WO2006046560A1 - Préparation orale particulaire contenant de la propivérine et procédé de fabrication de ladite préparation - Google Patents

Préparation orale particulaire contenant de la propivérine et procédé de fabrication de ladite préparation Download PDF

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Publication number
WO2006046560A1
WO2006046560A1 PCT/JP2005/019602 JP2005019602W WO2006046560A1 WO 2006046560 A1 WO2006046560 A1 WO 2006046560A1 JP 2005019602 W JP2005019602 W JP 2005019602W WO 2006046560 A1 WO2006046560 A1 WO 2006046560A1
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WIPO (PCT)
Prior art keywords
surfactant
suspension
propiverine
propiverine hydrochloride
regulator
Prior art date
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PCT/JP2005/019602
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English (en)
Japanese (ja)
Inventor
Tetsuo Ogata
Atsuo Koide
Original Assignee
Taiho Pharmaceutical Co., Ltd.
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Publication date
Application filed by Taiho Pharmaceutical Co., Ltd. filed Critical Taiho Pharmaceutical Co., Ltd.
Priority to JP2006543172A priority Critical patent/JP4895819B2/ja
Publication of WO2006046560A1 publication Critical patent/WO2006046560A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an oral powder granular preparation containing propiverine and a method for producing the same.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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. ⁇ Mi / ko.
  • a granular preparation can be produced by granulation using the suspension and a pharmaceutical additive used in a normal granular preparation.
  • Item 1 An oral powdered granular preparation containing a good feeling of administration, comprising (a) propiverine, (b) a surfactant and (c) a pH regulator.
  • Item 2 (a) Propiverine containing 0.5-10% (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.
  • 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
  • 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.
  • 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.
  • Item 7 The HLB of the surfactant is 14 to 18, and the pH regulator is dipotassium phosphate
  • 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.
  • 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,
  • the manufacturing method characterized by including.
  • Item 12 The method according to Item 11, wherein, in the step (2), the suspension is sprayed onto a pharmaceutical additive and granulated.
  • 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
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • Item 23 The method according to Item 21, wherein the surfactant is polyoxyl 40 stearate.
  • Item 24 The surfactant content in the suspension is 0.1% relative to the weight of propiverine hydrochloride.
  • Item 25 (or obtained by the production method according to any one of Items 11 to 24)
  • Oral powder granular formulation Oral powder granular formulation.
  • 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 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
  • 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.
  • 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,
  • r% ( w / w) j represents the percentage of weight relative to the weight of the solution or suspension or formulation.
  • % (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.
  • 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.
  • a granular preparation can be produced by granulation using the additive for preparation used in a normal granular preparation and the suspension.
  • 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.
  • 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.
  • 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.
  • alkaline earth metal salts of organic acids include salts of the above organic acids with alkaline earth metals such as magnesium and calcium.
  • amino acids include glycine, serine, threonine, asparagine, dartamine, lysine, arginine, histidine, and the like.
  • metal salts of amino acids alkali metal salts of amino acids are preferred.
  • alkali metal salts include salts of the above amino acids with alkali metals such as sodium and potassium.
  • 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.
  • 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
  • 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.
  • inferior, calcium salt, magnesium salt, aluminum salt, etc. can also be used.
  • 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.
  • 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.
  • carbonates When carbonates are used, the dispersibility of the drug particles may be improved by the generation of carbon dioxide.
  • 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).
  • 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!
  • 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
  • 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.
  • 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, polysorbitan fatty
  • 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.
  • 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.
  • a surfactant having an HLB of 11 to 40, particularly 14 to 40 is preferable.
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • the suspension of the present invention can be produced by other methods.
  • the pH adjuster is used to neutralize the raw material propiverine hydrochloride! Therefore, substantially all of propiverine hydrochloride is free base (free propiverine )
  • 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.
  • 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),
  • pH regulator Suspension pH 6.5-8.0, preferably 6.8-7.4, Suspension! "[: 6.5-8.0, preferably 6.8-7.4.
  • the concentration of each component, usage pattern, and the like are not particularly limited, but typically, the following may be performed.
  • 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.
  • 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 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.
  • w / w 0.1 to 100%
  • w / w preferably 0.5 to 15%
  • w / w more preferably 0.65 to 13%
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • the surfactant has an HLB of 14 to 18, and the pH adjuster is dipotassium phosphate.
  • the surfactant is particularly preferably polyoxyl 40 stearate.
  • 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.
  • 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%.
  • 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 ⁇ m 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 ⁇ m.
  • 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.
  • 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.
  • preparation additive When the above-mentioned preparation additive is used, it is used within a range not impeding the effects of the present invention.
  • 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.
  • saccharide examples 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.
  • excipient examples include starch, crystalline cellulose, light anhydrous kaic acid and calcium silicate.
  • Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, crospovidone, carmellose calcium, and croscarmellose sodium.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polybulal alcohol, and polybulurpyrrolidone.
  • 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 dianhydride and iron oxide, and acid and titanium.
  • Examples of the flavoring agent include various flavors of orange and lemon.
  • Examples of the corrigent include L-menthol, camphor, potato, and cocoa.
  • 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.
  • 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.
  • 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.
  • it is an oral powder granular preparation that is suppressed and has a good feeling of administration.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the surfactant has an HLB of 14 to 18, and the pH adjuster is dipotassium phosphate.
  • the surfactant is preferably polyoxyl 40 stearate.
  • 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.
  • 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.
  • polysorbate 80 was manufactured by Wako Pure Chemical Industries, Ltd.
  • polyoxyl stearate 40 was manufactured by Nikko Chemicals.
  • 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.
  • the pH of the resulting suspension (Liquid A + Liquid C) was 7.0.
  • 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.
  • 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.
  • sodium lauryl sulfate is Wako Pure Chemical Industries. Yakuhin Co., Ltd. product was used.
  • 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.
  • 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
  • 367.48 is the molecular weight of propiverine
  • 403.94 is the molecular weight of propiverine hydrochloride.
  • a pH regulator for example, a phosphate (dipotassium phosphate) is used as the pH regulator, and a surfactant having an HLB of 14 to 18 is used.
  • 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.
  • 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.
  • foaming carbonates sodium hydrogen carbonate
  • 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.
  • 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.
  • 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.
  • Table 2 the formulation and pH of Example 9 are also shown.
  • Example 9 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.
  • pH 7.0 Example 9 was evaluated as having the best bitterness and the best feeling.
  • Example 11 produced using a suspension having a pH of 6.8 to 7.4.
  • Example 9 a fine granule was produced in the same manner with the charge shown in Table 3.
  • Example 9 In FIG. 3, the formulation of Example 9 is also shown for comparison.
  • Table 3 shows the amount (% by weight) of polyoxyl stearate 40 (manufactured by Nikko Chemicals Co., Ltd.) to propiverine hydrochloride.
  • 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.
  • 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)
  • 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.
  • the shaking conditions are as follows.
  • Temperature chamber set temperature 25 ° C
  • 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.

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Abstract

La présente invention a pour objet une préparation orale contenant, au titre de principe thérapeutique, du chlorhydrate de propivérine disponible commercialement, et qui garantit une sensation agréable lors de son administration, évitant ainsi le non-respect de la posologie par le patient. Une préparation particulaire garantissant une sensation agréable lors de son administration peut être produite en élaborant une suspension obtenue à partir du mélange de chlorhydrate de propivérine, d'un agent tensioactif, d’un tampon de pH et d’eau, dont la valeur de pH est ajustée pour être comprise entre 6,5 et 8,0 par le tampon de pH, puis en mettant en forme la suspension avec les additifs courants pour une préparation de ce type, de façon à obtenir une préparation particulaire.
PCT/JP2005/019602 2004-10-29 2005-10-25 Préparation orale particulaire contenant de la propivérine et procédé de fabrication de ladite préparation WO2006046560A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090258066A1 (en) * 2008-04-15 2009-10-15 Gopi Venkatesh Compositions comprising weakly basic drugs and controlled-release dosage forms
JP2013231011A (ja) * 2012-05-01 2013-11-14 Sawai Pharmaceutical Co Ltd アトルバスタチン含有医薬組成物およびそれを用いた口腔内崩壊錠
WO2017026950A1 (fr) 2015-08-07 2017-02-16 Santa Farma Ilac San. A. S. Formulations de propivérine à libération contrôlée
WO2020101586A1 (fr) 2018-11-16 2020-05-22 Santa Farma İlaç Sanayi̇ A.Ş. Formulations de propivérine à libération contrôlée
WO2022115056A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Compositions de formulation à libération prolongée comprenant de la propivérine

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WO2003030869A1 (fr) * 2001-10-09 2003-04-17 Apogepha Arzneimittel Gmbh Formes d'administration orale de propiverine ou de ses sels pharmaceutiquement acceptables, a liberation prolongee des agents actifs
WO2003070233A1 (fr) * 2002-02-19 2003-08-28 Pharmacia Corporation Utilisation d'inhibiteurs de la cyclooxygenase et d'agents anti-muscariniques destinee au traitement de l'incontinence
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090258066A1 (en) * 2008-04-15 2009-10-15 Gopi Venkatesh Compositions comprising weakly basic drugs and controlled-release dosage forms
JP2013231011A (ja) * 2012-05-01 2013-11-14 Sawai Pharmaceutical Co Ltd アトルバスタチン含有医薬組成物およびそれを用いた口腔内崩壊錠
WO2017026950A1 (fr) 2015-08-07 2017-02-16 Santa Farma Ilac San. A. S. Formulations de propivérine à libération contrôlée
WO2020101586A1 (fr) 2018-11-16 2020-05-22 Santa Farma İlaç Sanayi̇ A.Ş. Formulations de propivérine à libération contrôlée
WO2022115056A1 (fr) 2020-11-27 2022-06-02 Santa Farma Ilac Sanayii A.S. Compositions de formulation à libération prolongée comprenant de la propivérine

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