JPWO2006046560A1 - Propiverine-containing oral powder granular preparation and its production method - Google Patents

Abstract

Propiverine hydrochloride, a surfactant, a pH regulator and water were used to produce an orally-administered formulation that has a good feeling of taking and avoids a decrease in patient compliance by using propiverine hydrochloride, which is generally available as a medicinal ingredient. The mixture is mixed to obtain a suspension adjusted to pH 6.5 to 8.0 with the pH adjuster, and then granulated with the known formulation additive and the suspension, so that the feeling of ingestion is obtained. A good granular formulation is obtained.

Description

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

  Propiverine has the following structure and exhibits anti-urination effect by anticholinergic action and smooth muscle direct action, neurogenic bladder, neural urinary frequency, unstable bladder, bladder stimulation state (chronic cystitis, chronic It is useful as a pharmaceutical that exhibits excellent effects on urinary incontinence and frequent urination associated with prostatitis (Japanese Patent Publication No. 62-51242).

  Propiverine hydrochloride, ie, propiverine hydrochloride, is water-soluble (512 mg / mL, 37 ° C) and has an unpleasant taste (severe bitterness with irritation) when taken. Currently, film-coated tablets are on the market. ing.

  However, there are many elderly people who have trouble with urinary incontinence, frequent urination, etc., and compliance with tablets tends to decrease due to dysphagia associated with aging.

  In clinical practice, for patients who have difficulty swallowing tablets (especially elderly people), in order to improve medication compliance, a technique 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 has a very unpleasant taste because the coating film is destroyed by the grinding operation and loses the masking effect. May result in reduced patient compliance.

  On the other hand, as a method for masking the unpleasant taste of oral powder granular preparations such as granules, fine granules and powders of drugs having unpleasant taste, (1) film coating method, (2) sugar, saccharin A method of blending a sweetener such as aspartame is known.

  However, in the preparation produced by the above method (1), the particles become hard due to the coating, so that when the particles are sandwiched between the gums and the dentures or the buccal mucosa, pain is caused. Furthermore, when particles remain in the oral cavity, a rough sensation that contains sand in the mouth remains forever, and the coating film dissolves over time and an unpleasant taste spreads in the oral cavity.

  In addition, when the method (2) is used, particularly for water-soluble drugs, an unpleasant taste masking effect is weak even if a large amount of saccharide is added. Furthermore, synthetic sweeteners such as saccharin and aspartame cause bitterness on the contrary by increasing the amount.

  Therefore, in taste masking of an oral powdered granular preparation containing a water-soluble and unpleasant taste drug such as propiverine hydrochloride, a preparation with good dosing feeling using either of the above methods (1) or (2) The reality is that it has not been effective enough to improve patient compliance.

In addition, as a taste masking method for drugs having a bitter taste, it is also known to insolubilize the drugs using a pH buffer or a pH regulator (see Non-Patent Document 1 and Patent Documents 1 to 3). However, it is not known whether this technique can be applied to propiverine hydrochloride.
PHARM TECH JAPAN Vol.6, No.7 (1990), 77-86 JP-A-2-96526 JP 58-4714 A International Publication No. WO99 / 16470

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

  In order to solve the above problems, the present inventors tried to apply a technique for insolubilizing the drug to propiverine hydrochloride using a pH regulator described in Non-Patent Document 1 or the like.

  However, this method has the following problems. When a pH regulator or an aqueous solution thereof and a propiverine hydrochloride aqueous solution are mixed, a large number of large particles exceeding 100 μm are generated, and in the worst case, a huge waxy substance is generated and adheres to the reaction vessel. As a result, (i) the particle size in the suspension becomes large, spraying by spray becomes difficult, and even if it can be sprayed, it is difficult to obtain a preparation with a uniform content of each component. ii) Since the precipitated 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. (iii) The waxy substance is a general powder. Inferior in handling properties, it is difficult to produce a granular preparation using this.

  Therefore, it seems that 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.

  However, the present inventors have made various studies and obtained the following findings.

  (a) When a specific surfactant is used instead of mixing a propiverine hydrochloride aqueous solution with a pH adjusting agent or an aqueous solution thereof, there are few large particles exceeding 100 μm and a suspension in which the particles are well dispersed. A liquid can be obtained.

  (b) A granular preparation can be produced by granulation using the suspension and the additive for preparation used in ordinary powder preparations.

  (c) The powdery granular preparation thus obtained has a significantly improved unpleasant taste, no residual feeling of the preparation in the oral cavity, and a good feeling of taking.

  The present invention has been completed by further studies based on such findings, and provides the following powdery granular preparation, a production method thereof, and the like.

  Item 1 An oral powder preparation containing a good feeling of administration, comprising (a) propiverine, (b) a surfactant and (c) a pH regulator.

  Item 2 (a) Propiverine containing 0.5 to 10% (w / w) of propiverine hydrochloride, and further comprising (b) a surfactant and (c) a pH regulator, An oral powdered granular preparation in which the pH of a 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.

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

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

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

  Item 6. The oral powder according to Item 5, wherein the surfactant 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. Granular formulation.

  Item 7. The oral granular preparation according to any one of Items 1 to 3, wherein the surfactant has an HLB of 14 to 18, and the pH regulator is dipotassium phosphate.

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

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

  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. 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
(2) A production method comprising the step of granulating the suspension obtained in step (1) together with a pharmaceutical additive.

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

  Item 13 In step (1), the suspension comprises (i) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH regulator or a pH regulator aqueous solution, and the pH of the suspension is 6.5 to 8.0. The manufacturing method of claim | item 11 obtained by mixing so that it may become.

  Item 14 In step (1), the suspension comprises (iii) a mixture containing a surfactant, a pH adjuster and water, and (iv) an aqueous propiverine hydrochloride solution, so that the suspension has a pH of 6.5 to 8.0. The manufacturing method of claim | item 11 obtained by mixing so that.

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

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

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

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

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

  Item 20 The method according to Item 19, wherein the surfactant 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. .

  Item 21 The method according to Item 11, wherein the surfactant has an HLB of 14 to 18, and the pH regulator is dipotassium phosphate.

  Item 22. The method according to Item 21, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.

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

  Item 24 The method according to any one of Items 11 to 23, wherein the content of the surfactant in the suspension is 0.1 to 100% (w / w) based on the weight of propiverine hydrochloride.

  Item 25 An oral powder preparation obtainable (or obtained) by the production method according to any one of Items 11 to 24.

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

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

Item 29 A method for producing a suspension comprising propiverine hydrochloride, a surfactant, a pH adjuster and water mixed, and adjusted to pH 6.5 to 8.0 with the pH adjuster,
(i) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH adjusting agent or an aqueous pH adjusting agent solution are mixed so that the pH of the suspension is 6.5 to 8.0, or
(iii) A production method comprising mixing a mixture containing a surfactant, a pH regulator and water, and (iv) an aqueous propiverine hydrochloride solution so that the pH of the suspension is 6.5 to 8.0.

  In the present description and claims, “% (w / w)” indicates the percentage of weight relative to the weight of the solution or suspension or formulation. For example, when the concentration (content) of a certain component C of the preparation S is 10% (w / w), it indicates that 10 g (w / w) of the component C is contained per 100 g of the preparation S.

  “% (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 component Y is 1% (w / w) with respect to component X, it indicates that 1 g of component Y is present per 100 g of component X.

  In the present specification and claims, the term “powdered 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.

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

  (a) Rather than mixing a propiverine hydrochloride aqueous solution with a pH regulator or an aqueous solution thereof, based on the use of a specific surfactant, there are few large particles exceeding 100 μm, and the dispersion state of the particles is good A suspension can be obtained.

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

  (c) The powdery granular preparation thus obtained has a significantly improved unpleasant taste, no residual feeling of the preparation in the oral cavity, and a good feeling of taking.

  (d) Therefore, according to the present invention, it is possible to avoid a decrease in medication compliance resulting from the unpleasant taste and feeling of taking propiverine hydrochloride.

  As described above, the present invention provides an oral powdered granular preparation containing (a) propiverine, (b) a surfactant, and (c) a pH regulator, which has a good dosing feeling.

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

pH adjuster The pH adjuster in the present invention is not particularly limited as long as the pH of the aqueous propiverine hydrochloride solution with or without the addition of a surfactant can be adjusted to 6.5 to 8.0. Mention may be made of metal salts, alkaline earth metal salts of organic acids, amino acids, metal salts of amino acids, and inorganic compounds.

  Specific examples of alkali metal salts of organic acids include citric acid, malic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, malonic acid, acetic acid, lactic acid and other organic acids and sodium, potassium and other alkali metals. Can be mentioned. Examples of the alkaline earth metal salt of an organic acid include a salt of the above organic acid with an alkaline earth metal such as magnesium or calcium.

  Specific examples of amino acids include glycine, serine, threonine, asparagine, glutamine, lysine, arginine and histidine. The metal salt of an amino acid is preferably an alkali metal salt of an amino acid. Examples thereof include salts of the above amino acids with alkali metals such as sodium and potassium.

  Examples of inorganic compounds include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide, Sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, aluminum metasilicate Magnesium phosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, dipotassium phosphate, sodium hydrogen phosphate, anhydrous sodium hydrogen phosphate, potassium carbonate, potassium hydrogen carbonate, sodium carbonate and poly Sodium phosphate, etc. can be mentioned.

  Among the above-mentioned alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, amino acid metal salts, and inorganic compounds, calcium salts, magnesium salts, aluminum salts and the like that hardly dissolve in water are used. When formulated, these salts may remain at the time of taking and it may feel rough on the tongue, leading to a decrease in the feeling of taking, so it is slightly inferior to sodium salts and potassium salts, Calcium salts, magnesium salts, aluminum salts and the like can also be used.

  In addition, when formulated with sodium salts among the alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, amino acid metal salts, and inorganic compounds, there is no rough feeling when taken. However, it is more preferable to use the above potassium salts because the salty taste is stronger and the feeling of taking may be slightly inferior to the case of formulating with the above potassium salts.

  Among the above pH regulators in the present invention, carbonates or phosphates are preferable, and phosphates are more preferable, from the viewpoint of dispersibility at the time of formulation or taking feeling and flavor.

  Specific examples of carbonates include aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, sodium bicarbonate, Examples thereof include magnesium carbonate, precipitated calcium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium carbonate and the like, and sodium hydrogen carbonate is particularly preferable. When carbonates are used, the dispersibility of drug particles may be improved by the generation of carbon dioxide.

  Specific examples of the phosphates include anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, dipotassium phosphate, sodium hydrogen phosphate, anhydrous sodium monohydrogen phosphate, sodium polyphosphate, and more preferably Dipotassium phosphate (ie, dipotassium hydrogen phosphate).

  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 in the range of 6.8 to 7.4. It is preferred to use a pH adjusting agent in an amount. If the pH of the mixed solution is lower than 6.5, the manufactured granular preparation has a bad taste and the feeling of taking is poor. On the other hand, even if a large amount of a pH regulator is used in order to make the pH of the mixed solution higher than 8.0, there is no significant change in the bitterness and feeling of administration of the preparation.

  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 moles, particularly 2.5 to 3.5 moles per mole of propiverine hydrochloride. Can be blended.

Surfactant The surfactant in the present invention is not particularly limited as long as it can be added to a propiverine hydrochloride aqueous solution and finely disperse the drug particles, and various types can be used. 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 (for example, polyoxyl 40 stearate (Japanese Pharmacopoeia)), sorbitan sesquioleate, cetanol, polyoxyethylene castor oil derivative (for example, polyoxyethylene hydrogenated castor oil 40, Polyoxyethylene hydrogenated castor oil 60), polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene sorbitan fatty acid ester (for example, polysorbate 60 (standard for pharmaceutical additives), polysorbate 80 (Japanese Pharmacopoeia, etc.), polyethylene glycol (for example, Macrogol 300, Macrogol 400, Macrogol 600, etc.), glyceryl monostearate, anionic surfactant (for example, And sodium lauryl sulfate). You may use these in mixture of 2 or more types.

  In the present invention, it is usually preferable to use a surfactant having a specific HLB (Hydrophile Lipophile Balance) value appropriately selected from the above surfactants according to the type of pH regulator. 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 HLB of 11 to 18 are preferred, and polyethylene glycol fatty acid esters and polyoxyethylenes having HLB of 14 to 18 are preferred. Castor oil derivatives or polyoxyethylene sorbitan fatty acid esters are preferred, and polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80 are particularly preferred.

    Moreover, when using the said carbonates as said pH regulator, HLB is 11-40, Especially the surfactant of 14-40 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 an anionic surfactant is preferred, and further, an HLB of 14 to Preferred are 40 sucrose fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters or anionic surfactants, particularly sucrose stearate ester, polyoxyl 40 stearate, polyoxyethylene Hardened castor oil 60, polysorbate 80, and sodium lauryl sulfate are preferred.

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

  The HLB (Hydrophile Lipophile Balance) value is an index that represents the lipophilicity and hydrophilicity of the surfactant. The closer to 0, the higher the lipophilicity, and the higher the value, the higher the hydrophilicity.

  The HLB value can be calculated by various calculation formulas. In the present invention, for example, the HLB value should be calculated by the method described in “New Edition Surfactant Handbook (Engineering Books Co., Ltd.) pp234-236 [1987]”. Can do.

Methods for Producing the Oral Powder Granule Formulation of the Present Invention Various methods can be adopted to produce the oral powder granule formulation of the present invention. In general, first, propiverine hydrochloride, a surfactant, a pH regulator and water are mixed. A suspension adjusted to pH 6.5 to 8.0 with the pH adjusting agent is obtained. Subsequently, the granular formulation of this invention can be manufactured by granulating using the well-known formulation additive and this suspension.

  The suspension is prepared by mixing (i) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH adjusting agent or an aqueous pH adjusting agent so that the pH of the suspension is 6.5 to 8.0. Can be obtained. Alternatively, the suspension is prepared by, for example, mixing (iii) a mixture containing a surfactant, a pH adjusting agent and water, and (iv) an aqueous propiverine hydrochloride solution so that the pH of the suspension is 6.5 to 8.0. Can also be obtained. Without being limited to these methods, the suspension of the present invention can be produced by other methods.

  In the resulting suspension, since the raw material propiverine hydrochloride is neutralized using a pH adjuster, substantially the entire amount of propiverine hydrochloride is a free base (free propiverine). However, a salt of propiverine, such as propiverine hydrochloride or a salt of propiverine and a pH adjusting agent, may be contained in a slight amount, particularly in an amount that does not cause a bitter taste in the final preparation. The amount of the propiverine salt is preferably less than 5%, particularly less than 2%, relative to the amount of propiverine hydrochloride charged.

In either case, 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, based on the suspension
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 ),
Content of pH adjusting agent: an amount such that the pH of the suspension is 6.5 to 8.0, preferably 6.8 to 7.4,
Suspension pH: 6.5-8.0, preferably 6.8-7.4.

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

  In the aqueous solution containing the surfactant (i) and propiverine hydrochloride, the amount of propiverine hydrochloride used is 1 to 50% (w / w), particularly 2 to 10% (w / w) based on the solvent water. w) is preferred.

  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. The addition amount is propiverine hydrochloride. In general, it may be added 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). Within this range, it is possible to prevent a large amount of drug from being dissolved by the action of the surfactant and to make it easier to feel the taste of the surfactant itself, so that bitterness is suppressed and the feeling of taking is good. In addition, when a surfactant is not used, the abundance ratio of coarse particles in the spray suspension becomes high, and granulation by a fluidized bed is impossible.

  Further, the amount of the pH regulator used in the above (ii) can be appropriately selected from a wide range as long as a desired suspension is obtained, but usually the pH of the finally obtained suspension is 6.5 to 8.0, preferably Is preferably used in an amount of 6.8 to 7.4. The pH regulator may be used as it is, but it can also be used in the form of an aqueous solution in advance.

  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 0.5 to the weight of propiverine hydrochloride. It may be added in the range of 15% (w / w), more preferably 0.65 to 13% (w / w). Further, the amount of the pH regulator used can be appropriately selected from a wide range as long as a desired suspension is obtained. Usually, the pH of the finally obtained suspension is 6.5 to 8.0, preferably 6.8 to 7.4. It is preferably used in such an amount. In the mixture containing the surfactant (iii), the pH adjuster and water, the total amount of the surfactant and the pH adjuster can be appropriately selected from a wide range, but generally 0.1 to 500% with respect to water ( w / w), particularly 1 to 150% (w / w) is preferred.

  In the above-mentioned (iv) aqueous propiverine hydrochloride, the amount of propiverine hydrochloride used is preferably 1 to 50% (w / w), particularly 2 to 10% (w / w) with respect to water as the solvent. .

  In the production method of the present invention, as described above, when the phosphates are used as a pH regulator, it is preferable to use a surfactant having an HLB of 11 to 18, particularly 14 to 18. Moreover, when using the said carbonates as a pH regulator, it is preferable to use the surfactant whose HLB is 11-40, especially 14-40.

  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.

  In the production of the suspension, the mixing of (i) and (ii) and the mixing of (iii) and (iv) can be carried out by a known apparatus such as a magnetic stirrer, homogenizer, homomixer, homogenizer. What is necessary is just to carry out using a disper, a stirring propeller, etc.

  The mixing conditions can be appropriately selected from a wide range, and are not particularly limited. In general, a desired suspension can be prepared at a temperature of 15 to 30 ° C., particularly 20 to 25 ° C., at a stirring speed at which both are sufficiently mixed. The mixing operation may be performed until it is obtained.

  The suspension obtained by mixing propiverine hydrochloride, a surfactant, a pH adjusting agent and water and adjusting the pH to 6.8 to 7.4 with the pH adjusting agent has few large particles having a particle size exceeding 100 μm, In addition, the dispersed state of the particles is good. The abundance ratio of large particles having a particle size exceeding 100 μm is usually 50% or less, particularly about 10 to 45%.

  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.

  When the above-mentioned 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 preparations. A powdery granular preparation having a good feeling can be obtained, and a decrease in compliance with medication resulting from an unpleasant taste and feeling of taking can be avoided. Therefore, the present invention also provides a suspension prepared by mixing the above propiverine hydrochloride, a surfactant, a pH adjusting agent and water and adjusted to pH 6.5 to 8.0 with the pH adjusting agent.

  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, a fluidized bed, using known preparation additives as necessary. A granulation method, an agitation granulation method, a rolling fluidized bed granulation method, an extrusion granulation method, a spray drying method, or the like can be used, but is not limited thereto. Among these, it is preferable to perform granulation by spraying the suspension of the present invention onto a known formulation additive.

  When using the above-mentioned preparation additive, it is used within a range not impeding the effects of the present invention. Examples of such formulation additives include various formulation additives generally used in the production of granular formulations, such as sugars, excipients, disintegrants, binders, lubricants, coloring agents, flavoring agents, and flavoring agents. An agent etc. can be mentioned.

  Specific examples of sugars include monosaccharides (arabinose, xylose, glucose, fructose, galactose, mannose, sorbose, etc.), oligosaccharides (sucrose, lactose, maltose, reduced maltose, isomaltose, etc.), sugar alcohols (xylitol, Erythritol, sorbitol, mannitol, etc.). These saccharides may be used alone or in combination of two or more.

  Examples of the excipient include starch, crystalline cellulose, light anhydrous silicic acid and calcium silicate.

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

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and the like.

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

  Examples of the colorant include edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow ferric oxide and titanium oxide.

  Examples of flavoring agents include oranges and lemons.

  Examples of the corrigent include L-menthol, camphor, and mint.

  As a typical production method of the oral powdery granular preparation of the present invention, for example, using the fluidized bed granulation coating apparatus, the suspension of the present invention is sprayed on the fluidized formulation additive and granulated. A method can be mentioned.

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. be able to. Granules, powders, and fine granules include dry syrups that are dissolved at the time of use, and also include granules that dissolve rapidly in the oral cavity and can be taken without water.

  The oral powder granular preparation of the present invention contains (a) propiverine, (b) surfactant and (c) pH adjuster, and, if necessary, the preparation additive, and bitterness is suppressed. In addition, it is an oral powder granular preparation with good taking feeling.

  In the present invention, it is general that propiverine is contained in a formulation of 0.5 to 10% (w / w), particularly 1 to 5% (w / w) in terms of propiverine hydrochloride. The medicinal component concentration may be outside this range, but it is usually not practical. Because a single dose of propiverine hydrochloride is expected to be around 20 mg, but if the drug concentration is lower than 0.5% (w / w), more than 4 g of a granular formulation is required to take propiverine hydrochloride equivalent to 20 mg. If the drug concentration is higher than 10% (w / w), the propiverine hydrochloride equivalent of 20 mg is less than 200 mg, but this amount is less This is because it is very difficult to fill with the apparatus.

  In the oral granular preparation of the present invention, propiverine hydrochloride is neutralized with a pH adjuster, and as a result, exists in the form of the free base of propiverine hydrochloride. The preparation of the present invention may contain only the free base, but may contain some amount of salt of propiverine, such as propiverine hydrochloride, salt of propiverine and pH adjuster. The amount of the propiverine salt is preferably less than 5%, particularly preferably less than 2%, relative to the amount of propiverine hydrochloride added. I don't feel bitterness.

  More specifically, the oral granular preparation of the present invention contains (a) propiverine in an amount of 0.5 to 10% (w / w) in terms of propiverine hydrochloride, and (b) a surfactant and (c) a pH regulator. An oral powdered granular formulation containing 25 mg of propiverine hydrochloride in the final formulation, and the suspension obtained by shaking with 25 mL of water has a pH of 6.5 to 8.0, preferably 7.0-7.5.

  The shaking is performed for 60 minutes in a constant temperature bath set at 25 ° C. under conditions of a width of 30 mm and a speed of 120 rpm.

  In the above, the content of the surfactant is 0.1 to 100% (w / w), particularly 0.5 to 15% (w / w), more preferably 0.65 to 13%, based on propiverine hydrochloride weight of propiverine in (a) (w / w) is preferred.

  Further, the amount of the pH regulator is an amount effective for the pH of the suspension obtained by shaking the preparation corresponding to 25 mg of propiverine hydrochloride to 25 mL of water to be 6.5 to 8.0. is there.

  In the preparation of the present invention, as described above, when the phosphates are used as a pH regulator, it is preferable to use a surfactant having an HLB of 11 to 18, particularly 14 to 18. Moreover, when using the said carbonates as a pH regulator, it is preferable to use the surfactant whose HLB is 11-40, especially 14-40.

  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 preferably polyoxyl stearate 40.

  The granular preparation of the present invention significantly improves the unpleasant taste of propiverine hydrochloride, provides a fine granular preparation when taken in the mouth, and can avoid a decrease in compliance with the unpleasant taste and feeling of taking. .

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

Example 1
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. On the other hand, 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 A) and stirred until uniform to prepare a suspension of the present invention. . The pH of the obtained suspension (Liquid A + Liquid B) was 7.0.

Examples 2 and 3
According to the same method as in Example 1, a suspension of the present invention was 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 was manufactured by Wako Pure Chemical Industries, Ltd., and polyoxyl stearate 40 was manufactured by Nikko Chemicals.

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

Example 4
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 solution (liquid A) and stirred until uniform to prepare a suspension of the present invention. The pH of the obtained suspension (liquid A + liquid C) was 7.0.

Examples 5-8
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 was manufactured by Wako Pure Chemical Industries, Ltd., polyoxyl stearate 40 was manufactured by Nikko Chemicals, sucrose stearate was Daiichi Kogyo Seiyaku Co., Ltd., and sodium lauryl sulfate was Wako Pure Chemical Industries, Ltd. Made from

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 added. The pH of the obtained suspension is shown in Table 1.

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.

<Evaluation method>
The precipitated drug particles in the suspension are collected by filtration through a filter having an opening of 100 μm and dried in a vacuum at 50 ° C. for 21 hours or more. This was weighed (WL), and the abundance P (%) of the drug particles having a particle diameter larger than 100 μm was calculated based on the amount of the charged drug (Wo, that is, the charged amount of propiverine hydrochloride) in terms of the free base. Calculated from the formula:
Presence P (%) = [WL / (Wo × (367.48) / (403.94))] × 100
In the above formula, 367.48 is the molecular weight of propiverine, and 403.94 is the molecular weight of propiverine hydrochloride.

  This means that the smaller the abundance P is, the more particles having a particle diameter of 100 μm or less are present in the suspension, and the better the dispersion state.

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

  In Comparative Examples 1 and 2 in which the surfactant was not used, a huge waxy substance was generated and adhered to the reaction vessel.

  In contrast, when a pH regulator is used in combination with a surfactant, for example, when phosphates (dipotassium phosphate) are used as the pH regulator and a surfactant having an HLB of 14 to 18 is used ( Examples 1 to 3), the presence rate (%) of drug particles having a particle size larger than 100 μm was lower than that of Comparative Example 1, and it was found that the dispersion state was improved. In addition, when a foaming carbonate (sodium hydrogen carbonate) is used as the pH adjuster, the HLB of the surfactant is 14 to 40, and the dispersion state is higher than that of Comparative Example 2 in which no surfactant is used. It turned out to be improved.

Example 9
10 g of propiverine hydrochloride and 0.13 g of polyoxyl stearate (manufactured by Nikko Chemicals Co., Ltd.) were dissolved in 225 g of purified water (liquid A ′). Further, a solution (liquid B) in which 12.94 g of dipotassium phosphate was dissolved in 150 g of purified water was added to the aqueous propiverine hydrochloride solution (liquid A ′), and the mixture was 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.

  On the other hand, D-mannitol 379.87g, refined white sugar 43g, low substituted hydroxypropylcellulose (trade name "LH-31" manufactured by Shin-Etsu Chemical Co., Ltd.) 47g, light anhydrous silicic acid 2g, fluidized bed granulation coating equipment (product) The name “Multiplex MP-01” (manufactured by POWREC Co., Ltd.) 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.

Example 10
10 g of propiverine hydrochloride and 0.13 g of polyoxyl stearate (Nikko Chemicals Co., Ltd.) are dissolved in 225 g of purified water (liquid A ′). Further, a solution (liquid B ′) 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 ′), followed by stirring 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.

  Meanwhile, 379.87g of D-mannitol, 43g of refined sucrose, 47g of low-substituted hydroxypropylcellulose (LH-31) and 2g of light anhydrous silicic acid were charged into a fluidized bed granulation coating device (Multiplex MP-01) and suspended. The liquid 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.

Test example 2
The preparations obtained in Examples 9 and 10 were subjected to a sensory test (standard panel test) for bitterness and feeling of ingestion. The evaluation items are as follows.
Evaluation items: The bitterness and feeling of administration of the preparation are evaluated according to the following criteria.

[Bitter taste]
4: Extremely bitter 3: Bitter 2: Slightly bitter 1: Does not feel bitter.

[Feeling of taking]
4: Cannot be taken 3: Not easy to take 2: Slightly difficult to take 1: Can be taken

  As a result, there was no evaluation of “very bitter” for bitterness, and an evaluation of “not feeling bitter” or “slightly bitter” was obtained. Was good. In addition, when both were compared, the sensory test for bitterness was the same for both, but in the sensory test for the feeling of dosing, compared to the preparation of Example 10 using sodium bicarbonate as a pH regulator, The evaluation that the preparation of Example 9 using dipotassium phosphate as a pH regulator was superior was obtained.

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 resulting suspension is shown in Table 2. In Table 2, the formulation and pH of Example 9 are also shown.

Comparative Example 3
10 g of propiverine hydrochloride and 0.13 g of polyoxyl stearate (manufactured by Nikko Chemicals Co., Ltd.) were dissolved in 225 g of purified water (liquid A ′). Further, 150 g of purified water (Liquid C) was added, and the mixture was stirred for 1 hour at 600 rpm using a magnetic stirrer. At this time, the pH of the solution (Liquid A ′ + Liquid C) was 4.2 (see Table 2).

  Meanwhile, 379.87g of D-mannitol, 43g of purified white sugar, 47g of low-substituted hydroxypropylcellulose (LH-31) and 2g of light anhydrous silicic acid were charged into a fluidized bed granulation coating device (Multiplex MP-01), and the above 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.

Test example 3
The preparations obtained in Examples 9, 11, 12 and Comparative Example 3 were subjected to a sensory test on bitterness and feeling of taking. The sensory test was performed according to Test Example 2.

  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 not evaluated as “very bitter” and “feeling bitter” “No” or “somewhat bitter” was obtained, and the feeling of taking was not evaluated as “cannot be taken”, and the feeling of taking was good. Above all, pH 7.0 (Example 9) was evaluated as having the weakest bitterness and the best feeling of dosing.

  On the other hand, when the pH of the solution is 4.2 (Comparative Example 3), the sensory test for bitterness is often evaluated as “bitter”, and the sensory test for feeling of taking is “difficult to take” or “cannot be taken” "There were many evaluations.

  As is clear from the above results, Examples 11, 9, and 12 produced using suspensions having a pH of 6.8 to 7.4 were bitter in preparation compared to Comparative Example 3 produced using a solution having a pH of 4.2. And the feeling of taking was improved.

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 3 also shows the formulation of Example 9 for comparison.

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

Comparative Example 4
10 g of propiverine hydrochloride is dissolved 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 stirred at 600 rpm for 1 hour using a magnetic stirrer.

  When the obtained suspension was visually observed, a huge wax-like substance was produced and adhered to the reaction vessel. In addition, for the solid that is not attached to the reaction vessel in the suspension (Liquid B + Liquid D), very large particles are confirmed, and the drug particles having a particle diameter larger than 100 μm are evaluated by the evaluation method used in Test Example 1. The abundance P was found to be 87.2 (%), and it was thought that spraying from a spray gun was difficult, so a fine granule could not be obtained.

Test example 4
The preparations obtained in Examples 9, 13 and 14 were subjected to a sensory test for bitterness and feeling of taking. The sensory test was performed according to Test Example 2.

  As a result, when the addition amount (%) of polyoxyl stearate (produced by Nikko Chemicals Co., Ltd.) to propiverine hydrochloride is 0.65% (Example 13), 1.3% (Example 9), 13% (Example 14), For bitterness, there was no evaluation of “extremely bitter”, and there was no evaluation of “bitterness” or “slightly bitter”. It was. Among these, when the addition amount (%) of polyoxyl stearate was 1.3% (Example 9), it was evaluated that the bitterness was the weakest and the feeling of taking was the best.

  On the other hand, when polyoxyl stearate 40 is not added to the mixed solution (Comparative Example 4), a huge wax-like substance is generated, adheres to the reaction vessel, and the drug particles are not sufficiently dispersed, so that the fluidized bed It was found that the formulation could not be obtained by granulation.

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 this was added to 25 mL of water and shaken. The pH of the resulting liquid was examined.

The shaking conditions are as follows.
Thermostatic bath set temperature: 25 ℃
Amplitude: Width 30mm
Shaking speed: 120rpm
Shaking time: 60 minutes The results are shown in Table 4 below.

  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). It turns out to be near neutral. Therefore, in consideration of the results of Test Examples 3 to 5, it is considered that an unpleasant taste can be improved if the pH obtained in the shaking test for the preparation of the present invention is near neutral.

  According to the present invention, when a granular preparation is produced using a liquid obtained by mixing a propiverine hydrochloride aqueous solution to which a surfactant is added and a liquid containing a pH adjuster, the unpleasant taste is remarkably improved. 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 (29)

  An oral powdered granular preparation containing (a) propiverine, (b) a surfactant, and (c) a pH regulator and having a good dosing feeling.   (a) Propiverine containing 0.5 to 10% (w / w) of propiverine hydrochloride, and further comprising (b) a surfactant and (c) a pH regulator, The oral powdery granular preparation according to claim 1, wherein the pH of a suspension obtained by adding the preparation containing 25 mg of propiverine hydrochloride to 25 mL of water and shaking is 6.5 to 8.0.   The oral powder granule preparation according to claim 1, wherein the pH regulator is a phosphate and the surfactant HLB is 11-18.   The oral powder preparation according to claim 3, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80 and polyoxyl 40 stearate.   The oral powder granule preparation according to claim 1, wherein the pH regulator is a carbonate, and the surfactant HLB is 11 to 40.   The oral powder according to claim 5, wherein the surfactant 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. Formulation.   The oral granular preparation according to claim 1, wherein the surfactant has an HLB of 14 to 18, and the pH regulator is dipotassium phosphate.   The oral powder preparation according to claim 7, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.   The oral powder preparation according to claim 1, wherein the surfactant is polyoxyl 40 stearate and the pH regulator is dipotassium phosphate.   2. The oral granular preparation according to claim 1, wherein the content of the surfactant is 0.1 to 100% (w / w) with respect to the weight of propiverine in terms of propiverine hydrochloride. A method for producing an oral powder formulation comprising 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
(2) A production method comprising the step of granulating the suspension obtained in step (1) together with a pharmaceutical additive.   12. The production method according to claim 11, wherein in the step (2), the suspension is granulated by spraying onto the formulation additive.   In step (1), the suspension comprises (i) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH regulator or a pH regulator aqueous solution, so that the suspension has a pH of 6.5 to 8.0. The manufacturing method of Claim 11 obtained by mixing so that.   In step (1), the suspension is prepared by adding (iii) a mixture containing a surfactant, a pH regulator and water, and (iv) an aqueous propiverine hydrochloride solution so that the pH of the suspension is 6.5 to 8.0. The manufacturing method of Claim 11 obtained by mixing.   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.   The production method according to claim 11, wherein the pH regulator is a phosphate or a carbonate.   The production method according to claim 11, wherein the pH regulator is a phosphate, and the HLB of the surfactant is 11-18.   The production method according to claim 17, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.   The production method according to claim 11, wherein the pH adjuster is a carbonate, and the surfactant has an HLB of 11 to 40.   The method according to claim 19, wherein the surfactant 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 production method according to claim 11, wherein the surfactant has an HLB of 14 to 18, and the pH regulator is dipotassium phosphate.   The production method according to claim 21, wherein the surfactant is at least one selected from the group consisting of polyoxyethylene hydrogenated castor oil 60, polysorbate 80, and polyoxyl 40 stearate.   The production method according to claim 21, wherein the surfactant is polyoxyl 40 stearate.   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.   The oral powder granular preparation which can be obtained with the manufacturing method of Claim 11.   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.   27. The propiverine is present in an amount of 1 to 45% (w / w) in terms of propiverine hydrochloride, and the surfactant content is 0.1 to 100% (w / w) based on the weight of propiverine hydrochloride. Suspension.   27. The suspension of claim 26, wherein the abundance of large particles having a particle size greater than 100 μm is about 50% or less. Propiverine hydrochloride, a surfactant, a pH adjuster and water are mixed to produce a suspension adjusted to pH 6.5 to 8.0 with the pH adjuster,
(i) an aqueous solution containing a surfactant and propiverine hydrochloride and (ii) a pH adjusting agent or an aqueous pH adjusting agent solution are mixed so that the pH of the suspension is 6.5 to 8.0, or
(iii) A production method comprising mixing a mixture containing a surfactant, a pH regulator and water, and (iv) an aqueous propiverine hydrochloride solution so that the pH of the suspension is 6.5 to 8.0.