JPWO2017209106A1 - Tipepidine oral formulation - Google Patents

Abstract

  The present invention relates to a new once or twice daily oral dose containing tipepidine or a pharmaceutically acceptable salt thereof by controlling the drug dissolution rate of tipepidine or a pharmaceutically acceptable salt thereof. A composition is provided.

Description

  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.

  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 Have also been reported for use in dementia and Alzheimer's disease (Patent Documents 1 to 9).

  Until now, tipepidine has been used as an antitussive expectorant or 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.

  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.

Special republication 2007-37258 JP2009-227631 Special republication 2007-139153 JP2012-62272 JP2011-246446 JP2013-63958 Special republication 2012-118172 JP2007-204366 JP2017-36242

  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.

  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 pharmacokinetics of tipepidine, and stably and continuously release tipepidine in the stomach to intestine. It was found that a sustained-release preparation for oral use is possible.

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 hypromellose content 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 50-100 mPa · s and at least one of 4000-100,000 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 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 a mixing mass ratio between low viscosity and 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 between low viscosity and 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 a mixing mass ratio between low viscosity and 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 during wet granulation is a solvent having a mixed 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) Resistant obsessive compulsive disorder), Parkinson's disease, dysuria, pain, dementia induced by amyloid β protein, Alzheimer's disease and the like, the composition according to any one of (1) to (20) object,
It is.

  The oral solid composition of the present invention controls the dissolution rate of tipepidine in the stomach and can stably and continuously release tipepidine from 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.

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 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. Examples of 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 with respect to the whole composition.

  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 mL 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%, preferably the test 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. 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.

  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, carboxybi One or more polymers selected from polymers selected from nil polymer, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum can be used in combination.

  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.

  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.

  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.

  Examples of the binder used in the preparation of the present invention include use of a mixture of one or more selected from the group consisting of hydroxypropylcellulose, polyvinylpyrrolidone, pullulan, starch paste, and the like.

  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.

  As the water-soluble polymer in the present invention, hypromellose or carboxyvinyl polymer is preferable, and hypromellose is more preferable.

  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 Pharmacopoeia). The preferred viscosity is 50 to 100,000 mPa · s, and more preferably 100 to 15000 mPa · s.

  The compounding quantity of the hypromellose in this invention becomes like this. Preferably, it is 3-90 mass% in an oral composition, More preferably, it is 5-60 mass%, Most preferably, it is 5-45 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.

  In order to provide more stable sustained release of the active ingredient, it is preferable to use hypromellose having a different viscosity. 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.

  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 compounding 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. 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.

  The range of 100: 0 to 0: 100 may be sufficient as the mixing mass ratio of water and ethanol which is a solvent used at the time of wet granulation. More preferably, it is the range of 100: 0-20: 80, More preferably, it is the range of 100: 0-40: 60.

  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.

  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 Hereinafter, although an Example is given and this invention is demonstrated further in detail, these do not limit this invention, You may change in the range which does not deviate from the scope of the present invention.

Examples 1 and 2
Components 1 to 4 described 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.

Examples 3 and 4
Components 1 to 5 described in Table 2 were mixed and tableted to obtain tablets.

Example 5
Components 1 to 4 listed in Table 3 were mixed, granulated with water, and then 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 described 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.

^{1) Use} of hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s in a ratio of 90:10 (ratio means mass ratio; the same applies hereinafter)
²⁾ Hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s are combined in a ratio of 50:50.

Examples 8 and 9
In Example 8, components 1 to 7 described in Table 5 were mixed and tableted to obtain tablets. About Example 9, the components 1-4 described in Table 5 were mixed, and after granulating using water, it dried and the granulated granule was prepared. Ingredients 5 to 7 listed in Table 5 were mixed with the granulated granules, 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.

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.

Examples 13 and 14
Components 1 to 4 described 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.

³⁾ Hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s are combined in a ratio of 80:20.
⁴⁾ Hypromellose with a viscosity of 100 mPa · s and 4000 mPa · s combined in a ratio of 40:60

Test Example 1: Dissolution test The dissolution properties of Examples 1 to 12 and Comparative Example 1 obtained were confirmed. Using Examples 1-12 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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  The result of Comparative Example 1 is shown in FIG. In 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.

  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).

  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).

  The results of Example 13 are 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).

  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).

  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 intestine. Tipepidine or a pharmaceutically acceptable salt thereof can be sustainedly released for oral administration. It became possible to provide it as a modified preparation.

Claims (21)

A sustained-release oral solid composition comprising tipepidine or a pharmaceutically acceptable salt thereof as an active ingredient. 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. 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. The composition according to claim 3, wherein the water-soluble polymer base is hypromellose or carboxyvinyl polymer. The composition according to claim 3, wherein the water-soluble polymer base is hypromellose. The composition according to claim 5, wherein the content of hypromellose is in the range of 5 to 90% by mass in the composition. The composition according to any one of claims 4 to 6, wherein the hypromellose is a mixture of hypromellose having different viscosities. 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. 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 of hypromellose 4000 to 15000 mPa · s. 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. 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. The composition according to any one of claims 7 to 11, wherein a mixing mass ratio between low viscosity and high viscosity of hypromellose having different viscosities is in the range of 25:75 to 90:10. The composition according to any one of claims 7 to 11, wherein a mixing mass ratio between low viscosity and high viscosity of hypromellose having different viscosities is in the range of 25:75 to 80:20. The composition according to any one of claims 7 to 11, wherein a mixing mass ratio of low viscosity and high viscosity of hypromellose having different viscosities is in the range of 40:60 to 60:40. The composition according to any one of claims 1 to 14, further comprising granules containing an excipient. The composition according to claim 15, wherein the granule is produced by wet granulation or dry granulation. The composition according to claim 16, wherein the solvent used in wet granulation is a solvent having a mixed mass ratio of water and ethanol in the range of 100: 0 to 20:80. 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. The composition according to any one of claims 1 to 18, wherein the tipepidine or a pharmaceutically acceptable salt thereof is tipepidine hibenzate. The composition according to any one of claims 1 to 19, wherein the oral solid composition is selected from tablets, capsules or granules. 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 of any one of Claims 1-20 for prevention or treatment of Parkinson's disease, dysuria, pain, dementia induced by amyloid β protein, or Alzheimer's disease.