WO2017209106A1 - Oral tipepidine preparation - Google Patents
Oral tipepidine preparation Download PDFInfo
- Publication number
- WO2017209106A1 WO2017209106A1 PCT/JP2017/020038 JP2017020038W WO2017209106A1 WO 2017209106 A1 WO2017209106 A1 WO 2017209106A1 JP 2017020038 W JP2017020038 W JP 2017020038W WO 2017209106 A1 WO2017209106 A1 WO 2017209106A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hypromellose
- composition according
- tipepidine
- range
- different viscosities
- Prior art date
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/24—Antidepressants
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a sustained-release oral preparation containing tipepidine or a pharmaceutically acceptable salt thereof, and can be applied to the pharmaceutical field.
- Tipepidine is a substance that has antitussive activity equal to or greater than that of codeine phosphate, and also has expectorant activity, and is non-narcotic, and has long been used as an antitussive expectorant and cold drug for medical and over-the-counter medicines. It is widely used.
- tipepidine suppresses G protein-coupled inwardly rectifying K ion (GIRK) channels.
- GIRK G protein-coupled inwardly rectifying K ion
- tipepidine has been used as an antitussive expectorant and cold medicine in the form of oral preparations such as tablets, powders and syrups containing tipepidine hibenzate as an active ingredient.
- Tipepidine hibenzate is effective only about a short time, about 1.3 hours after oral administration, and about 1.8 hours in plasma to reach the maximum plasma concentration, 3 times a day It has been prescribed to patients as an oral dosage form.
- tipepidine hibenzate shows good solubility in the stomach that is acidic, but because it is extremely difficult to dissolve in water, its solubility in the lower digestive tract is low due to its neutrality and low water content. Stable and sustained release is difficult in the stomach to intestine.
- An object of the present invention is to provide a new sustained release oral preparation containing tipepidine, particularly a once or twice daily sustained release oral preparation.
- the present inventors have controlled the dissolution rate of tipepidine in the stomach despite the above pharmacokinetics of tipepidine, and stably and continuously release tipepidine in the stomach to the intestine. It was found that a sustained-release preparation for oral use is possible.
- the present invention (1) A sustained-release oral solid composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient, (2) A sustained-release oral solid composition of the once or twice daily administration type comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient, (3) The composition according to (1) or (2), comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient and further containing a water-soluble polymer base, (4) The composition according to (3), wherein the water-soluble polymer base is hypromellose or carboxyvinyl polymer, (5) The composition according to (3), wherein the water-soluble polymer base is hypromellose, (6) The composition according to (5), wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition, (7) The composition according to any one of (4) to (6), wherein the hypromellose is a mixture of hypromellose having different viscosities.
- composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of at least one of hypromellose 50 to 100 mPa ⁇ s and at least one of 4000 to 100,000 mPa ⁇ s, (9) The composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of hypromellose 100 mPa ⁇ s and at least one of 4000 to 15000 mPa ⁇ s, (10) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition, (11) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 10 to 30% by mass in the composition, (12) The composition according to any one of (7) to (11), wherein the mixing mass ratio of low viscosity to high
- composition according to any one of (1) to (14), further comprising granules containing an excipient (16) The composition according to (15), wherein the granule is produced by wet granulation or dry granulation, (17) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 20:80, (18) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 40:60. (19) The composition according to any one of (1) to (18), wherein the tipepidine or a pharmaceutically acceptable salt thereof is tipepidine hibenzate.
- the oral solid composition of the present invention controls the dissolution rate of tipepidine in the stomach and can stably and continuously release tipepidine in the stomach to the intestine.
- sustained release with controlled elution rate of tipepidine or a pharmaceutically acceptable salt thereof was observed, it was administered once or twice a day in consideration of improvement of compliance. Can provide.
- Example 1 and 2 The result of the elution test of Example 1 and 2 is shown.
- the result of the elution test of Example 3 and 4 is shown.
- the result of the elution test of Examples 1 and 5 is shown.
- the result of the elution test of Example 6 and 7 is shown.
- the result of the elution test of Example 8 and 9 is shown.
- the result of the elution test of Example 9 and 10 is shown.
- the result of the elution test of Example 11 and 12 is shown.
- the result of the dissolution test of Comparative Example 1 is shown.
- the result of the elution test of the test liquid of different pH of Example 6 is shown.
- the result of the elution test of the test liquid of different pH of Example 7 is shown.
- the result of the elution test of the test liquid of different pH of Example 13 is shown.
- the result of the elution test of the test liquid of different pH of Example 14 is shown.
- One embodiment of the present invention is a sustained-release pharmaceutical composition
- a sustained-release pharmaceutical composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient.
- Tipepidine can be used as a free form or as a pharmaceutically acceptable salt of tipepidine.
- pharmaceutically acceptable salts of tipepidine include tipepidine hibenzate, tipepidine citrate, and tipepidine stearyl sulfate.
- the content of tipepidine or a pharmaceutically acceptable salt thereof is usually 10 to 50% by mass relative to the whole composition.
- sustained release means, for example, as a test solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). (1 volume of water added))
- the dissolution rate of the active ingredient at 2 hours after the start of the test is controlled to 5 to 70%. It means that the dissolution rate of the active ingredient at 2 hours after the start is controlled to 5 to 60%, more preferably the dissolution rate of the active ingredient at 6 hours after the start of the test is controlled to 30 to 80%.
- the sustained-release preparation of the present invention can be provided as granules, powders, capsules, tablets and the like by a conventional method by mixing an inert carrier as necessary.
- the inert carrier in the present invention refers to a component other than a water-soluble polymer base that is contained in a preparation together with a medicinal component but does not exhibit medicinal properties.
- an excipient, a lubricant, a disintegrant, a binder, a fluidizing agent, an antioxidant, a coating agent, a coloring agent, a corrigent, a surfactant, a plasticizer and the like are included.
- the water-soluble polymer base used in the present invention is a sustained-release base water-soluble polymer.
- the water-soluble polymer include hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succin Nate, carboxyl methyl ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, cellulose acetate phthalate, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylic copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, carboxy One or more polymers selected from polymers selected from vinyl polymers, gum arabic, sodium alginate, propylene glycol alginate, a
- excipient used in the preparation of the present invention examples include lactose, crystalline cellulose, sucrose, powdered sugar, granulated sugar, glucose, mannitol, sorbitol, corn starch, starches, gum arabic, dextrin, pullulan, and light anhydrous silicic acid. 1 type or 2 types or more selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, synthetic aluminum silicate, magnesium aluminate metasilicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate Use.
- the lubricant used in the preparation of the present invention is, for example, from the group consisting of magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate, and magnesium aluminate metasilicate.
- One type or a mixture of two or more types may be used.
- disintegrant used in the preparation of the present invention examples include crospovidone, croscarmellose sodium, carmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, crystalline cellulose, hydroxypropyl starch, corn starch, potato
- One type or two or more types selected from the group consisting of starch and partially pregelatinized starch may be used.
- binder used in the preparation of the present invention for example, one or two or more kinds selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, pullulan, starch paste and the like can be mixed and used.
- the sustained-release base of the present invention may use a fat-soluble polymer or a combination of a water-soluble polymer and a fat-soluble polymer. More preferred is a water-soluble polymer.
- the water-soluble polymer in the present invention is preferably hypromellose or carboxyvinyl polymer, more preferably hypromellose.
- Hypromellose in the present invention is synonymous with hydroxypropyl methylcellulose and is a mixed ether of cellulose methyl and hydroxypropyl.
- hypromellose having different methoxy group and hydroxypropoxy group substitution degrees can be used.
- substitution types of 1828, 2208, 2906 and 2910 see, for example, the 17th revised Japanese Pharmacopoeia page 1305), and any of them can be used in the sustained-release preparation of the present invention.
- hypromellose having various viscosities can be used.
- the viscosity of hypromellose is a value measured according to the 17th revised Japanese pharmacopoeia (displayed viscosity: 2% aqueous solution viscosity at 20 ° C of the Japanese Pharmacopeia).
- the preferred viscosity is 50 to 100,000 mPa ⁇ s, more preferably 100 to 15000 mPa ⁇ s.
- the amount of hypromellose in the present invention is preferably 3 to 90% by mass, more preferably 5 to 60% by mass, and particularly preferably 5 to 45% by mass.
- the amount of hypromellose may vary depending on the viscosity of hypromellose. For example, when the viscosity of hypromellose is 50 to 100 mPa ⁇ s, the preferable amount is 15 to 90% by mass, the more preferable amount is 35 to 90% by mass, and the more preferable amount is 35 to 60% by mass. .
- the preferable blending amount is 5 to 40% by mass, and the more preferable blending amount is 10 to 30% by mass.
- the hypromellose having different viscosities is preferably a combination of a low-viscosity hypromellose such as 50 to 100 mPa ⁇ s and a high-viscosity hypromellose such as 4000 to 100,000 mPa ⁇ s.
- the mixing mass ratio is in the range of 25:75 to 90:10, more preferably 25:75 to 80:20, still more preferably 40:60 to 60:40, and particularly preferably 50: 50.
- the viscosity of the carboxyvinyl polymer refers to the viscosity of a 0.5 mass% aqueous solution (pH 7.5), and is preferably 4000 to 39400 mPa ⁇ s.
- the blending amount of the carboxyvinyl polymer in the present invention is preferably 15 to 90% by mass in the oral composition.
- Tipepidine or a pharmaceutically acceptable salt thereof can be used in a granulated or ungranulated state with excipients.
- Hypromellose can be used in a granulated state or an ungranulated state after being mixed with tipepidine or a pharmaceutically acceptable salt thereof.
- hypromellose is preferably an oral preparation prepared by mixing tipepidine or a pharmaceutically acceptable salt thereof, granulating and then tableting.
- the mixing mass ratio of water and ethanol which is a solvent used during wet granulation, may be in the range of 100: 0 to 0: 100. More preferably, it is in the range of 100: 0 to 20:80, and still more preferably in the range of 100: 0 to 40:60.
- the sustained-release pharmaceutical composition of the present invention contains tipepidine as a G protein-coupled inward rectifying K ion. Since (GIRK) channel is suppressed, it is used for the following applications.
- Attention deficit / hyperactivity disorder depression (eg, treatment-resistant depression), bipolar disorder, schizophrenia (positive symptoms, negative symptoms, cognitive impairment), anxiety disorder, dementia (Alzheimer type, Lewy body type) ), Obsessive-compulsive disorder (for example, treatment-resistant obsessive-compulsive disorder), Parkinson's disease, dysuria, pain, and the like.
- Examples 1 and 2 Ingredients 1 to 4 listed in Table 1 were mixed, granulated with water, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 1 were mixed with the granulated granules, and tableted to obtain tablets.
- Example 5 Components 1 to 4 listed in Table 3 were mixed, granulated with water, and dried to prepare granulated granules. Ingredients 5 to 6 listed in Table 3 were mixed with the granulated granules, and tableted to obtain tablets.
- Examples 6 and 7 Components 1 to 4 listed in Table 4 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 4 were mixed with the granulated granules, and tableted to obtain tablets.
- Example 8 ingredients 1 to 7 listed in Table 5 were mixed and tableted to obtain tablets.
- ingredients 1 to 4 listed in Table 5 were mixed, granulated with water, and dried to prepare granulated granules.
- Ingredients 5 to 7 listed in Table 5 were mixed in the granulated granule and tableted.
- Example 10 Components 1 to 4 described in Table 6 were mixed, granulated using a water / ethanol (mass ratio: 20:80) mixture, and then dried to prepare granulated granules. Ingredient 5 described in Table 6 was mixed with the granulated granule and tableted to obtain a tablet.
- Example 11 the components 1 to 4 described in Table 7 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 7 were mixed with the granulated granules, and tableted to obtain tablets. In Example 12, component 8 dispersed in a solvent was coated on the tablet of Example 11 to obtain a tablet.
- Examples 13 and 14 Components 1 to 4 listed in Table 8 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 8 were mixed with the granulated granules, and tableted to obtain tablets.
- Hypromellose with a viscosity of 100 mPa ⁇ s and 4000 mPa ⁇ s are combined in a ratio of 80:20.
- Test Example 1 Dissolution Test The dissolution properties of Examples 1 to 12 and Comparative Example 1 obtained were confirmed. Using Examples 1 to 12 and Comparative Example 1, according to the dissolution test method (paddle method) of the JP General Test Method, using 900 mL of the second dissolution test solution as the test solution, automatically collecting at 50 rpm, automatic absorbance measurement The dissolution test was performed. The dissolution rate at each sampling time was determined from the measured values obtained.
- Example 1 containing hypromellose and Example 2 containing carboxyvinyl polymer showed excellent sustained release properties.
- Example 1 The results of Examples 1 and 5 are shown in FIG. As apparent from FIG. 3, the elution rate of tipepidine was controlled by changing the viscosity of hypromellose.
- Example 6 The results of Examples 6 and 7 are shown in FIG. As is apparent from FIG. 4, the elution rate of tipepidine was controlled by using a combination of hypromellose having different viscosities.
- Example 8 produced by the direct tableting method and Example 9 produced by the wet granulation method showed excellent sustained release properties of tipepidine.
- Example 9 using water as the granulating solvent and Example 10 using the water / ethanol mixture showed excellent sustained release properties of tipepidine.
- Examples 11 and 12 were shown in FIG. As is apparent from FIG. 7, Examples 11 and 12 showed excellent sustained release properties of chipepidine regardless of the presence or absence of coating.
- Comparative Example 1 The result of Comparative Example 1 is shown in FIG.
- Comparative Example 1 a commercially available asverin tablet 20 was used.
- Test Example 2 Dissolution test of test solutions having different pHs Using Examples 6, 7, 13 and 14, the dissolution test first solution (pH 1...) was added to the test solution according to the dissolution test method (paddle method) of the JP General Test Method. 2; 2.0 g of sodium chloride dissolved in 7.0 mL of hydrochloric acid and water to 1000 mL) 900 mL and dissolution test second solution 900 mL were used, and the elution test was performed by automatic collection at a rotation speed of 50 rpm and automatic absorbance measurement. . The dissolution rate at each sampling time was determined from the measured values obtained.
- Example 6 The result of Example 6 is shown in FIG. As is apparent from FIG. 9, the tablet of Example 6 using hypromellose having different viscosities showed a constant tipepidine dissolution rate regardless of the test solution (pH).
- Example 7 The result of Example 7 is shown in FIG. As is apparent from FIG. 10, the tablet of Example 7 using hypromellose having different viscosities showed a constant chipepidine dissolution rate regardless of the test solution (pH).
- Example 13 The result of Example 13 is shown in FIG. As is apparent from FIG. 11, the tablet of Example 13 using hypromellose having different viscosities showed a constant tipepidine dissolution rate regardless of the test solution (pH).
- Example 14 The results of Example 14 are shown in FIG. As is clear from FIG. 12, the tablet of Example 14 using hypromellose having different viscosities showed a constant dissolution rate of tipepidine regardless of the test solution (pH).
- the rate of dissolution of tipepidine in the stomach can be controlled, and it can be stably and continuously released in the stomach to the intestine.
- Tipepidine or a pharmaceutically acceptable salt thereof can be sustained-released for oral administration. It became possible to provide it as a modified preparation.
Abstract
The present invention provides a novel oral composition of a single or twice daily dose type, which contains tipepidine or a pharmaceutically acceptable salt thereof, wherein the drug dissolution rate of tipepidine or the pharmaceutically acceptable salt thereof is controlled.
Description
本発明は、チペピジン又は医薬的に許容されるその塩を含有する徐放性の経口用製剤に関し、医薬品の分野に応用できるものである。
The present invention relates to a sustained-release oral preparation containing tipepidine or a pharmaceutically acceptable salt thereof, and can be applied to the pharmaceutical field.
チペピジンは、コデインリン酸塩と同等又はそれ以上の鎮咳作用を有すると共に、去痰作用を併有する物質であり、しかも非麻薬性であるため医療用及び一般用医薬品の鎮咳去痰薬やかぜ薬として古くから汎用されている。
Tipepidine is a substance that has antitussive activity equal to or greater than that of codeine phosphate, and also has expectorant activity, and is non-narcotic, and has long been used as an antitussive expectorant and cold drug for medical and over-the-counter medicines. It is widely used.
近年、チペピジンが、Ｇタンパク質共役型内向き整流性Ｋイオン（ＧＩＲＫ）チャンネルを抑制することがわかり、上記の鎮咳去痰薬やかぜ薬としての用途以外に、中枢機能障害、例えば、注意欠陥・多動性障害、うつ病などの気分障害若しくは感情障害、環境化学物質等に起因する脳機能障害、強迫性障害、パーキンソン病、統合失調症、神経因性疼痛、排尿障害、アミロイドβ蛋白質により誘発される認知症、アルツハイマー病等への用途についても報告されている（特許文献１～９）。
In recent years, it has been found that tipepidine suppresses G protein-coupled inwardly rectifying K ion (GIRK) channels. In addition to its use as an antitussive expectorant and cold medicine, central dysfunction such as attention deficit Induced by mood disorders, emotional disorders such as depression, brain dysfunction caused by environmental chemicals, obsessive compulsive disorder, Parkinson's disease, schizophrenia, neuropathic pain, dysuria, amyloid β protein The use for dementia and Alzheimer's disease has also been reported (Patent Documents 1 to 9).
これまで、チペピジンは、チペピジンヒベンズ酸塩を有効成分とする錠剤、散剤、シロップ剤等の経口用製剤の形で、鎮咳去痰薬やかぜ薬として用いられている。チペピジンヒベンズ酸塩は、最高血漿中濃度に到達するのに、経口投与後約１．３時間、血漿中半減期は、約１．８時間であり、短時間しか有効ではなく、１日３回投与型の経口剤として患者に処方されてきた。
Up to now, tipepidine has been used as an antitussive expectorant and cold medicine in the form of oral preparations such as tablets, powders and syrups containing tipepidine hibenzate as an active ingredient. Tipepidine hibenzate is effective only about a short time, about 1.3 hours after oral administration, and about 1.8 hours in plasma to reach the maximum plasma concentration, 3 times a day It has been prescribed to patients as an oral dosage form.
一方、近年見出されてきた注意欠陥・多動性障害やうつ病などを適用とした予防・治療薬の用途では、その効果が安定的、持続的に作用することが望ましく、学校や職場などの外出先での服用をできるだけ控えることができる１日１回又は２回投与型の経口用製剤は服用忘れを減らすことでそれらの適用疾患に対する予防・治療効果が十分に発揮されることが期待される。また、それらの用途では、チペピジンを数か月、場合によっては数年もの長期間に渡って服用することが前提となるため、服薬コンプライアンスの向上も考慮した１日１回又は２回投与型の経口用製剤が求められる。しかしながら、チペピジンヒベンズ酸塩は、酸性である胃では良好な溶解性を示すが、水に極めて難溶であるため、中性でかつ水分の少ない消化管下部での溶解性が大きく低下するため、胃～腸において安定した持続放出が困難である。
On the other hand, in the use of prophylactic / therapeutic drugs for attention deficit / hyperactivity disorder and depression that have been found in recent years, it is desirable that the effect be stable and continuous, such as school and workplace Oral once-daily or twice-dose oral preparations that can refrain from taking them on the go as much as possible are expected to exert their preventive and therapeutic effects on their applicable diseases by reducing forgetting to take Is done. In addition, for these uses, it is assumed that chipepidine is taken for a long period of several months, and in some cases, several years. Oral formulations are sought. However, tipepidine hibenzate shows good solubility in the stomach that is acidic, but because it is extremely difficult to dissolve in water, its solubility in the lower digestive tract is low due to its neutrality and low water content. Stable and sustained release is difficult in the stomach to intestine.
本発明はチペピジンを含有する新たな徐放性の経口用製剤、特には１日１回又は２回投与型の徐放性の経口用製剤を提供することを課題とする。
An object of the present invention is to provide a new sustained release oral preparation containing tipepidine, particularly a once or twice daily sustained release oral preparation.
本発明者らは前記課題を解決すべく鋭意検討した結果、チペピジンの上記薬物動態にもかかわらず、チペピジンの胃での溶出速度を制御し、胃～腸においてチペピジンを安定に持続的に放出する経口用の徐放性製剤化が可能であることを見出した。
As a result of intensive studies to solve the above problems, the present inventors have controlled the dissolution rate of tipepidine in the stomach despite the above pharmacokinetics of tipepidine, and stably and continuously release tipepidine in the stomach to the intestine. It was found that a sustained-release preparation for oral use is possible.
即ち本発明は、
（１）チペピジン又は医薬的に許容されるその塩を有効成分として含む徐放性の経口固形組成物、
（２）チペピジン又は医薬的に許容されるその塩を有効成分として含む１日１回又は２回投与型の徐放性の経口固形組成物、
（３）チペピジン又は医薬的に許容されるその塩を有効成分とし、さらに水溶性高分子基剤を含む（１）又は（２）に記載の組成物、
（４）水溶性高分子基剤がヒプロメロース又はカルボキシビニルポリマーである（３）に記載の組成物、
（５）水溶性高分子基剤がヒプロメロースである（３）に記載の組成物、
（６）ヒプロメロースの含量が、組成物中５～９０質量％の範囲である（５）に記載の組成物、
（７）ヒプロメロースが粘度の異なるヒプロメロースの混合物である（４）～（６）のいずれか１つに記載の組成物、
（８）粘度の異なるヒプロメロースの混合物が、ヒプロメロース５０～１００ｍＰａ・ｓの少なくとも１種と４０００～１０００００ｍＰａ・ｓの少なくとも１種との組み合わせである、（７）に記載の組成物、
（９）粘度の異なるヒプロメロースの混合物が、ヒプロメロース１００ｍＰａ・ｓと４０００～１５０００ｍＰａ・ｓの少なくとも１種との組み合わせである、（７）に記載の組成物、
（１０）粘度の異なるヒプロメロースの混合物の含量が組成物中５～４５質量％の範囲である（７）～（９）のいずれか１つに記載の組成物、
（１１）粘度の異なるヒプロメロースの混合物の含量が組成物中１０～３０質量％の範囲である（７）～（９）のいずれか１つに記載の組成物、
（１２）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～９０：１０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１３）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～８０：２０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１４）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が４０：６０～６０：４０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１５）さらに賦形剤を含む顆粒を含んでなる（１）～（１４）いずれか１つに記載の組成物、
（１６）顆粒が湿式造粒又は乾式造粒で製造される（１５）に記載の組成物、
（１７）湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～２０：８０の範囲の溶媒である（１６）に記載の組成物、
（１８）湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～４０：６０の範囲の溶媒である（１６）に記載の組成物、
（１９）チペピジン又は医薬的に許容されるその塩が、チペピジンヒベンズ酸塩である（１）～（１８）のいずれか１つに記載の組成物、
（２０）経口固形組成物が、錠剤、カプセル剤及び顆粒剤から選択される（１）～（１９）のいずれか１つに記載の組成物、
（２１）咳嗽、喀痰喀出困難、注意欠陥・多動性障害、うつ病（例えば、治療抵抗性うつ病）、双極性障害、統合失調症、不安障害、認知症、強迫性障害（例えば、治療抵抗性強迫性障害）、パーキンソン病、排尿障害、疼痛、アミロイドβ蛋白質により誘発される認知症又はアルツハイマー病等の予防又は治療用の（１）～（２０）のいずれか１つに記載の組成物、
である。 That is, the present invention
(1) A sustained-release oral solid composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient,
(2) A sustained-release oral solid composition of the once or twice daily administration type comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient,
(3) The composition according to (1) or (2), comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient and further containing a water-soluble polymer base,
(4) The composition according to (3), wherein the water-soluble polymer base is hypromellose or carboxyvinyl polymer,
(5) The composition according to (3), wherein the water-soluble polymer base is hypromellose,
(6) The composition according to (5), wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition,
(7) The composition according to any one of (4) to (6), wherein the hypromellose is a mixture of hypromellose having different viscosities.
(8) The composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of at least one of hypromellose 50 to 100 mPa · s and at least one of 4000 to 100,000 mPa · s,
(9) The composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of hypromellose 100 mPa · s and at least one of 4000 to 15000 mPa · s,
(10) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition,
(11) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 10 to 30% by mass in the composition,
(12) The composition according to any one of (7) to (11), wherein the mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 25:75 to 90:10,
(13) The composition according to any one of (7) to (11), wherein a mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 25:75 to 80:20,
(14) The composition according to any one of (7) to (11), wherein the mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 40:60 to 60:40.
(15) The composition according to any one of (1) to (14), further comprising granules containing an excipient,
(16) The composition according to (15), wherein the granule is produced by wet granulation or dry granulation,
(17) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 20:80,
(18) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 40:60.
(19) The composition according to any one of (1) to (18), wherein the tipepidine or a pharmaceutically acceptable salt thereof is tipepidine hibenzate.
(20) The composition according to any one of (1) to (19), wherein the oral solid composition is selected from tablets, capsules and granules.
(21) Cough, difficulty in squeezing, attention deficit / hyperactivity disorder, depression (eg, treatment-resistant depression), bipolar disorder, schizophrenia, anxiety disorder, dementia, obsessive-compulsive disorder (eg, treatment) (1) to (20) for prevention or treatment of resistance obsessive compulsive disorder), Parkinson's disease, dysuria, pain, dementia induced by amyloid β protein, Alzheimer's disease, etc. object,
It is.
（１）チペピジン又は医薬的に許容されるその塩を有効成分として含む徐放性の経口固形組成物、
（２）チペピジン又は医薬的に許容されるその塩を有効成分として含む１日１回又は２回投与型の徐放性の経口固形組成物、
（３）チペピジン又は医薬的に許容されるその塩を有効成分とし、さらに水溶性高分子基剤を含む（１）又は（２）に記載の組成物、
（４）水溶性高分子基剤がヒプロメロース又はカルボキシビニルポリマーである（３）に記載の組成物、
（５）水溶性高分子基剤がヒプロメロースである（３）に記載の組成物、
（６）ヒプロメロースの含量が、組成物中５～９０質量％の範囲である（５）に記載の組成物、
（７）ヒプロメロースが粘度の異なるヒプロメロースの混合物である（４）～（６）のいずれか１つに記載の組成物、
（８）粘度の異なるヒプロメロースの混合物が、ヒプロメロース５０～１００ｍＰａ・ｓの少なくとも１種と４０００～１０００００ｍＰａ・ｓの少なくとも１種との組み合わせである、（７）に記載の組成物、
（９）粘度の異なるヒプロメロースの混合物が、ヒプロメロース１００ｍＰａ・ｓと４０００～１５０００ｍＰａ・ｓの少なくとも１種との組み合わせである、（７）に記載の組成物、
（１０）粘度の異なるヒプロメロースの混合物の含量が組成物中５～４５質量％の範囲である（７）～（９）のいずれか１つに記載の組成物、
（１１）粘度の異なるヒプロメロースの混合物の含量が組成物中１０～３０質量％の範囲である（７）～（９）のいずれか１つに記載の組成物、
（１２）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～９０：１０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１３）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～８０：２０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１４）粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が４０：６０～６０：４０の範囲である（７）～（１１）のいずれか１つに記載の組成物、
（１５）さらに賦形剤を含む顆粒を含んでなる（１）～（１４）いずれか１つに記載の組成物、
（１６）顆粒が湿式造粒又は乾式造粒で製造される（１５）に記載の組成物、
（１７）湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～２０：８０の範囲の溶媒である（１６）に記載の組成物、
（１８）湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～４０：６０の範囲の溶媒である（１６）に記載の組成物、
（１９）チペピジン又は医薬的に許容されるその塩が、チペピジンヒベンズ酸塩である（１）～（１８）のいずれか１つに記載の組成物、
（２０）経口固形組成物が、錠剤、カプセル剤及び顆粒剤から選択される（１）～（１９）のいずれか１つに記載の組成物、
（２１）咳嗽、喀痰喀出困難、注意欠陥・多動性障害、うつ病（例えば、治療抵抗性うつ病）、双極性障害、統合失調症、不安障害、認知症、強迫性障害（例えば、治療抵抗性強迫性障害）、パーキンソン病、排尿障害、疼痛、アミロイドβ蛋白質により誘発される認知症又はアルツハイマー病等の予防又は治療用の（１）～（２０）のいずれか１つに記載の組成物、
である。 That is, the present invention
(1) A sustained-release oral solid composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient,
(2) A sustained-release oral solid composition of the once or twice daily administration type comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient,
(3) The composition according to (1) or (2), comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient and further containing a water-soluble polymer base,
(4) The composition according to (3), wherein the water-soluble polymer base is hypromellose or carboxyvinyl polymer,
(5) The composition according to (3), wherein the water-soluble polymer base is hypromellose,
(6) The composition according to (5), wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition,
(7) The composition according to any one of (4) to (6), wherein the hypromellose is a mixture of hypromellose having different viscosities.
(8) The composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of at least one of hypromellose 50 to 100 mPa · s and at least one of 4000 to 100,000 mPa · s,
(9) The composition according to (7), wherein the mixture of hypromellose having different viscosities is a combination of hypromellose 100 mPa · s and at least one of 4000 to 15000 mPa · s,
(10) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition,
(11) The composition according to any one of (7) to (9), wherein the content of the mixture of hypromellose having different viscosities is in the range of 10 to 30% by mass in the composition,
(12) The composition according to any one of (7) to (11), wherein the mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 25:75 to 90:10,
(13) The composition according to any one of (7) to (11), wherein a mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 25:75 to 80:20,
(14) The composition according to any one of (7) to (11), wherein the mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 40:60 to 60:40.
(15) The composition according to any one of (1) to (14), further comprising granules containing an excipient,
(16) The composition according to (15), wherein the granule is produced by wet granulation or dry granulation,
(17) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 20:80,
(18) The composition according to (16), wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 40:60.
(19) The composition according to any one of (1) to (18), wherein the tipepidine or a pharmaceutically acceptable salt thereof is tipepidine hibenzate.
(20) The composition according to any one of (1) to (19), wherein the oral solid composition is selected from tablets, capsules and granules.
(21) Cough, difficulty in squeezing, attention deficit / hyperactivity disorder, depression (eg, treatment-resistant depression), bipolar disorder, schizophrenia, anxiety disorder, dementia, obsessive-compulsive disorder (eg, treatment) (1) to (20) for prevention or treatment of resistance obsessive compulsive disorder), Parkinson's disease, dysuria, pain, dementia induced by amyloid β protein, Alzheimer's disease, etc. object,
It is.
本発明の経口固形組成物は、チペピジンの胃での溶出速度を制御し、胃～腸においてチペピジンを安定に持続的に放出することができる。本発明の経口固形組成物では、チペピジン又は医薬的に許容されるその塩の溶出速度を制御した徐放化が認められたため、服薬コンプライアンスの向上を考慮した１日１回又は２回投与型製剤を提供できる。
The oral solid composition of the present invention controls the dissolution rate of tipepidine in the stomach and can stably and continuously release tipepidine in the stomach to the intestine. In the oral solid composition of the present invention, since sustained release with controlled elution rate of tipepidine or a pharmaceutically acceptable salt thereof was observed, it was administered once or twice a day in consideration of improvement of compliance. Can provide.
本発明の一つの態様は、チペピジン又は医薬的に許容されるその塩を有効成分とした徐放性医薬組成物である。
One embodiment of the present invention is a sustained-release pharmaceutical composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient.
チペピジンはフリー体としても使用可能であり、また医薬的に許容されるチペピジンの塩としても使用可能である。医薬的に許容されるチペピジンの塩としては、チペピジンヒベンズ酸塩、チペピジンクエン酸塩、チペピジンステアリル硫酸エステル塩等が挙げられる。
Tipepidine can be used as a free form or as a pharmaceutically acceptable salt of tipepidine. Examples of pharmaceutically acceptable salts of tipepidine include tipepidine hibenzate, tipepidine citrate, and tipepidine stearyl sulfate.
チペピジン又は医薬的に許容されるその塩の含有量は、組成物全体に対して通常１０～５０質量％である。
The content of tipepidine or a pharmaceutically acceptable salt thereof is usually 10 to 50% by mass relative to the whole composition.
本発明において、「徐放性」とは、例えば、日本薬局方溶出試験第２法（パドル法）により、試験液として、溶出試験第２液（ｐＨ６．８のリン酸塩緩衝液１容量に水１容量を加えたもの）９００ｍＬを用い、パドル回転数５０ｒｐｍの条件で溶出したときに、試験開始後２時間時点の有効成分の溶出率を、５～７０％に制御する、好ましくは、試験開始後２時間時点の有効成分の溶出率を、５～６０％に制御する、より好ましくは、試験開始後６時間時点の有効成分の溶出率を、３０～８０％に制御することを意味する。
In the present invention, “sustained release” means, for example, as a test solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). (1 volume of water added)) When 900 mL is used and elution is performed at a paddle rotation speed of 50 rpm, the dissolution rate of the active ingredient at 2 hours after the start of the test is controlled to 5 to 70%. It means that the dissolution rate of the active ingredient at 2 hours after the start is controlled to 5 to 60%, more preferably the dissolution rate of the active ingredient at 6 hours after the start of the test is controlled to 30 to 80%. .
本発明の徐放性製剤は、必要に応じて不活性キャリアを混合して常法により、顆粒剤、散剤、カプセル剤、錠剤等として提供することができる。本発明における不活性キャリアとは、薬効成分と共に製剤に含まれるが薬効を示さない、水溶性高分子基剤以外の成分をいう。例えば、賦形剤、滑沢剤、崩壊剤、結合剤、流動化剤、抗酸化剤、コーティング剤、着色剤、矯味剤、界面活性剤、可塑剤等がこれに含まれる。
The sustained-release preparation of the present invention can be provided as granules, powders, capsules, tablets and the like by a conventional method by mixing an inert carrier as necessary. The inert carrier in the present invention refers to a component other than a water-soluble polymer base that is contained in a preparation together with a medicinal component but does not exhibit medicinal properties. For example, an excipient, a lubricant, a disintegrant, a binder, a fluidizing agent, an antioxidant, a coating agent, a coloring agent, a corrigent, a surfactant, a plasticizer and the like are included.
本発明に用いられる水溶性高分子基剤とは、徐放性基剤の水溶性高分子であり、水溶性高分子としては、ヒプロメロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボシキメチルエチルセルロース、カルボキシルメチルセルロースナトリウム、ヒドロキシエチルセルロース、メチルセルロース、酢酸フタル酸セルロース、ポリエチレングリコール、ポリビニルアルコール、ポリビニルピロリドン、ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリルコポリマーRS、メタクリル酸コポリマーL、メタクリル酸コポリマーLD、メタクリル酸コポリマーS、カルボキシビニルポリマー、アラビアゴム、アルギン酸ナトリウム、アルギン酸プロピレングリコールエステル、寒天、ゼラチン、トラガント、キサンタンガムから選ばれる高分子から選ばれる高分子の１種又は２種以上を混合して用いることができる。
The water-soluble polymer base used in the present invention is a sustained-release base water-soluble polymer. Examples of the water-soluble polymer include hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succin Nate, carboxyl methyl ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, cellulose acetate phthalate, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylic copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, carboxy One or more polymers selected from polymers selected from vinyl polymers, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum can be used.
本発明の製剤に用いられる賦形剤としては、例えば、乳糖、結晶セルロース、白糖、粉糖、グラニュウ糖、ブドウ糖、マンニトール、ソルビトール、コーンスターチ、デンプン類、アラビアゴム、デキストリン、プルラン、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、及び無水リン酸水素カルシウムからなる群から選ばれる１種又は２種以上を混合して用いることが挙げられる。
Examples of the excipient used in the preparation of the present invention include lactose, crystalline cellulose, sucrose, powdered sugar, granulated sugar, glucose, mannitol, sorbitol, corn starch, starches, gum arabic, dextrin, pullulan, and light anhydrous silicic acid. 1 type or 2 types or more selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, synthetic aluminum silicate, magnesium aluminate metasilicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate Use.
本発明の製剤に用いられる滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、タルク、軽質無水ケイ酸、コロイドシリカ、合成ケイ酸アルミニウム、及びメタケイ酸アルミン酸マグネシウムからなる群から選ばれる１種又は２種以上を混合して用いることが挙げられる。
The lubricant used in the preparation of the present invention is, for example, from the group consisting of magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silicic acid, colloidal silica, synthetic aluminum silicate, and magnesium aluminate metasilicate. One type or a mixture of two or more types may be used.
本発明の製剤に用いられる崩壊剤としては、例えば、クロスポビドン、クロスカルメロースナトリウム、カルメロース、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースカルシウム、結晶セルロース、ヒドロキシプロピルスターチ、コーンスターチ、馬鈴薯デンプン、及び部分アルファー化デンプンからなる群から選ばれる１種又は２種以上を混合して用いることが挙げられる。
Examples of the disintegrant used in the preparation of the present invention include crospovidone, croscarmellose sodium, carmellose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, crystalline cellulose, hydroxypropyl starch, corn starch, potato One type or two or more types selected from the group consisting of starch and partially pregelatinized starch may be used.
本発明の製剤に用いられる結合剤としては、例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン、プルラン、及びデンプン糊等からなる群から選ばれる１種又は２種以上を混合して用いることが挙げられる。
As the binder used in the preparation of the present invention, for example, one or two or more kinds selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, pullulan, starch paste and the like can be mixed and used.
本発明の徐放化基剤は、水溶性高分子以外に、脂溶性高分子や水溶性高分子と脂溶性高分子との組み合わせも使用してもよい。より好ましくは水溶性高分子である。
In addition to the water-soluble polymer, the sustained-release base of the present invention may use a fat-soluble polymer or a combination of a water-soluble polymer and a fat-soluble polymer. More preferred is a water-soluble polymer.
本発明における水溶性高分子としては、ヒプロメロース又はカルボキシビニルポリマーが好ましく、ヒプロメロースがより好ましい。
The water-soluble polymer in the present invention is preferably hypromellose or carboxyvinyl polymer, more preferably hypromellose.
本発明におけるヒプロメロースとはヒドロキシプロピルメチルセルロースと同義であり、セルロースのメチル及びヒドロキシプロピルの混合エーテルである。本発明では、ヒプロメロースとしてメトキシ基及びヒドロキシプロポキシ基の置換度が異なる物を利用することができる。ヒプロメロースには、その代表例として１８２８、２２０８、２９０６及び２９１０の置換度タイプがあり（例えば第１７改正日本薬局方１３０５頁参照）、いずれも本発明の徐放性製剤に使用可能である。また、種々の粘度のヒプロメロースが使用可能である。ここで、ヒプロメロースの粘度とは、第１７改正日本薬局方にしたがって測定される値（表示粘度：日本薬局方２０ ℃ における ２ % 水溶液粘度をいう）である。好ましい粘度は５０～１０００００ｍＰａ・ｓであり、より好ましくは、１００～１５０００ｍＰａ・ｓである。
Hypromellose in the present invention is synonymous with hydroxypropyl methylcellulose and is a mixed ether of cellulose methyl and hydroxypropyl. In the present invention, hypromellose having different methoxy group and hydroxypropoxy group substitution degrees can be used. As representative examples of hypromellose, there are substitution types of 1828, 2208, 2906 and 2910 (see, for example, the 17th revised Japanese Pharmacopoeia page 1305), and any of them can be used in the sustained-release preparation of the present invention. In addition, hypromellose having various viscosities can be used. Here, the viscosity of hypromellose is a value measured according to the 17th revised Japanese pharmacopoeia (displayed viscosity: 2% aqueous solution viscosity at 20 ° C of the Japanese Pharmacopeia). The preferred viscosity is 50 to 100,000 mPa · s, more preferably 100 to 15000 mPa · s.
本発明におけるヒプロメロースの配合量は、経口組成物中、好ましくは、３～９０質量％であり、より好ましくは５～６０質量％であり、特に好ましくは５～４５質量％である。ヒプロメロースの配合量は、ヒプロメロースの粘度により変動する場合もある。例えば、ヒプロメロースの粘度が５０～１００ｍＰａ・ｓにおいて、好ましい配合量は１５～９０質量％であり、より好ましい配合量は３５～９０質量％であり、さらに好ましい配合量は３５～６０質量％である。粘度が４０００～１０００００ｍＰａ・ｓ、例えば４０００、１５０００、１０００００ｍＰａ・ｓにおいて、好ましい配合量は５～４０質量％であり、より好ましい配合量は、１０～３０質量％である。
In the oral composition, the amount of hypromellose in the present invention is preferably 3 to 90% by mass, more preferably 5 to 60% by mass, and particularly preferably 5 to 45% by mass. The amount of hypromellose may vary depending on the viscosity of hypromellose. For example, when the viscosity of hypromellose is 50 to 100 mPa · s, the preferable amount is 15 to 90% by mass, the more preferable amount is 35 to 90% by mass, and the more preferable amount is 35 to 60% by mass. . When the viscosity is 4000 to 100000 mPa · s, for example, 4000, 15000, and 100000 mPa · s, the preferable blending amount is 5 to 40% by mass, and the more preferable blending amount is 10 to 30% by mass.
また、有効成分のより安定した徐放性を提供するためには、粘度の異なるヒプロメロースを用いることが好ましい。粘度の異なるヒプロメロースとは、例えば、５０～１００ｍＰａ・ｓのような低粘度ヒプロメロースと４０００～１０００００ｍＰａ・ｓのような高粘度ヒプロメロースとを組み合わせて用いることが好ましく、低粘度ヒプロメロースと高粘度ヒプロメロースとの混合質量比は２５：７５～９０：１０の範囲であり、より好ましくは、２５：７５～８０：２０であり、さらに好ましくは、４０：６０～６０：４０であり、特に好ましくは、５０：５０である。低粘度ヒプロメロースと高粘度ヒプロメロースとを上記の特定の混合比で用いることによって、有効成分の非常に安定した徐放性を達成することができる。
In order to provide more stable sustained release of the active ingredient, it is preferable to use hypromellose having different viscosities. The hypromellose having different viscosities is preferably a combination of a low-viscosity hypromellose such as 50 to 100 mPa · s and a high-viscosity hypromellose such as 4000 to 100,000 mPa · s. The mixing mass ratio is in the range of 25:75 to 90:10, more preferably 25:75 to 80:20, still more preferably 40:60 to 60:40, and particularly preferably 50: 50. By using low-viscosity hypromellose and high-viscosity hypromellose in the above specific mixing ratio, it is possible to achieve very stable sustained release of the active ingredient.
カルボキシビニルポリマーの粘度は、０．５質量％水溶液（ｐＨ７．５）の粘度をいい、好ましくは、４０００～３９４００ｍＰａ・ｓである。本発明におけるカルボキシビニルポリマーの配合量は、経口組成物中、好ましくは、１５～９０質量％である。
The viscosity of the carboxyvinyl polymer refers to the viscosity of a 0.5 mass% aqueous solution (pH 7.5), and is preferably 4000 to 39400 mPa · s. The blending amount of the carboxyvinyl polymer in the present invention is preferably 15 to 90% by mass in the oral composition.
チペピジン又は医薬的に許容されるその塩は賦形剤とともに造粒した状態でも未造粒の状態でも使用可能である。またヒプロメロースはチペピジン又は医薬的に許容されるその塩とともに混合した後、造粒した状態でも未造粒の状態でも使用可能である。例えば、製造方法の違いにかかわらず十分な徐放化が認められる。より好ましくは、ヒプロメロースはチペピジン又は医薬的に許容されるその塩を混合し、造粒後、打錠して製造された経口製剤が好ましい。
Tipepidine or a pharmaceutically acceptable salt thereof can be used in a granulated or ungranulated state with excipients. Hypromellose can be used in a granulated state or an ungranulated state after being mixed with tipepidine or a pharmaceutically acceptable salt thereof. For example, sufficient sustained release is observed regardless of the production method. More preferably, hypromellose is preferably an oral preparation prepared by mixing tipepidine or a pharmaceutically acceptable salt thereof, granulating and then tableting.
湿式造粒時に使用する溶媒である水とエタノールとの混合質量比は、１００：０～０：１００の範囲でもよい。より好ましくは１００：０～２０：８０の範囲であり、さらに好ましくは１００：０～４０：６０の範囲である。
The mixing mass ratio of water and ethanol, which is a solvent used during wet granulation, may be in the range of 100: 0 to 0: 100. More preferably, it is in the range of 100: 0 to 20:80, and still more preferably in the range of 100: 0 to 40:60.
本発明の徐放性医薬組成物は、咳嗽、喀痰喀出困難等の予防又は治療のために、鎮咳去痰剤やかぜ薬として用いる以外にも、チペピジンが、Ｇタンパク質共役型内向き整流性Ｋイオン（ＧＩＲＫ）チャンネルを抑制することから、下記用途に用いられる。
In addition to being used as an antitussive expectorant or a cold medicine for the prevention or treatment of coughing, difficulty in erecting, etc., the sustained-release pharmaceutical composition of the present invention contains tipepidine as a G protein-coupled inward rectifying K ion. Since (GIRK) channel is suppressed, it is used for the following applications.
注意欠陥・多動性障害、うつ病（例えば、治療抵抗性うつ病）、双極性障害、統合失調症（陽性症状、陰性症状、認知障害）、不安障害、認知症（アルツハイマー型、レビー小体型）、強迫性障害（例えば、治療抵抗性強迫性障害）、パーキンソン病、排尿障害、疼痛等の予防又は治療薬としても使用可能である。
Attention deficit / hyperactivity disorder, depression (eg, treatment-resistant depression), bipolar disorder, schizophrenia (positive symptoms, negative symptoms, cognitive impairment), anxiety disorder, dementia (Alzheimer type, Lewy body type) ), Obsessive-compulsive disorder (for example, treatment-resistant obsessive-compulsive disorder), Parkinson's disease, dysuria, pain, and the like.
以下、実施例を挙げて本発明を更に詳細に説明するが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
Hereinafter, the present invention will be described in more detail with reference to examples, but these are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
実施例１及び２
表１に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表１に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 1 and 2
Ingredients 1 to 4 listed in Table 1 were mixed, granulated with water, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 1 were mixed with the granulated granules, and tableted to obtain tablets.
表１に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表１に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 1 and 2
Ingredients 1 to 4 listed in Table 1 were mixed, granulated with water, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 1 were mixed with the granulated granules, and tableted to obtain tablets.
実施例３及び４
表２に記載した成分１～５を混合し、打錠して錠剤を得た。 Examples 3 and 4
Ingredients 1 to 5 listed in Table 2 were mixed and compressed into tablets.
表２に記載した成分１～５を混合し、打錠して錠剤を得た。 Examples 3 and 4
Ingredients 1 to 5 listed in Table 2 were mixed and compressed into tablets.
実施例５
表３に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表３に記載した成分５～６を混合し、打錠して錠剤を得た。 Example 5
Components 1 to 4 listed in Table 3 were mixed, granulated with water, and dried to prepare granulated granules. Ingredients 5 to 6 listed in Table 3 were mixed with the granulated granules, and tableted to obtain tablets.
表３に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表３に記載した成分５～６を混合し、打錠して錠剤を得た。 Example 5
Components 1 to 4 listed in Table 3 were mixed, granulated with water, and dried to prepare granulated granules. Ingredients 5 to 6 listed in Table 3 were mixed with the granulated granules, and tableted to obtain tablets.
実施例６及び７
表４に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表４に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 6 and 7
Components 1 to 4 listed in Table 4 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 4 were mixed with the granulated granules, and tableted to obtain tablets.
表４に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表４に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 6 and 7
Components 1 to 4 listed in Table 4 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 4 were mixed with the granulated granules, and tableted to obtain tablets.
2)粘度１００ｍＰａ・ｓと４０００ｍＰａ・ｓのヒプロメロースを５０：５０の比率で組み合わせて使用
2) Hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s are combined in a ratio of 50:50.
実施例８及び９
実施例８については表５に記載した成分１～７を混合し、打錠して錠剤を得た。実施例９については表５に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒を調製した。造粒顆粒に、表５に記載した成分５～７を混合し、打錠した。 Examples 8 and 9
For Example 8, ingredients 1 to 7 listed in Table 5 were mixed and tableted to obtain tablets. For Example 9, ingredients 1 to 4 listed in Table 5 were mixed, granulated with water, and dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 5 were mixed in the granulated granule and tableted.
実施例８については表５に記載した成分１～７を混合し、打錠して錠剤を得た。実施例９については表５に記載した成分１～４を混合し、水を用いて造粒後、乾燥し、造粒顆粒を調製した。造粒顆粒に、表５に記載した成分５～７を混合し、打錠した。 Examples 8 and 9
For Example 8, ingredients 1 to 7 listed in Table 5 were mixed and tableted to obtain tablets. For Example 9, ingredients 1 to 4 listed in Table 5 were mixed, granulated with water, and dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 5 were mixed in the granulated granule and tableted.
実施例１０
表６に記載した成分１～４を混合し、水／エタノール（質量比：２０：８０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表６に記載した成分５を混合し、打錠して錠剤を得た。 Example 10
Components 1 to 4 described in Table 6 were mixed, granulated using a water / ethanol (mass ratio: 20:80) mixture, and then dried to prepare granulated granules. Ingredient 5 described in Table 6 was mixed with the granulated granule and tableted to obtain a tablet.
表６に記載した成分１～４を混合し、水／エタノール（質量比：２０：８０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表６に記載した成分５を混合し、打錠して錠剤を得た。 Example 10
Components 1 to 4 described in Table 6 were mixed, granulated using a water / ethanol (mass ratio: 20:80) mixture, and then dried to prepare granulated granules. Ingredient 5 described in Table 6 was mixed with the granulated granule and tableted to obtain a tablet.
実施例１１及び１２
実施例１１は、表７に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒を調製した。造粒顆粒に、表７に記載した成分５～７を混合し、打錠して錠剤を得た。実施例１２は、溶媒に分散させた成分８を実施例１１の錠剤にコーティングし、錠剤を得た。 Examples 11 and 12
In Example 11, the components 1 to 4 described in Table 7 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 7 were mixed with the granulated granules, and tableted to obtain tablets. In Example 12,component 8 dispersed in a solvent was coated on the tablet of Example 11 to obtain a tablet.
実施例１１は、表７に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒を調製した。造粒顆粒に、表７に記載した成分５～７を混合し、打錠して錠剤を得た。実施例１２は、溶媒に分散させた成分８を実施例１１の錠剤にコーティングし、錠剤を得た。 Examples 11 and 12
In Example 11, the components 1 to 4 described in Table 7 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 7 were mixed with the granulated granules, and tableted to obtain tablets. In Example 12,
実施例１３及び１４
表８に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表８に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 13 and 14
Components 1 to 4 listed in Table 8 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 8 were mixed with the granulated granules, and tableted to obtain tablets.
表８に記載した成分１～４を混合し、水／エタノール（質量比：５０：５０）混液を用いて造粒後、乾燥し、造粒顆粒をそれぞれ調製した。造粒顆粒に、表８に記載した成分５～７を混合し、打錠して錠剤を得た。 Examples 13 and 14
Components 1 to 4 listed in Table 8 were mixed, granulated using a water / ethanol (mass ratio: 50:50) mixture, and then dried to prepare granulated granules. Ingredients 5 to 7 listed in Table 8 were mixed with the granulated granules, and tableted to obtain tablets.
4)粘度１００ｍＰａ・ｓと４０００ｍＰａ・ｓのヒプロメロースを４０：６０の比率で組み合わせて使用
4) Hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s combined in a ratio of 40:60
試験例１：溶出試験
得られた実施例１～１２及び比較例１について溶出性を確認した。実施例１～１２及び比較例１を用い、日局一般試験法の溶出試験法（パドル法）に従い、試験液に溶出試験第２液９００ｍＬを使用し、回転数５０ｒｐｍで自動採取、自動吸光度測定により溶出試験を行った。得られた測定値から各採取時間における溶出率を求めた。 Test Example 1: Dissolution Test The dissolution properties of Examples 1 to 12 and Comparative Example 1 obtained were confirmed. Using Examples 1 to 12 and Comparative Example 1, according to the dissolution test method (paddle method) of the JP General Test Method, using 900 mL of the second dissolution test solution as the test solution, automatically collecting at 50 rpm, automatic absorbance measurement The dissolution test was performed. The dissolution rate at each sampling time was determined from the measured values obtained.
得られた実施例１～１２及び比較例１について溶出性を確認した。実施例１～１２及び比較例１を用い、日局一般試験法の溶出試験法（パドル法）に従い、試験液に溶出試験第２液９００ｍＬを使用し、回転数５０ｒｐｍで自動採取、自動吸光度測定により溶出試験を行った。得られた測定値から各採取時間における溶出率を求めた。 Test Example 1: Dissolution Test The dissolution properties of Examples 1 to 12 and Comparative Example 1 obtained were confirmed. Using Examples 1 to 12 and Comparative Example 1, according to the dissolution test method (paddle method) of the JP General Test Method, using 900 mL of the second dissolution test solution as the test solution, automatically collecting at 50 rpm, automatic absorbance measurement The dissolution test was performed. The dissolution rate at each sampling time was determined from the measured values obtained.
実施例１及び２の結果を図１に示す。図１から明らかな通り、ヒプロメロースを含有した実施例１及びカルボキシビニルポリマーを含有した実施例２は、優れた徐放性を示した。
The results of Examples 1 and 2 are shown in FIG. As is apparent from FIG. 1, Example 1 containing hypromellose and Example 2 containing carboxyvinyl polymer showed excellent sustained release properties.
実施例３及び４の結果を図２に示す。図２から明らかな通り、ヒプロメロースの含量を変更することで、チペピジンの溶出速度を制御した。
The results of Examples 3 and 4 are shown in FIG. As apparent from FIG. 2, the elution rate of tipepidine was controlled by changing the content of hypromellose.
実施例１及び５の結果を図３に示す。図３から明らかな通り、ヒプロメロースの粘度を変更することで、チペピジンの溶出速度を制御した。
The results of Examples 1 and 5 are shown in FIG. As apparent from FIG. 3, the elution rate of tipepidine was controlled by changing the viscosity of hypromellose.
実施例６及び７の結果を図４に示す。図４から明らかな通り、粘度の異なるヒプロメロースを組み合わせて使用することで、チペピジンの溶出速度を制御した。
The results of Examples 6 and 7 are shown in FIG. As is apparent from FIG. 4, the elution rate of tipepidine was controlled by using a combination of hypromellose having different viscosities.
実施例８及び９の結果を図５に示す。図５から明らかな通り、直接打錠法で製造した実施例８及び湿式造粒法で製造した実施例９は、チペピジンの優れた徐放性を示した。
The results of Examples 8 and 9 are shown in FIG. As is apparent from FIG. 5, Example 8 produced by the direct tableting method and Example 9 produced by the wet granulation method showed excellent sustained release properties of tipepidine.
実施例９及び１０の結果を図６に示す。図６から明らかな通り、造粒溶媒に水を用いた実施例９及び水／エタノール混液を用いた実施例１０は、チペピジンの優れた徐放性を示した。
The results of Examples 9 and 10 are shown in FIG. As is apparent from FIG. 6, Example 9 using water as the granulating solvent and Example 10 using the water / ethanol mixture showed excellent sustained release properties of tipepidine.
実施例１１及び１２の結果を図７に示す。図７から明らかな通り、コーティングの有無に関わらず実施例１１及び１２はチペピジンの優れた徐放性を示した。
The results of Examples 11 and 12 are shown in FIG. As is apparent from FIG. 7, Examples 11 and 12 showed excellent sustained release properties of chipepidine regardless of the presence or absence of coating.
比較例１の結果を図８に示す。比較例１には市販のアスベリン錠２０を用いた。
The result of Comparative Example 1 is shown in FIG. In Comparative Example 1, a commercially available asverin tablet 20 was used.
試験例２：異なるｐＨの試験液の溶出試験
実施例６、７、１３及び１４を用い、日局一般試験法の溶出試験法（パドル法）に従い、試験液に溶出試験第１液（ｐＨ１．２；塩化ナトリウム２．０ｇを塩酸７．０ｍＬ及び水に溶かして１０００ｍＬにしたもの）９００ｍＬ及び溶出試験第２液９００ｍＬを使用し、回転数５０ｒｐｍで自動採取、自動吸光度測定により溶出試験を行った。得られた測定値から各採取時間における溶出率を求めた。 Test Example 2: Dissolution test of test solutions having different pHs Using Examples 6, 7, 13 and 14, the dissolution test first solution (pH 1...) Was added to the test solution according to the dissolution test method (paddle method) of the JP General Test Method. 2; 2.0 g of sodium chloride dissolved in 7.0 mL of hydrochloric acid and water to 1000 mL) 900 mL and dissolution test second solution 900 mL were used, and the elution test was performed by automatic collection at a rotation speed of 50 rpm and automatic absorbance measurement. . The dissolution rate at each sampling time was determined from the measured values obtained.
実施例６、７、１３及び１４を用い、日局一般試験法の溶出試験法（パドル法）に従い、試験液に溶出試験第１液（ｐＨ１．２；塩化ナトリウム２．０ｇを塩酸７．０ｍＬ及び水に溶かして１０００ｍＬにしたもの）９００ｍＬ及び溶出試験第２液９００ｍＬを使用し、回転数５０ｒｐｍで自動採取、自動吸光度測定により溶出試験を行った。得られた測定値から各採取時間における溶出率を求めた。 Test Example 2: Dissolution test of test solutions having different pHs Using Examples 6, 7, 13 and 14, the dissolution test first solution (pH 1...) Was added to the test solution according to the dissolution test method (paddle method) of the JP General Test Method. 2; 2.0 g of sodium chloride dissolved in 7.0 mL of hydrochloric acid and water to 1000 mL) 900 mL and dissolution test second solution 900 mL were used, and the elution test was performed by automatic collection at a rotation speed of 50 rpm and automatic absorbance measurement. . The dissolution rate at each sampling time was determined from the measured values obtained.
実施例６の結果を図９に示す。図９から明らかな通り、粘度の異なるヒプロメロースを用いた実施例６の錠剤は、試験液（pH）によらず一定のチペピジンの溶出速度を示した。
The result of Example 6 is shown in FIG. As is apparent from FIG. 9, the tablet of Example 6 using hypromellose having different viscosities showed a constant tipepidine dissolution rate regardless of the test solution (pH).
実施例７の結果を図１０に示す。図１０から明らかな通り、粘度の異なるヒプロメロースを用いた実施例７の錠剤は、試験液（pH）によらず一定のチペピジンの溶出速度を示した。
The result of Example 7 is shown in FIG. As is apparent from FIG. 10, the tablet of Example 7 using hypromellose having different viscosities showed a constant chipepidine dissolution rate regardless of the test solution (pH).
実施例１３の結果を図１１に示す。図１１から明らかな通り、粘度の異なるヒプロメロースを用いた実施例１３の錠剤は、試験液（pH）によらず一定のチペピジンの溶出速度を示した。
The result of Example 13 is shown in FIG. As is apparent from FIG. 11, the tablet of Example 13 using hypromellose having different viscosities showed a constant tipepidine dissolution rate regardless of the test solution (pH).
実施例１４の結果を図１２に示す。図１２から明らかな通り、粘度の異なるヒプロメロースを用いた実施例１４の錠剤は、試験液（pH）によらず一定のチペピジンの溶出速度を示した。
The results of Example 14 are shown in FIG. As is clear from FIG. 12, the tablet of Example 14 using hypromellose having different viscosities showed a constant dissolution rate of tipepidine regardless of the test solution (pH).
本発明により、チペピジンの胃での溶出速度を制御し、胃～腸においてチペピジンを安定に持続的に放出することができ、チペピジン又は医薬的に許容されるその塩を、経口投与用の徐放化製剤として提供することが可能となった。
According to the present invention, the rate of dissolution of tipepidine in the stomach can be controlled, and it can be stably and continuously released in the stomach to the intestine. Tipepidine or a pharmaceutically acceptable salt thereof can be sustained-released for oral administration. It became possible to provide it as a modified preparation.
Claims (21)
- チペピジン又は医薬的に許容されるその塩を有効成分として含む徐放性の経口固形組成物。 A sustained-release oral solid composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient.
- チペピジン又は医薬的に許容されるその塩を有効成分として含む１日１回又は２回投与型の徐放性の経口固形組成物。 A sustained-release oral solid composition that is administered once or twice a day, containing tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient.
- チペピジン又は医薬的に許容されるその塩を有効成分とし、さらに水溶性高分子基剤を含む請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient and further containing a water-soluble polymer base.
- 水溶性高分子基剤がヒプロメロース又はカルボキシビニルポリマーである請求項３に記載の組成物。 The composition according to claim 3, wherein the water-soluble polymer base is hypromellose or carboxyvinyl polymer.
- 水溶性高分子基剤がヒプロメロースである請求項３に記載の組成物。 The composition according to claim 3, wherein the water-soluble polymer base is hypromellose.
- ヒプロメロースの含量が、組成物中５～９０質量％の範囲である請求項５に記載の組成物。 The composition according to claim 5, wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition.
- ヒプロメロースが粘度の異なるヒプロメロースの混合物である請求項４～６のいずれか１項に記載の組成物。 The composition according to any one of claims 4 to 6, wherein the hypromellose is a mixture of hypromellose having different viscosities.
- 粘度の異なるヒプロメロースの混合物が、ヒプロメロース５０～１００ｍＰａ・ｓの少なくとも１種とヒプロメロース４０００～１０００００ｍＰａ・ｓの少なくとも１種との組み合わせである、請求項７に記載の組成物。 The composition according to claim 7, wherein the mixture of hypromellose having different viscosities is a combination of at least one of hypromellose 50 to 100 mPa · s and at least one of hypromellose 4000 to 100,000 mPa · s.
- 粘度の異なるヒプロメロースの混合物が、ヒプロメロース１００ｍＰａ・ｓとヒプロメロース４０００～１５０００ｍＰａ・ｓの少なくとも１種との組み合わせである、請求項７記載の組成物。 The composition according to claim 7, wherein the mixture of hypromellose having different viscosities is a combination of hypromellose 100 mPa · s and at least one hypromellose 4000 to 15000 mPa · s.
- 粘度の異なるヒプロメロースの混合物の含量が組成物中５～４５質量％の範囲である請求項７～９のいずれか１項に記載の組成物。 The composition according to any one of claims 7 to 9, wherein the content of the mixture of hypromellose having different viscosities is in the range of 5 to 45% by mass in the composition.
- 粘度の異なるヒプロメロースの混合物の含量が組成物中１０～３０質量％の範囲である請求項７～９のいずれか１項に記載の組成物。 The composition according to any one of claims 7 to 9, wherein the content of the mixture of hypromellose having different viscosities is in the range of 10 to 30% by mass in the composition.
- 粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～９０：１０の範囲である請求項７～１１のいずれか１項に記載の組成物。 The composition according to any one of claims 7 to 11, wherein the mixing mass ratio between low viscosity and high viscosity of hypromellose having different viscosities is in the range of 25:75 to 90:10.
- 粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が２５：７５～８０：２０の範囲である請求項７～１１のいずれか１項に記載の組成物。 The composition according to any one of claims 7 to 11, wherein the mixing mass ratio between low viscosity and high viscosity of hypromellose having different viscosities is in the range of 25:75 to 80:20.
- 粘度の異なるヒプロメロースの低粘度と高粘度との混合質量比が４０：６０～６０：４０の範囲である請求項７～１１のいずれか１項に記載の組成物。 The composition according to any one of claims 7 to 11, wherein a mixing mass ratio of low viscosity to high viscosity of hypromellose having different viscosities is in the range of 40:60 to 60:40.
- さらに賦形剤を含む顆粒を含んでなる請求項１～１４いずれか１項に記載の組成物。 The composition according to any one of claims 1 to 14, further comprising granules containing an excipient.
- 顆粒が湿式造粒又は乾式造粒で製造される請求項１５に記載の組成物。 The composition according to claim 15, wherein the granule is produced by wet granulation or dry granulation.
- 湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～２０：８０の範囲の溶媒である請求項１６に記載の組成物。 The composition according to claim 16, wherein the solvent used in the wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 20:80.
- 湿式造粒時に使用する溶媒が、水とエタノールとの混合質量比が１００：０～４０：６０の範囲の溶媒である請求項１６に記載の組成物。 The composition according to claim 16, wherein the solvent used in wet granulation is a solvent having a mixing mass ratio of water and ethanol in the range of 100: 0 to 40:60.
- チペピジン又は医薬的に許容されるその塩が、チペピジンヒベンズ酸塩である請求項１～１８のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 18, wherein the tipepidine or a pharmaceutically acceptable salt thereof is tipepidine hibenzate.
- 経口固形組成物が、錠剤、カプセル剤又は顆粒剤から選択される請求項１～１９のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 19, wherein the oral solid composition is selected from tablets, capsules or granules.
- 咳嗽、喀痰喀出困難、注意欠陥・多動性障害、うつ病（治療抵抗性うつ病を含む）、双極性障害、統合失調症、不安障害、認知症、強迫性障害（治療抵抗性強迫性障害を含む）、パーキンソン病、排尿障害、疼痛、アミロイドβ蛋白質により誘発される認知症又はアルツハイマー病の予防又は治療用の請求項１～２０のいずれか１項に記載の組成物。
Cough, difficulty in ejaculation, attention deficit / hyperactivity disorder, depression (including treatment-resistant depression), bipolar disorder, schizophrenia, anxiety disorder, dementia, obsessive-compulsive disorder (treatment-resistant obsessive-compulsive disorder) The composition according to any one of claims 1 to 20, for use in the prevention or treatment of Parkinson's disease, dysuria, pain, dementia induced by amyloid β protein, or Alzheimer's disease.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SG11201810308TA SG11201810308TA (en) | 2016-05-30 | 2017-05-30 | Oral tipepidine preparation |
| JP2018518663A JP6380922B2 (en) | 2016-05-30 | 2017-05-30 | Tipepidine oral formulation |
| KR1020187035519A KR20180137566A (en) | 2016-05-30 | 2017-05-30 | Oral formulations of tipepidine |
| PH12018502490A PH12018502490A1 (en) | 2016-05-30 | 2018-11-26 | Oral tipepidine preparation |
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| JP2016-107387 | 2016-05-30 | ||
| JP2016107387 | 2016-05-30 |
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| PCT/JP2017/020038 WO2017209106A1 (en) | 2016-05-30 | 2017-05-30 | Oral tipepidine preparation |
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| JP (1) | JP6380922B2 (en) |
| KR (1) | KR20180137566A (en) |
| PH (1) | PH12018502490A1 (en) |
| SG (1) | SG11201810308TA (en) |
| TW (1) | TW201803564A (en) |
| WO (1) | WO2017209106A1 (en) |
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-
2017
- 2017-05-30 KR KR1020187035519A patent/KR20180137566A/en not_active Application Discontinuation
- 2017-05-30 SG SG11201810308TA patent/SG11201810308TA/en unknown
- 2017-05-30 JP JP2018518663A patent/JP6380922B2/en not_active Expired - Fee Related
- 2017-05-30 WO PCT/JP2017/020038 patent/WO2017209106A1/en active Application Filing
- 2017-05-31 TW TW106117949A patent/TW201803564A/en unknown
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- 2018-11-26 PH PH12018502490A patent/PH12018502490A1/en unknown
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| JP6380922B2 (en) | 2018-08-29 |
| KR20180137566A (en) | 2018-12-27 |
| PH12018502490A1 (en) | 2019-09-30 |
| JPWO2017209106A1 (en) | 2018-07-19 |
| SG11201810308TA (en) | 2018-12-28 |
| TW201803564A (en) | 2018-02-01 |
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