WO2006046560A1

WO2006046560A1 - Propiverine-containing oral particulate preparation and process for producing the same

Info

Publication number: WO2006046560A1
Application number: PCT/JP2005/019602
Authority: WO
Inventors: Tetsuo Ogata; Atsuo Koide
Original assignee: Taiho Pharmaceutical Co., Ltd.
Priority date: 2004-10-29
Filing date: 2005-10-25
Publication date: 2006-05-04
Also published as: JPWO2006046560A1; JP4895819B2; TW200621309A

Abstract

It is intended to produce an oral preparation that contains generally procurable propiverine hydrochloride as a medicinal ingredient, and that ensures good sensation upon administration thereof, thereby avoiding any lowering of patients’ dosing compliance. A particulate preparation ensuring good sensation upon administration thereof can be produced by obtaining a suspension resulting from mixing of propiverine hydrochloride, a surfactant, a pH adjusting agent and water and having its pH value adjusted so as to fall within the range of 6.5 to 8.0 with the pH adjusting agent, and subsequently granulating the suspension together with common additives for preparation.

Description

Specification

Propiverine-containing oral powder granular preparation and its production method

Technical field

[0001] The present invention relates to an oral powder granular preparation containing propiverine and a method for producing the same.

Background art

[0002] Propiverine has the following structure and exerts an anti-cholinergic action and a smooth muscle direct action to exert an effect of suppressing micturition, and neurogenic bladder, neurogenic urination, unstable bladder, bladder-stimulated state (chronic bladder It is useful as a medicine that exhibits excellent effects on urinary incontinence and frequent urination associated with inflammation (chronic prostatitis) (Japanese Patent Publication No. 62-51242).

[0003] [Chemical 1]

[0004] Hydrochloride of propiverine, that is, propiverine hydrochloride, is water-soluble (512mg / mL, 37 ° C) and has an unpleasant taste (severe bitterness with irritation) when taken. Pills are sold! Speak.

[0005] However, for patients suffering from urinary incontinence, frequent urination, etc., compliance with tablets tends to decrease due to dysphagia associated with aging.

[0006] In clinical practice, for patients who have difficulty swallowing tablets (especially elderly people), in order to improve medication compliance, a method of crushing tablets and taking them as powders may be employed. However, when this technique is used on tablets that have been coated to mask unpleasant taste, the pulverized powder is very unpleasant because the coating film is destroyed by the grinding operation and loses the masking effect. It may be tasty and consequently reduce patient compliance. [0007] On the other hand, as a technique for masking the unpleasant taste of oral powdered granular preparations such as granules, fine granules and powders of drugs having an unpleasant taste, (1) a film coating method, (2) Methods of blending sweeteners such as sugar, saccharin and aspartame are known.

[0008] However, in the preparation produced by the above method (1), the particles become hard due to the coating, and therefore, when the particles are sandwiched between the gums and the denture or vaginal mucosa, pain is caused. Furthermore, when particles remain in the mouth, a rough sensation as if sand is contained in the mouth remains, and the coating film dissolves over time, and an unpleasant taste spreads in the mouth.

[0009] In addition, when the method (2) is used, an unpleasant taste masking effect is weak even when a large amount of saccharide is added, particularly for water-soluble drugs. In addition, synthetic sweeteners such as saccharin and arsenolite, on the other hand, cause bitterness when they are increased.

[0010] Therefore, in taste masking of an oral powdered granular preparation containing a water-soluble and unpleasant taste drug such as propiverine hydrochloride, (1) or (2) The reality is that a formulation with a good feeling of administration is effective enough to improve the compliance of patients who are difficult to take.

[0011] Further, as a taste masking method for drugs having a bitter taste, it is also known to use a pH buffer or pH adjuster to insolubilize the drug (Non-patent Document 1, Patent Documents 1 to 3). reference). However, it is not known whether this technique can be applied to propiverine hydrochloride. Non-Patent Document 1: PHARM TECH JAPAN Vol.6, No.7 (1990), 77-86

Patent Document 1: Japanese Patent Laid-Open No. 2-96526

Patent Document 2: JP-A-58-4714

Patent Document 3: International Publication WO99 / 16470

Disclosure of the invention

Problems to be solved by the invention

[0012] An object of the present invention is to produce an orally-administered preparation using propiverine hydrochloride, which is generally obtained as a medicinal ingredient, having a good feeling of taking and avoiding a decrease in patient compliance.

In the present specification and claims, “good feeling” means that the unpleasant taste is reduced when it is put in the mouth, and the residual feeling of the preparation in the mouth (rough sensation) That there is no Say.

Means for solving the problem

[0014] The present inventors apply a technique for insolubilizing the drug to propiverine hydrochloride using a pH regulator described in Non-Patent Document 1 or the like to solve the above problems. ρ Mi / ko.

[0015] However, this method clearly has the following problems. When the ρΗ modifier or its aqueous solution and the propiverine hydrochloride aqueous solution are mixed, a large number of large particles exceeding 100 m are formed. In the worst case, a huge waxy substance is generated and adheres to the reaction vessel. As a result, the particle size in the suspension becomes larger, making spraying difficult by spraying, and even if it can be sprayed, it is difficult to obtain a preparation with a uniform content of each component. Since the deposited waxy substance adheres to the reaction vessel, it does not become a suspension and tends to be a two-phase system consisting of a waxy substance and water. (M) The waxy substance is converted into a general powder. It is inferior in handling property, and it is difficult to produce a granular preparation using this.

[0016] Therefore, it is impossible to obtain a suspension suitable for producing a granular preparation with few large particles having a particle size of more than 100 μm and good particle dispersion. It seemed.

[0017] However, the present inventors continued various studies and obtained the following knowledge.

[0018] (a) When a specific surfactant is used in addition to mixing an aqueous propiverine hydrochloride solution with a pH adjusting agent or an aqueous solution thereof, there are few large particles exceeding 100 m and the dispersion state of the particles is reduced. A good suspension can be obtained.

[0019] (b) A granular preparation can be produced by granulation using the suspension and a pharmaceutical additive used in a normal granular preparation.

[0020] (c) The powdery granular preparation thus obtained has a significantly improved unpleasant taste and a good feeling of taking in which there is no residual feeling of the preparation in the oral cavity.

[0021] The present invention has been completed by further studies based on such findings, and provides the following granular preparation, production method thereof, and the like. Item 1 An oral powdered granular preparation containing a good feeling of administration, comprising (a) propiverine, (b) a surfactant and (c) a pH regulator.

[0023] Item 2 (a) Propiverine containing 0.5-10% (w / w) in terms of propiverine hydrochloride, and further comprising (b) a surfactant and (c) a pH regulator. An oral powdered granular preparation having a pH of 6.5 to 8.0 obtained by shaking the preparation containing 25 mg of propiverine in terms of propiverine hydrochloride added to 25 mL of water and shaking.

[0024] Item 3. The oral granular preparation according to Item 1 or 2, wherein the pH adjuster is a phosphate and the surfactant HLB is 11-18.

Item 4 Surfactant power The oral powder preparation according to Item 3, which is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

[0026] Item 5. The oral granular preparation according to Item 1 or 2, wherein the pH adjuster is a carbonate, and the surfactant has an HLB of 11 to 40.

[0027] Item 6 Surfactant power Polyoxyethylene hydrogenated castor oil 60, polysorbate 80, stearic acid polyoxyl 40, sucrose stearate and sodium lauryl sulfate Power of at least one selected 5. An oral powder granular preparation according to 5.

[0028] Item 7: The HLB of the surfactant is 14 to 18, and the pH regulator is dipotassium phosphate

3. An oral powder granular preparation according to any one of the above.

Item 8 Surfactant power The oral powder preparation according to Item 7, which is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

Item 9 The oral granular preparation according to any one of Items 1 to 3 and 7, wherein the surfactant is polyoxyl stearate 40 and the pH adjuster is dibasic sodium phosphate.

[0031] Item 10 The oral granular preparation according to any one of Items 1 to 9, wherein the surfactant content is 0.1 to 100% (w / w) based on propiverine hydrochloride converted weight of propiverine .

Item 11 is a method for producing an oral powdered granular preparation containing propiverine, a surfactant and a pH regulator,

(1) Propiverine hydrochloride, a surfactant, a pH regulator and water are mixed, and the pH regulator Obtaining a suspension adjusted to pH 6.5-8.0 with, and

(2) Step of granulating the suspension obtained in step (1) together with formulation additives

The manufacturing method characterized by including.

[0033] Item 12. The method according to Item 11, wherein, in the step (2), the suspension is sprayed onto a pharmaceutical additive and granulated.

[0034] Item 13 In step (1), the suspension is prepared by combining an aqueous solution containing (0) a surfactant and propiverine hydrochloride with a GOpH adjusting agent or a pH adjusting agent aqueous solution. Item 12. The production method according to Item 11, obtained by mixing so that

[0035] Item 14 In step (1), the suspension comprises (iii) a mixture containing a surfactant, a pH adjuster and water, and Gv) an aqueous propiverine hydrochloride solution. Item 12. The production method according to Item 11, obtained by mixing to obtain 8.0.

Item 15 The method according to any one of Items 11 to 14, wherein 1 to 45% (w / w) of propiverine is present in the suspension in terms of propiverine hydrochloride.

[0037] Item 16. The method according to any one of Items 11 to 14, wherein the pH regulator is a phosphate or a carbonate.

[0038] Item 17. The production method according to Item 11, wherein the pH regulator is a phosphate, and the HLB of the surfactant is 11-18.

Item 18 The method according to Item 17, wherein the surfactant power is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

[0040] Item 19. The production method according to Item 11, wherein the pH regulator is a carbonate, and the surfactant has an HLB of 11 to 40.

Item [0041] Item 20 Surfactant power Polyoxyethylene hydrogenated castor oil 60, polysorbate 80, polyoxyl 40 stearate, sucrose stearate, sodium lauryl sulfate power Group power at least one selected Manufacturing method.

[0042] Item 21. The production method according to Item 11, wherein the surfactant has an HLB of 14 to 18, and the pH adjuster is dipotassium phosphate.

Item 22 Surfactant Power Polyoxyethylene hydrogenated castor oil 60, polysorbate 80 and suso Item 22. The production method according to Item 21, which is at least one selected from the group power consisting of polyoxyl 40 thearate.

[0044] Item 23. The method according to Item 21, wherein the surfactant is polyoxyl 40 stearate.

[0045] Item 24 The surfactant content in the suspension is 0.1% relative to the weight of propiverine hydrochloride.

The manufacturing method according to any one of Items 11 to 23, which is ˜100% (w / w).

[0046] Item 25 (or obtained by the production method according to any one of Items 11 to 24)

) Oral powder granular formulation.

[0047] Item 26 A suspension prepared by mixing propiverine hydrochloride, a surfactant, a pH adjusting agent and water, and adjusted to pH 6.5 to 8.0 with the pH adjusting agent.

Item [0048] Item 27: Propiverine is present in an amount of 1 to 45% (w / w) in terms of propiverine hydrochloride, and the content of the surfactant is 0.1 to 100% (w / w) based on the weight of propiverine hydrochloride Suspension described in 26

[0049] Item 28. The suspension according to Item 26 or 27, wherein the abundance ratio of large particles having a particle size exceeding 100 m is about 50% or less.

[0050] Item 29. A method for producing a suspension comprising propiverine hydrochloride, a surfactant, a pH adjusting agent and water mixed, and adjusted to pH 6.5 to 8.0 with the pH adjusting agent,

(0 The ability to mix an aqueous solution containing a surfactant and propiverine hydrochloride and a GOpH adjuster or pH adjuster aqueous solution so that the pH of the suspension is 6.5 to 8.0, or

(iii) Mix the mixture containing the surfactant, pH adjuster and water and (iv) the aqueous propiverine hydrochloride so that the pH of the suspension is 6.5 to 8.0.

The manufacturing method characterized by the above-mentioned.

[0051] Throughout this specification and claims, r% ( _w / w) j represents the percentage of weight relative to the weight of the solution or suspension or formulation. For example, the concentration of component C in formulation S (content

) Is 10% (w / w), it indicates that 10 g of component C is contained per formulation SlOOg.

In addition, “% (w / w)” indicates a percentage of the weight of the component Y with respect to the weight of the component X. For example, when the amount of the component Y is 1% (w / w) with respect to the component X, this indicates that the component Y is present in lg per 100 g of the component X. [0053] Further, in the present specification and claims, the "powder-form preparation" refers to a preparation prepared by making a pharmaceutical product into powder or granules. Powders, granules, granules, etc. are classified according to the particle size distribution of these powders or granules. Here, powders, fine granules and granules follow the classification described in the Japanese Pharmacopoeia.

The invention's effect

[0054] According to the present invention, the following excellent effects are exhibited.

[0055] (a) Based on the use of a specific surfactant rather than mixing a propiverine hydrochloride aqueous solution with a pH adjusting agent or an aqueous solution thereof, there are few large particles exceeding 100 m, and A suspension having a good dispersion state can be obtained.

[0056] (b) A granular preparation can be produced by granulation using the additive for preparation used in a normal granular preparation and the suspension.

[0057] (c) The powdery granular preparation thus obtained has a significantly improved unpleasant taste and a good feeling of taking in which there is no residual feeling of the preparation in the oral cavity.

[0058] (Accordingly, according to the present invention, it is possible to avoid a decrease in medication compliance, which also causes an unpleasant taste and feeling of taking propiverine hydrochloride.

[0059] As described above, the present invention provides an oral powdery granular preparation containing (a) propiverine, (b) a surfactant, and (c) a pH regulator and having a good dosing feeling.

[0060] Propiverine hydrochloride

In producing the granular preparation of the present invention, propiverine hydrochloride is used as a medicinal ingredient. Propiverine hydrochloride is commercially available and easily available.

The pH adjusting agent in the present invention, a surfactant or added to the addition! /, It! /, Particularly limited as long as it can adjust the _P H of hydrochloric acid propiverine aqueous solution 6.5 to 8.0 is if example embodiment Nag And alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, metal salts of amino acids, and inorganic compounds.

[0062] Specific examples of alkali metal salts of organic acids include citrate, malic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, malonic acid, acetic acid, lactic acid, and other organic acids, sodium, potassium, etc. And a salt with an alkali metal. Examples of the alkaline earth metal salts of organic acids include salts of the above organic acids with alkaline earth metals such as magnesium and calcium.

[0063] Specific examples of amino acids include glycine, serine, threonine, asparagine, dartamine, lysine, arginine, histidine, and the like. As the metal salts of amino acids, alkali metal salts of amino acids are preferred. Examples of the alkali metal salts include salts of the above amino acids with alkali metals such as sodium and potassium.

[0064] Examples of inorganic compounds include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium magnesium hydroxide, hydroxide Aluminum gel, aluminum hydroxide 'sodium bicarbonate coprecipitation product, hydroxyaluminum-magnesium carbonate mixed drying gel, hydroxyaluminum' magnesium carbonate 'calcium carbonate coprecipitation product, magnesium hydroxide, carbonate Sodium hydrogen, magnesium carbonate, precipitated calcium carbonate, metasilicic acid magnesium aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, dipotassium phosphate, sodium hydrogen phosphate, anhydrous sodium monohydrogen phosphate, potassium carbonate, potassium hydrogen carbonate , Carbonate It can be mentioned the presence and sodium polyphosphate and the like.

[0065] Among the alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, metal salts of amino acids, and inorganic compounds, salts that hardly dissolve in water, such as calcium salts, magnesium salts, and aluminum salts When the drug is formulated, these salts may remain at the time of taking and it may feel rough on the tongue, which tends to reduce the feeling of taking. Although inferior, calcium salt, magnesium salt, aluminum salt, etc. can also be used.

[0066] In addition, when formulated with sodium salts among the alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, metal salts of amino acids, and inorganic compounds, Although there is no rough feeling, it is more preferable to use the potassium salts because the salty taste may be slightly inferior compared to the case of formulating with the potassium salts.

[0067] Among the pH regulators in the present invention, from the viewpoint of dispersibility at the time of formulation or feeling of taking- From the viewpoint of flavor, carbonates or phosphates are preferred, and phosphates are more preferred.

[0068] Specific examples of carbonates include hydroxide-aluminum 'sodium bicarbonate coprecipitation product, hydroxide-aluminum' magnesium carbonate mixed dried gel, hydroxide-aluminum 'magnesium carbonate' and calcium carbonate. A coprecipitation product, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium carbonate and the like can be mentioned, and sodium hydrogen carbonate is particularly preferable. When carbonates are used, the dispersibility of the drug particles may be improved by the generation of carbon dioxide.

[0069] Specific examples of phosphates include anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, dipotassium phosphate, sodium hydrogen phosphate, anhydrous sodium monohydrogen phosphate, sodium polyphosphate, and the like. More preferably, it is dipotassium phosphate (ie, dipotassium hydrogen phosphate).

[0070] In the present invention, the pH of a mixed solution (suspension of the present invention described later) obtained by mixing propiverine hydrochloride, a surfactant, and a pH adjusting agent is in the range of 6.5 to 8.0, preferably 6.8. It is preferable to use the pH regulator in an amount that is in the range of ~ 7.4. If the pH of the mixed solution is lower than 6.5, the taste of the produced granular preparation is bitter and the taking feeling is bad. On the other hand, even if a large amount of pH adjuster is used to make the pH of the mixture higher than 8.0, there is no significant change in the bitterness and feeling of administration of the preparation!

[0071] The blending ratio of the pH adjusting agent can be adjusted as appropriate depending on the pH adjusting ability. For example, in the case of dipotassium phosphate, 2 to 5 mol, particularly 2.5 to 3.5 mol, per 1 mol of propiverine hydrochloride. It can mix | blend in the ratio.

[0072] KAI rif active agent

As the surfactant in the present invention, various surfactants can be used as long as they can be added to a propiverine hydrochloride aqueous solution and finely disperse the drug particles. Specifically, cholesterol, sucrose fatty acid esters (for example, sucrose C12-C18 such as sucrose laurate, sucrose myristic ester, sucrose palmitate, sucrose stearate, sucrose oleate, etc.) Fatty acid ester), stearyl alcohol, polyethylene glycol fatty acid ester (eg, polyoxyl 40 stearate (Japan Pharmacopoeia)), sorbitan sesquioleate, cetanol, polyoxyethylene castor Oil derivatives (eg, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, etc.), polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol , Polyoxyethylene sorbitan fatty acid esters (for example, polysorbate 60 (pharmaceutical additive standard), polysorbate 80 (Japanese Pharmacopoeia), etc.), polyethylene glycol (for example, Macrogol 300, Macrogol 400, Macoral Gol 600, etc.) Examples thereof include glyceryl monostearate and a ionic surfactant (for example, sodium lauryl sulfate). Use a mixture of two or more of these.

[0073] In the present invention, a surfactant having a specific HLB (Hydrophile Lipophile Balance) value may be appropriately selected and used depending on the type of pH regulator. Usually preferred. For example, when the phosphates are used as the pH regulator, a surfactant having an HLB of 11 to 18, particularly 14 to 18 is preferable. Specifically, polyethylene glycol fatty acid esters, polyoxyethylene castor oil derivatives or polyoxyethylene sorbitan fatty acid esters having an HLB of 11 to 18 are preferred, and polyethylene glycol fatty acid esters and poly Oxyethylene castor oil derivatives or polyoxyethylene sorbitan fatty acid esters are preferred, and polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80 are particularly preferred.

[0074] When the carbonates are used as the pH regulator, a surfactant having an HLB of 11 to 40, particularly 14 to 40 is preferable. Specifically, a sucrose fatty acid ester having a HLB of 11 to 40, a polyethylene glycol fatty acid ester, a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester, or a ionic surfactant is preferred. Sucrose fatty acid esters with a HLB of 14 to 40, polyethylene glycol fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters or ionic surfactants are preferred, especially sucrose stearates Polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, sodium lauryl sulfate are preferred.

[0075] By using a surfactant having an HLB within this range, drug particles in the suspension can be finely dispersed, and the abundance ratio of coarse particles that cannot be sprayed with a spray gun is reduced. This is preferable because granulation by a fluidized bed suitable for the production of a large-scale granular preparation becomes easy.

[0076] The HLB (Hydrophile Lipophile Balance) value is an index indicating the lipophilicity and hydrophilicity of the surfactant. The closer to 0, the higher the lipophilicity, the higher the hydrophilicity. .

[0077] The HLB value can be calculated by various calculation formulas. In the present invention, for example, the method described in "New Edition Surfactant Handbook (Engineering Books, Inc.) PP234-236 [1987]" is used. Can be calculated.

[0078] Method of making oral powder granular preparation of the present invention

In order to produce the oral powdered granular preparation of the present invention, various methods can be adopted. In general, first, propiverine hydrochloride, a surfactant, a pH adjuster and water are mixed, and pH 6. A suspension adjusted to 5-8.0 is obtained. Subsequently, the granular preparation of the present invention can be produced by granulating using a known additive for preparation and the suspension.

[0079] The suspension is prepared by mixing (0 an aqueous solution containing a surfactant and propiverine hydrochloride with a GOpH adjusting agent or an aqueous pH adjusting agent so that the pH of the suspension is 6.5 to 8.0. Alternatively, the suspension is prepared, for example, by mixing (iii) a mixture containing a surfactant, a pH adjusting agent and water, and Gv) an aqueous propiverine hydrochloride solution, wherein the pH of the suspension is 6.5 to 6.5. It can also be obtained by mixing to 8.0. Without being limited to these methods, the suspension of the present invention can be produced by other methods.

[0080] In the resulting suspension, the pH adjuster is used to neutralize the raw material propiverine hydrochloride! Therefore, substantially all of propiverine hydrochloride is free base (free propiverine ) However, a salt of propiverine, for example, propiverine hydrochloride or a salt of propiverine and a pH adjuster, is contained in a slight amount, particularly in an amount that does not cause a bitter taste in the final preparation. Also good. The amount of the propiverine salt is preferably less than 5%, especially less than 2%, relative to the amount of propiverine hydrochloride U.

[0081] V, also in the case of deviation, mix so that the composition of the resulting suspension is as follows:

Propiverine content: 1 to 45% (w / w), especially 2 to 10% (w / w) in terms of propiverine hydrochloride, Surfactant content: 0.1 to 100% (w / w), preferably 0.5 to 15% (w / w), more preferably 0.65 to 13% (w / w) of propiverine in terms of propiverine hydrochloride w),

Content of pH regulator: Suspension pH 6.5-8.0, preferably 6.8-7.4, Suspension! "[: 6.5-8.0, preferably 6.8-7.4.

[0082] As long as the resulting suspension has the above composition, the concentration of each component, usage pattern, and the like are not particularly limited, but typically, the following may be performed.

[0083] (In an aqueous solution containing 0 surfactant and propiverine hydrochloride, the amount of propiverine hydrochloride used is 1 to 50% (w / w), especially 2 to 10%, based on water as a solvent) (w / w) is preferred.

[0084] The surfactant is added to finely disperse the drug particles in the suspension and prevent the wax-like substance from forming and adhering to the reaction vessel. In general, in the range of 0.1 to 100% (w / w), preferably 0.5 to 15% (w / w), more preferably 0.65 to 13% (w / w) based on the weight of propiverine hydrochloride. What is necessary is just to add. Within this range, it is possible to prevent the drug from being dissolved in a large amount by the action of the surfactant and to easily feel the taste of the surfactant itself, so that the bitter taste is suppressed and the feeling of taking is good. In addition, when no surfactant is used, the abundance ratio of coarse particles in the spray suspension becomes high, and granulation by a fluidized bed cannot be performed.

[0085] In addition, the amount of the above-mentioned (ii) PH regulator used can be appropriately selected from a wide range as long as the desired suspension is obtained. Usually, the pH of the finally obtained suspension is 6.5 to It is preferably used in an amount of 8.0, preferably 6.8 to 7.4. The pH regulator may be used as it is. It can also be used in the form of an aqueous solution in advance.

[0086] In the mixture containing the surfactant (iii), the pH adjuster and water, the amount of the surfactant added is generally 0.1 to 100% (w / w), preferably 0.1% to the weight of propiverine hydrochloride. May be added in the range of 0.5 to 15% (w / w), more preferably 0.65 to 13% (w / w). In addition, the amount of the pH regulator used can be appropriately selected within a wide range as long as the desired suspension is obtained. Usually, however, the pH of the finally obtained suspension is 6.5 to 8.0, preferably 6.8 to 7.4. It is preferable to use it in such an amount. In the mixture of (iii) surfactant, pH adjuster and water, the total amount of surfactant and pH adjuster can be selected as appropriate over a wide range. Is preferably 0.1 to 500% (w / w), particularly 1 to 150% (w / w) with respect to water.

[0087] In the above-mentioned (iv) aqueous propiverine hydrochloride, propiverine hydrochloride is used in an amount of 1 to 50% (w / w), especially 2 to 10% (w / w) based on the solvent water. ) Is preferred.

[0088] In the production method of the present invention, as described above, when the phosphates are used as the pH regulator, it is preferable to use a surfactant having an HLB of 11 to 18, particularly 14 to 18. . In addition, when the carbonates are used as pH adjusters, it is preferable to use a surfactant having an HLB of 11 to 40, particularly 14 to 40.

[0089] Further, it is more preferable that the surfactant has an HLB of 14 to 18, and the pH adjuster is dipotassium phosphate. In this case, the surfactant is particularly preferably polyoxyl 40 stearate.

[0090] In producing the suspension, the mixing of (0 and (ii) and the mixing of () and Gv) is carried out by a known apparatus such as a magnetic stirrer, homogenizer, homomixer, What is necessary is just to carry out using a homodesper, a stirring propeller, etc.

[0091] The mixing conditions can be appropriately selected over a wide range of forces, and are not particularly limited, but in general, at a temperature of 15 to 30 ° C, particularly 20 to 25 ° C, at a stirring speed such that both are sufficiently mixed. Mix until the desired suspension is obtained.

[0092] The suspension obtained by mixing propiverine hydrochloride, a surfactant, a pH adjusting agent and water and adjusted to pH 6.8 to 7.4 with the pH adjusting agent has a particle size of more than 100 m. Fewer large particles and good particle dispersion. The abundance of large particles having a particle size exceeding 100 / z m is usually 50% or less, especially about 10 to 45%.

[0093] The method for obtaining the abundance ratio is as follows. That is, the precipitated drug particles are collected by a filter having an opening of 100 μm and vacuum-dried at 50 ° C. for 21 hours or more. This is weighed, and calculated from the amount of propiverine hydrochloride charged with the abundance (%) of drug particles having a particle size larger than 100 μm.

[0094] When the above-described suspension of the present invention and, if necessary, known formulation additives are used, the unpleasant taste is remarkably improved by the known methods used for the production of granular products, When included, a powdery granular preparation with good dosing feeling is obtained, and it is possible to avoid a decrease in compliance, which causes unpleasant taste and taking sensitivity. Therefore, the present invention provides the propiverine hydrochloride, the interface It also provides a suspension prepared by mixing an active agent, a pH adjuster and water and adjusted to pH 6.5 to 8.0 with the pH adjuster.

[0095] In order to produce the oral powder preparation of the present invention using the suspension of the present invention, a known method for producing an oral powder preparation, for example, using known preparation additives as necessary, for example, The force capable of using a fluidized bed granulation method, a stirring granulation method, a rolling fluidized bed granulation method, an extrusion granulation method, a spray drying method, etc. is not limited to these. Among these, it is preferable to perform granulation by spraying the suspension of the present invention onto a known formulation additive.

[0096] When the above-mentioned preparation additive is used, it is used within a range not impeding the effects of the present invention. Examples of pharmaceutical additives include various pharmaceutical additives generally used in the production of granular preparations, such as sugars, excipients, disintegrants, binders, lubricants, coloring agents, and flavorings. Agents, flavoring agents and the like.

[0097] Specific examples of the saccharide include monosaccharides (arabinose, xylose, glucose, fructose, galactose, mannose, sorbose, etc.), oligosaccharides (sucrose, lactose, maltose, reduced maltose, isomaltose, etc.), saccharides Alcohols (such as xylitol, erythritol, sorbitol, mannitol) can be mentioned. Use these sugars alone or in combination of two or more.

[0098] Examples of the excipient include starch, crystalline cellulose, light anhydrous kaic acid and calcium silicate.

[0099] Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, crospovidone, carmellose calcium, and croscarmellose sodium.

[0100] Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polybulal alcohol, and polybulurpyrrolidone.

[0101] Examples of the lubricant include magnesium stearate, calcium stearate, talc and sucrose fatty acid ester.

[0102] Examples of the colorant include edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow dianhydride and iron oxide, and acid and titanium.

[0103] Examples of the flavoring agent include various flavors of orange and lemon. [0104] Examples of the corrigent include L-menthol, camphor, potato, and cocoa.

[0105] As a typical method for producing the oral powdered granular preparation of the present invention, for example, the suspension of the present invention is sprayed onto the formulation additive in a fluid state using a fluidized bed granulation coating apparatus. The method of granulating can be mentioned.

[0106] The oral powder granular preparation of the present invention

The dosage form of the oral powder granular preparation of the present invention obtained by the production method of the present invention is not particularly limited, and examples thereof include granules, powders, and fine granules. Granules, powders, and fine granules include dry syrups that are dissolved at the time of use, and granules that dissolve rapidly in the oral cavity and can be taken without water.

[0107] The oral powder granular preparation of the present invention comprises (a) propiverine, (b) a surfactant and (c) a pH adjuster, and, if necessary, the above-mentioned preparation additive, and has a bitter taste. In addition, it is an oral powder granular preparation that is suppressed and has a good feeling of administration.

[0108] In the present invention, propiverine is generally contained in a formulation of 0.5 to 10% (w / w), particularly 1 to 5% (w / w) in terms of propiverine hydrochloride. Medicinal component concentrations may be outside this range, but are usually not practical. This is because a single dose of propiverine hydrochloride is expected to be approximately 20 mg. If the drug concentration is lower than 0.5% (w / w), a dose of 4 g or more is required to take propiverine hydrochloride equivalent to 20 mg. It is difficult to say that it is easy to take, and when the drug concentration is higher than 10% (w / w), propiverine hydrochloride equivalent to 20 mg is a force that reduces it to less than 200 mg. This is because it is extremely difficult to fill with a packaging device.

[0109] In the oral powder granular preparation of the present invention, propiverine hydrochloride is neutralized with a pH adjuster, and as a result, exists in the form of propiverine hydrochloride free base. The preparation of the present invention may contain only the free base, but may contain some amount of propiverine salt, for example, propiverine hydrochloride, propiverine and a pH regulator. If the amount of the salt of propiverine is less than 5%, particularly less than 2%, relative to the amount of propiverine hydrochloride charged, it is generally a problem in compliance with administration. I don't feel a bitter taste.

[0110] More specifically, the oral powdered granular preparation of the present invention comprises (a) propiverine replacement with propiverine hydrochloride. An oral powdered formulation containing 0.5 to 10% (w / w), and further containing (b) a surfactant and (c) a pH regulator, in an amount corresponding to 25 mg propiverine hydrochloride in the final formulation The pH of the suspension obtained by adding this preparation to 25 mL of water and shaking is 6.5 to 8.0, preferably 7.0 to 7.5.

[0111] Shaking is performed for 60 minutes in a thermostatic chamber set at a temperature of 25 ° C under conditions of a width of 30 mm and a speed of 120 rpm.

[0112] In the above, the content of the surfactant is 0.1 to 100% (w / w), particularly 0.5 to 15% (w / w), and further 0.65 based on the propiverine hydrochloride equivalent weight of propiverine in (a). It is preferably ˜13% (w / w).

[0113] In addition, the amount of the pH adjusting agent is effective for the pH of the suspension obtained by shaking the preparation corresponding to 25 mg of propiverine hydrochloride added to 25 mL of water to be 6.5 to 8.0. It is an amount.

[0114] In the preparation of the present invention, as described above, when the phosphates are used as a pH adjuster, it is preferable to use a surfactant having an HLB of 11 to 18, particularly 14 to 18. . In addition, when the carbonates are used as a pH adjuster, it is preferable to use a surfactant having an HLB of 11 to 40, particularly 14 to 40.

[0115] Furthermore, it is more preferable that the surfactant has an HLB of 14 to 18, and the pH adjuster is dipotassium phosphate. In this case, the surfactant is preferably polyoxyl 40 stearate.

[0116] The powdered granular preparation of the present invention significantly improves the unpleasant taste of propiverine hydrochloride, and gives a powdered granular preparation having a good feeling when taken in the mouth, resulting in an unpleasant taste and taking sensitivity. Reduced compliance can be avoided.

Example

[0117] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited only to these Examples.

[0118] ¾fine

10 g of propiverine hydrochloride and 0.13 g of polyoxyethylene hydrogenated castor oil 60 (manufactured by Nikko Chemicals Co., Ltd.) were dissolved in 225 g of purified water, and the resulting solution (liquid A) was sufficiently stirred using a magnetic stirrer. Meanwhile, a solution of 12.94 g of dipotassium phosphate dissolved in 150 g of purified water (Liquid B) was added to the propiverine hydrochloride aqueous solution (Liquid A) and stirred until uniform to prepare a suspension of the present invention. The pH of the resulting suspension (Liquid A + Liquid B) was 7.0.

[0119] Examples 2 and 3

According to the same method as in Example 1, the surfactants shown in Table 1 were used in the amounts shown in Table 1 to prepare suspensions of the present invention. The pH of the obtained suspension is shown in Table 1. In these examples, polysorbate 80 was manufactured by Wako Pure Chemical Industries, Ltd., and polyoxyl stearate 40 was manufactured by Nikko Chemicals.

[0120] Comparative Example 1

A comparative suspension was prepared in the same manner as in Example 1, except that polyoxyethylene hydrogenated castor oil 60 as a surfactant was not added. The pH of the obtained suspension is shown in Table 1.

[0121] ¾ Thin 14

A solution (liquid A) in which 10 g of propiverine hydrochloride and 0.13 g of polyoxyethylene hydrogenated castor oil 60 (manufactured by Nikko Chemicals) was dissolved in 225 g of purified water was sufficiently stirred using a magnetic stirrer. On the other hand, a solution (liquid C) obtained by dissolving 6.24 g of sodium hydrogen carbonate in 150 g of purified water was added to the aqueous propiverine hydrochloride (liquid A) and stirred until uniform to prepare a suspension of the present invention. The pH of the resulting suspension (Liquid A + Liquid C) was 7.0.

[0122] Decoration 15-8

According to the method of Example 4, suspensions of the present invention were prepared using the surfactants shown in Table 1 in the amounts shown in Table 1. The pH of the obtained suspension is shown in Table 1. In these examples, polysorbate 80 is manufactured by Wako Pure Chemical Industries, Ltd., polyoxyl stearate 40 is manufactured by Nikko Chemicals Co., Ltd., sucrose stearate is Daiichi Kogyo Seiyaku Co., Ltd., and sodium lauryl sulfate is Wako Pure Chemical Industries. Yakuhin Co., Ltd. product was used.

[0123] Comparative Example 2

A comparative suspension was prepared in the same manner as in Example 4 except that the surfactant polyoxyethylene hydrogenated castor oil 60 was not used. The pH of the obtained suspension is shown in Table 1.

[0124] Test Example 1

The dispersion state of the suspensions prepared in Examples 1 to 8 and Comparative Examples 1 and 2 were evaluated according to the following evaluation methods. The results are shown in Table 1. [0125] <Evaluation method>

The precipitated drug particles in the suspension are filtered through a filter with a mesh opening of 100 m and vacuum-dried at 50 ° C for 21 hours or longer. This is weighed (WL), and the abundance ratio P (%) of drug particles with a particle size larger than 100 / zm is calculated based on the free base equivalent of the amount of drug charged (Wo, that is, the amount of propiverine hydrochloride charged). Calculated from the following formula:

Presence P (%) = [WL / (Wo X (367.48) / (403.94))] X 100

In the above formula, 367.48 is the molecular weight of propiverine, and 403.94 is the molecular weight of propiverine hydrochloride.

[0126] This means that the abundance P is small! /, So that particles with a particle size of 100 μm or less are present in the suspension! /, And the dispersion state is good. .

[0127] [Table 1]

[0128] As is apparent from the results shown in Table 1, it can be seen that a suspension having a good dispersion state can be produced by adding a surfactant.

[0129] In Comparative Examples 1 and 2, which did not use a surfactant, a huge waxy substance was formed. It adhered to the reaction vessel.

[0130] On the other hand, when a pH regulator is used in combination with a surfactant, for example, a phosphate (dipotassium phosphate) is used as the pH regulator, and a surfactant having an HLB of 14 to 18 is used. When used (Examples 1 to 3), the abundance (%) force of drug particles having a particle size larger than 100 m was found to be improved compared to Comparative Example 1 in a low dispersion state. In addition, when foaming carbonates (sodium hydrogen carbonate) are used as the pH adjuster, the HLB of the surfactant is 14 to 40, and the dispersion state is higher than in Comparative Example 2 where no surfactant is used. It turned out to be improved.

[0131] Example 9

10 g of propiverine hydrochloride and polyoxyl stearate 40 (manufactured by Nikko Chemicals) 0.13 g were dissolved in 225 g of purified water (liquid A ′). Further, a solution (liquid B) obtained by dissolving 12.94 g of dipotassium phosphate in 150 g of purified water was added to the propiverine hydrochloride aqueous solution (liquid 1) and stirred at 600 rpm for 1 hour using a magnetic stirrer. At this time, the pH of the suspension (Liquid A ′ + Liquid B) was 7.0.

[0132] On the other hand, 379.87 g of D-mannthol, 43 g of purified sucrose, 47 g of low-substituted hydroxypropyl cellulose (trade name “LH-31” manufactured by Shin-Etsu Chemical Co., Ltd.), 2 g of light anhydrous silicic acid, It was charged in a fluidized bed granulation coating apparatus (trade name “Multiplex MP-01”, manufactured by Purreck Co., Ltd.), and the suspension was sprayed at a spray rate of 6.2 g / min for granulation. After drying, the obtained granulated product was sieved with a sieve having an opening of 500 μm to obtain a fine granule.

[0133] Example 10

Dissolve 10 g of propiverine hydrochloride and polyoxyl stearate 40 (manufactured by Nikko Chemicals Co., Ltd.) 0.13 g in 225 g of purified water (liquid A ′). Further, a solution (liquid Β ') obtained by dissolving 6.24 g of sodium hydrogen carbonate in 150 g of purified water was added to the propiverine hydrochloride aqueous solution (liquid Α') and stirred at 600 rpm for 1 hour using a magnetic stirrer. . At this time, the pH of the suspension (liquid A, + liquid B) was 7.0.

[0134] On the other hand, 379.87 g of D-mannthol, 43 g of purified sucrose, 47 g of low-substituted hydroxypropyl cellulose (LH-31) and 2 g of light caustic anhydride were mixed in a fluidized bed granulation coating device (Multiplex MP -01), and the above suspension was sprayed at a spray rate of 5.5 g / min for granulation. After drying, the obtained granulated product was sieved with a sieve having an opening of 500 μm to obtain a fine granule. [0135] Test Example 2

The preparations obtained in Examples 9 and 10 were subjected to a sensory test (standard panel test) for bitterness and feel. The evaluation items are as follows.

Evaluation item: Evaluate the bitterness of the preparation and the feeling of taking it according to the following criteria.

[0136] [Bitter taste]

4: Extremely bitter

3: Bitter

2: Slightly bitter

1: I do not feel bitterness.

[0137] [Dosage]

4: Cannot be taken

3: Difficult to take

2: Slightly difficult to take

1: Can be taken.

[0138] As a result, the bitterness is evaluated! As a result, there is no evaluation of "very bitter," and there is no evaluation, and an evaluation of "does not feel bitter! /," Or "somewhat bitter" is obtained. The evaluation of “cannot be taken” was good. When both were compared, the sensory test for bitterness was equivalent to both, but the sensory test for feeling of taking was compared with the preparation of Example 10 using sodium bicarbonate as a pH regulator. In addition, it was evaluated that the preparation of Example 9 using dipotassium phosphate as a pH regulator was superior.

[0139] Examples 11 and 12

A fine granule was produced according to the method described in Example 9 except that the pH regulator was used in the amount shown in Table 2. The pH of the obtained suspension is shown in Table 2. In Table 2, the formulation and pH of Example 9 are also shown.

[0140] Comparative Example 3

10 g of propiverine hydrochloride and polyoxyl stearate 40 (manufactured by Nikko Chemicals) 0.13 g were dissolved in 225 g of purified water (liquid A,). Furthermore, 150 g of purified water (Liquid C) was stirred at 600 rpm for 1 hour using a magnetic magnetic stirrer. At this time, the pH of the solution (Liquid A, + Liquid C) is 4. 2 (see Table 2).

[0141] On the other hand, 379.87 g of D-mannthol, 43 g of purified sucrose, 47 g of low-substituted hydroxypropyl cellulose (LH-31) and 2 g of light caustic anhydride were mixed in a fluidized bed granulation coating device (multiple status MP- The mixture was sprayed at a spray rate of 6.4 g / min for granulation. After drying, the obtained granulated product was sieved with a sieve having an opening of 500 μm to obtain a fine granule.

[0142] [Table 2]

[0143] Test Example 3

The preparations obtained in Examples 9, 11, 12 and Comparative Example 3 were subjected to a sensory test for bitterness and feeling of taking. The sensory test was performed according to Test Example 2. [0144] As a result, when the pH of the suspension was 6.8 (Example 11), 7.0 (Example 9) and 7.4 (Example 12), the bitterness was evaluated as “very bitter”. “I don't feel” or “slightly bitter”, and the feeling of taking was “good” and the feeling of taking was good. Above all, pH 7.0 (Example 9) was evaluated as having the best bitterness and the best feeling.

[0145] On the other hand, when the pH of the solution is 4.2 (Comparative Example 3), regarding the sensory test for bitterness,

In the sensory test on the feeling of taking, which is often evaluated as “bitter”, the evaluation was “hard to take” or “not take”.

As is apparent from the above results, Example 11 produced using a suspension having a pH of 6.8 to 7.4.

, 9, and 12 improved the bitterness and feeling of administration of the preparation compared to Comparative Example 3 produced using a solution having a pH of 0.2.

[0147] Examples 13 and 14

According to Example 9, a fine granule was produced in the same manner with the charge shown in Table 3. Table

In FIG. 3, the formulation of Example 9 is also shown for comparison.

[0148] In addition, Table 3 shows the amount (% by weight) of polyoxyl stearate 40 (manufactured by Nikko Chemicals Co., Ltd.) to propiverine hydrochloride.

[0149] Comparative Example 4

Dissolve 10 g of propiverine hydrochloride in 225 g of purified water (Liquid D). Further, a solution (liquid B) obtained by dissolving 12.94 g of dipotassium phosphate in 150 g of purified water was added to the aqueous propiverine hydrochloride solution (liquid D), and the mixture was stirred for 1 hour at 600 rpm using a magnetic stirrer.

[0150] When the obtained suspension was visually observed, a huge waxy substance was formed and adhered to the reaction vessel. In addition, very large particles were confirmed for the solid in the suspension (Liquid B + Liquid D) that did not adhere to the reaction vessel, and the particle size was larger than ^ 00 μm according to the evaluation method used in Test Example 1. The abundance ratio of drug particles was determined to be 87.2 (%), and it was thought that spraying from a spray gun was difficult, so it was difficult to obtain fine granules.

[0151] [Table 3]

[0152] Test Example 4

Example 9 The preparations obtained in 13 and 14 were subjected to a sensory test for bitterness and feeling of ingestion. The sensory test was performed according to Test Example 2.

[0153] As a result, the amount of polyoxyl stearate (manufactured by Nikko Chemicals Co., Ltd.) to propiverine hydrochloride (%) force 0.65% (Example 13), 1.3% (Example 9), 13% (Example 14) In the case of bitterness, an evaluation of `` extremely bitter '' does not feel a bitter taste, or an evaluation of `` somewhat bitter '' is obtained. there were. Among them, the amount of polyoxyl stearate added (%) was 1.3% (Example In the case of 9), the bitterness was the weakest and the evaluation was best.

[0154] On the other hand, in the case where polyoxyl 40 stearate was not added to the mixed solution (Comparative Example 4

) Produced a huge waxy substance, adhered to the reaction vessel, the drug particles were not sufficiently dispersed, and the formulation could not be obtained by fluidized bed granulation.

[0155] Test Example 5

A certain amount of the preparations obtained in Examples 11, 9, 12 and Comparative Example 3, that is, an amount containing 25 mg of propiverine in terms of propiverine hydrochloride was weighed and added to 25 mL of water and shaken. The pH of the resulting liquid was examined.

[0156] The shaking conditions are as follows.

Temperature chamber set temperature: 25 ° C

Amplitude: Width 30mm

Shaking speed: 120rpm

Shaking time: 60 minutes

The results are shown in Table 4 below.

[0157] [Table 4]

Size

From Table 4, the pH of the liquid obtained in the shaking test is weakly acidic in the case of the preparation of Comparative Example 3, whereas in the case of the preparation of the present invention (Examples 11, 9, and 12). , May be near neutral I understand. Therefore, considering the results of Test Examples 3 to 5, it is considered that the unpleasant taste can be improved if the pH obtained in the shaking test for the preparation of the present invention is near neutral. Industrial applicability

According to the present invention, when a granular preparation is produced using a solution obtained by mixing a propiverine hydrochloride aqueous solution to which a surfactant is added and a solution containing a pH adjuster, the unpleasant taste is remarkably improved, and it is taken when it is in the mouth. A preparation with good feeling can be obtained. Therefore, it is possible to avoid a decrease in medication compliance resulting from an unpleasant taste and feeling of taking according to the present invention.

Claims

The scope of the claims

[I] An oral powder preparation containing a good feeling of administration containing (a) propiverine, (b) a surfactant, and (c) a _PH regulator.

[2] An oral powdered preparation containing (a) propiverine 0.5 to 10% (w / w) in terms of propiverine hydrochloride, and further containing (b) a surfactant and (c) a pH regulator. The oral powdery granular preparation according to claim 1, wherein the pH of the suspension obtained by adding the preparation containing 25 mg of propiverine in terms of propiverine hydrochloride to 25 mL of water and shaking is 6.5 to 8.0.

[3] The oral granular preparation according to claim 1, wherein the pH regulator is a phosphate and the surfactant HLB is 11-18.

[4] Surfactant power The trans-PI granular preparation according to claim 3, which is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80 and polyoxyl 40 stearate.

[5] The oral granular preparation according to claim 1, wherein the pH regulator is a carbonate, and the HLB of the surfactant is 11 to 40.

[6] The surfactant power is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, polyoxyl 40 stearate, sucrose stearate and sodium lauryl sulfate. The oral powder granular preparation described.

7. The oral powder preparation according to claim 1, wherein the surfactant has an HLB of 14 to 18, and the pH regulator is dipotassium phosphate.

[8] Surfactant power The trans-PI granular preparation according to claim 7, which is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

[9] The oral powder granule according to claim 1, wherein the surfactant is polyoxyl 40 stearate and the pH regulator is dipotassium phosphate.

[10] The content of the surfactant is from 0.1 to the propiverine hydrochloride equivalent weight of propiverine.

The oral powder granular preparation according to claim 1, which is 100% (w / w).

[II] A method for producing an oral powder preparation containing propiverine, a surfactant and a pH regulator, (1) a step of mixing a propiverine hydrochloride, a surfactant, a pH adjusting agent and water to obtain a suspension adjusted to pH 6.5 to 8.0 with the pH adjusting agent; and

The manufacturing method characterized by including.

[12] The production method according to claim 11, wherein in the step (2), the suspension is granulated by spraying on the additive for preparation.

[13] In step (1), the suspension is prepared by combining (0) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH adjuster or an aqueous pH adjuster solution. 12. The production method according to claim 11, obtained by mixing so as to be 6.5 to 8.0.

[14] In step (1), the suspension comprises (iii) a mixture containing a surfactant, a pH adjuster and water;

12. The production method according to claim 11, which is obtained by mixing an aqueous propiverine hydrochloride solution so that the pH of the suspension is 6.5 to 8.0.

15. The production method according to claim 11, wherein propiverine is present in the suspension in an amount of 1 to 45% (w / w) in terms of propiverine hydrochloride.

[16] The production method of claim 11, wherein the pH regulator is a phosphate or a carbonate.

[17] The production method according to claim 11, wherein the pH regulator is a phosphate, and the HLB of the surfactant is 11-18.

[18] The production method according to claim 17, which is at least one selected from the group power consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

[19] The production method according to claim 11, wherein the pH regulator is a carbonate, and the HLB of the surfactant is 11-40.

[20] Surfactant power Polyoxyethylene hydrogenated castor oil 60, polysorbate 80, polyoxyl 40 stearate, sucrose stearate, sodium lauryl sulfate power is at least one selected from the group power of claim 19 Method.

21. The production method according to claim 11, wherein the surfactant has an HLB of 14 to 18, and is a pH regulator dipotassium carbonate.

[22] Surfactant power Polyoxyethylene hydrogenated castor oil 60, polysorbate 80 and steari The production method according to claim 21, which is at least one selected from the group power consisting of polyoxyl acid 40.

[23] The production method according to [21], wherein the surfactant is polyoxyl 40.

[24] The production method according to claim 11, wherein the content of the surfactant in the suspension is 0.1 to 100% (w / w) based on the weight of propiverine hydrochloride.

[25] An oral powder granular preparation obtainable by the production method according to claim 11.

[26] Propiverine hydrochloride, surfactant, pH adjuster, and water are mixed together.

Suspension adjusted to H6.5-8.0.

[27] The propiverine is present in an amount of 1 to 45% (w / w) in terms of propiverine hydrochloride, and the content of the surfactant is 0.1 to 100% (w / w) based on the weight of propiverine hydrochloride. 26. Suspension liquid according to 26.

28. The suspension according to claim 26, wherein the abundance power of large particles having a particle size exceeding 100 μm is about 50% or less.

[29] A method for producing a suspension comprising propiverine hydrochloride, a surfactant, a pH adjusting agent and water mixed, and adjusted to pH 6.5 to 8.0 with the pH adjusting agent,

The manufacturing method characterized by the above-mentioned.