틴의 ED 50은 34.33 ㎍ (CI, 26.83 ~ 43.92 ㎍)이었고, 혼합 투여 시 프레가발린의 ED 50은 0.24 ㎍ (CI, 0.19 ~ 0.31 ㎍)이었다. 이 수치를 이용하여 구한 총 분율 값(total dose fraction value)은 0.63으로 1보다 작으며, 이는 두 약물 간에 상승 효과(synergistic effect)가 있다는 것을 나타낸다.When both drugs were administered intrathecally alone, the ED 50 of tianeptine was 108.80 μg (CI, 87.46 ~ 135.35 μg), and the ED 50 of pregabalin was 0.78 μg (CI, 0.56 ~ 1.10 μg), and when administered in combination, thia The ED 50 of neptine was 34.33 μg (CI, 26.83 ~ 43.92 μg), and the ED 50 of pregabalin was 0.24 μg (CI, 0.19 ~ 0.31 μg) when administered in combination. The total dose fraction value obtained using this number is 0.63, which is less than 1, indicating that there is a synergistic effect between the two drugs.

Claims (4)

  1. 프레가발린(pregabalin) 또는 이의 약학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 약학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 치료용 약학 조성물.pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or a pharmaceutical composition for the treatment of neuropathic pain comprising a pharmaceutically acceptable salt thereof.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 신경병성 통증은 대상포진 후 신경통, 수술 후 신경병성 통증, 암에 의한 신경병성 통증, 암 치료에 의한 신경병성 통증, 약물 노출에 의한 신경병성 통증, 독성 화학물질 노출에 의한 신경병성 통증, 당뇨병성 말초 신경병증, 3차 신경통, 복합 부위 통증 증후군, 반사 교감신경 이영양증, 편두통, 환상지통, 다발성 경화증에 의한 신경병성 통증, HIV에 의한 신경병성 통증, 외상(작열통)에 의한 신경병성 통증, 좌골신경통, 손목 터널 증후군, 감염에 의한 신경병성 통증, 감염 후 신경병성 통증, 손상된 장기 기능에 의한 신경병성 통증, 혈관 질환에 의한 신경병성 통증, 대사 질환에 의한 신경병성 통증, 자가면역 질환에 의한 신경병성 통증, 신경병성 요통, 섬유근육통에 의한 신경병성 통증 또는 원인 미상(특발성) 신경병성 통증인, 신경병성 통증 치료용 약학 조성물.The neuropathic pain includes postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure-induced neuropathic pain, diabetes Sexual peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain due to multiple sclerosis, neuropathic pain due to HIV, neuropathic pain due to trauma (burning pain), sciatica Neuralgia, carpal tunnel syndrome, neuropathic pain caused by infection, post-infection neuropathic pain, neuropathic pain caused by impaired organ function, neuropathic pain caused by vascular disease, neuropathic pain caused by metabolic disease, nerve caused by autoimmune disease A pharmaceutical composition for the treatment of neuropathic pain, which is neuropathic pain, neuropathic back pain, neuropathic pain caused by fibromyalgia or unknown (idiopathic) neuropathic pain.
  3. 프레가발린(pregabalin) 또는 이의 식품학적으로 허용되는 염; 및 티아넵틴(tianeptine) 또는 이의 식품학적으로 허용되는 염을 포함하는 신경병성 통증(neuropathic pain) 개선용 건강기능식품.pregabalin or a pharmaceutically acceptable salt thereof; And tianeptine (tianeptine) or a functional food for improving neuropathic pain comprising a pharmaceutically acceptable salt thereof.
  4. 청구항 3에 있어서,4. The method according to claim 3,
    상기 신경병성 통증은 대상포진 후 신경통, 수술 후 신경병성 통증, 암에 의한 신경병성 통증, 암 치료에 의한 신경병성 통증, 약물 노출에 의한 신경병성 통증, 독성 화학물질 노출에 의한 신경병성 통증, 당뇨병성 말초 신경병증, 3차 신경통, 복합 부위 통증 증후군, 반사 교감신경 이영양증, 편두통, 환상지통, 다발성에 경화증에 의한 신경병성 통증, HIV에 의한 신경병성 통증, 외상(작열통)에 의한 신경병성 통증, 좌골신경통, 손목 터널 증후군, 감염에 의한 신경병성 통증, 감염 후 신경병성 통증, 손상된 장기 기능에 의한 신경병성 통증, 혈관 질환에 의한 신경병성 통증, 대사 질환에 의한 신경병성 통증, 자가면역 질환에 의한 신경병성 통증, 신경병성 요통, 섬유근육통에 의한 신경병성 통증 또는 원인 미상(특발성) 신경병성 통증인, 신경병성 통증 개선용 건강기능식품.The neuropathic pain includes postherpetic neuralgia, postoperative neuropathic pain, cancer-induced neuropathic pain, cancer treatment-induced neuropathic pain, drug exposure-induced neuropathic pain, toxic chemical exposure-induced neuropathic pain, diabetes mellitus Sexual peripheral neuropathy, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, migraine, phantom limb pain, neuropathic pain due to multiple sclerosis, neuropathic pain due to HIV, neuropathic pain due to trauma (burning pain), Sciatica, carpal tunnel syndrome, neuropathic pain due to infection, neuropathic pain after infection, neuropathic pain due to impaired organ function, neuropathic pain due to vascular disease, neuropathic pain due to metabolic disease, autoimmune disease Health functional food for improving neuropathic pain, which is neuropathic pain, neuropathic back pain, neuropathic pain caused by fibromyalgia or unknown (idiopathic) neuropathic pain.
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