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WO2000018396A1 - PREPARATIONS A BASE D'INHIBITEUR DE HMG-CoA - Google Patents

PREPARATIONS A BASE D'INHIBITEUR DE HMG-CoA Download PDF

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Publication number
WO2000018396A1
WO2000018396A1 PCT/JP1999/005200 JP9905200W WO0018396A1 WO 2000018396 A1 WO2000018396 A1 WO 2000018396A1 JP 9905200 W JP9905200 W JP 9905200W WO 0018396 A1 WO0018396 A1 WO 0018396A1
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WO
WIPO (PCT)
Prior art keywords
hmg
reductase inhibitor
coa reductase
preparation
coated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1999/005200
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English (en)
Japanese (ja)
Inventor
Fusao Usui
Shuichi Yada
Kiyoshi Kawabata
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Sankyo Co Ltd
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Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sankyo Co Ltd filed Critical Sankyo Co Ltd
Priority to AU57587/99A priority Critical patent/AU5758799A/en
Publication of WO2000018396A1 publication Critical patent/WO2000018396A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to a coating formulation containing an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase drugs for the treatment of hyperlipidemia, which specifically inhibit the rate-limiting enzyme in the cholesterol biosynthesis system (HMG-CoA reductase), have been developed and their preparations are known.
  • formulations coated with pravastatin sodium are disclosed in, for example, No. 59-193,831, Japanese Patent Application Laid-Open No. Sho 59-193,332, and US Pat. No. 5,225,022.
  • JP-A-59-1933381 discloses that uncoated tablets containing pravastatin sodium are coated with hydroxypropyl methylcellulose, and furthermore, It describes a preparation in which carboxymethylethylcellulose is added with, for example, sodium alginate and coated with a coating solution whose dissolution starting pH has been adjusted.
  • Japanese Unexamined Patent Publication (Kokai) No. 59-193382 discloses that uncoated tablets containing pravastatin sodium are coated with hydroxypropylmethylcellulose, and carboxymethylethylcellulose is further placed thereon. Describes a preparation coated with a coating solution to which sodium hydroxide is added and the dissolution start pH is adjusted.
  • U.S. Pat.No. 5,252,502 discloses that uncoated pellets containing pravastatin sodium are draped with hydroxypropylmethylcellulose, and then hydroxypropylmethylcellulose phthalate is further added thereto. Preparations in which sodium oxide was added and the dissolution was initiated were coated with a coating solution whose pH was adjusted. You.
  • the major absorption site of pravastatin sodium in the digestive tract is the duodenum, that is, the upper part of the small intestine. It is known that the hydroxyl group bonded to the hexahydronaphthalene ring is isomerized by the transfer of an acid (3.alpha.-hydroxyxy sopravastatin) (J. C1 inn. ., 1 995
  • the present inventors have found that the above-mentioned preparation has the above-mentioned isomer (by-product) in blood and lacks stability over time.
  • the present inventors diligently studied to develop a formulation that does not produce pravastatin sodium by-product and has excellent temporal stability of pravastatin sodium.
  • the present invention relates to a preparation containing an HMG-CoA reductase inhibitor coated with cell mouth acetate or hydroxypropylmethylcellulose trimellitate.
  • the present invention relates to pravastatin sodium preparations coated with cellulose acetate maleates or hydroxypropinolemethyl cellulose trimellitate.
  • the present invention [1] HMG-CoA reductase inhibitor (particularly pravastatin sodium) coated with cellulose acetate maleates.
  • the cellulose acetate maleates are coating bases in which a water-soluble cellulose derivative is substituted with an acetyl group and a maleyl group.
  • substitution number of the acetyl group and the maleyl group to be substituted for the water-soluble cellulose derivative affects the solubility of the product, cellulose acetate maleate.
  • the number of substituents of the acetyl group is in the range of 0.2 to 0.5 per glucose ring of the water-soluble cellulose derivative. Preferably it is in the range of 0.2 to 0.4, particularly preferably 0.3. If the number of substitution of the acetyl group is less than 0.2, the hydrophobicity of the acetyl group is insufficient and the acid resistance is insufficient. On the other hand, when the number of substitution of the acetyl group exceeds 0.5, the cellulose acetate maleates become too hydrophobic and the dissolution start pH becomes higher than 4.
  • the number of substituents of the maleyl group is suitably in the range of 0.3 to 0.6.
  • the number of substitution of the maleyl group is in the range of 0.5 to 0.6, and particularly preferably 0.6.
  • the number of substitution of the maleyl group is less than 0.3, dissolution of the cellulose acetate maleate by dissociation of the maleyl group becomes insufficient, and the dissolution start pH becomes larger than 4, while the substitution of the maleyl group is performed. If the number exceeds 0.6, dissolution starting pH of cellulose acetate maleates becomes 3 or less, and the acid resistance as a coating base is insufficient. In addition, a large amount of cellulose acetate maleates dissolve in water during the crystallization and washing steps, making washing difficult.
  • water-soluble cellulose derivative as a raw material of the above-mentioned cell-to-acetate-to-maleates
  • examples of the water-soluble cellulose derivative as a raw material of the above-mentioned cell-to-acetate-to-maleates include, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hydroxyshethyl cell mouth.
  • the viscosity of a 2% by weight aqueous solution of the water-soluble cellulose derivative is preferably 3 to 10 cP at 20 C. If it is less than 3 cP, the strength of the finally obtained coating film will be insufficient: If it exceeds 10 cP, the viscosity when reacting by dissolving in a solvent will decrease. too high.
  • hydroxypropinolemethinoresenolose acetates of H et al. Particularly preferably, hydroxypropyl methylcellulose has 0.2 to 0.4 per glucose ring (optimally, (0.3) acetyl group and 0.5 to 0.6 (optimally 0.6) maleyl group, and its dissolution starting pH is between 3 and 4. It is droxypropyl methylcellulose acetate maleate.
  • HMG-CoA reductase inhibitor particularly pravastatin sodium coated with hydroxypropyl methylcellulose trimethylate.
  • another one of the coating materials used in the present invention is hydroxypropylmethylcellulose trimellitate in which hydroxypropylmethylcellulose is substituted with a trimellityl group.
  • hydroxypropyl methylcellulose trimellitate used in the present invention can be added to hydroxypropyl methylcellulose having 1.1 to 2.1 methoxy groups per gnorecose ring and from 0.2 to 1 per glucose ring. Hydroxypropyl methylcellulose trimellitate substituted with 0 trimellityl groups (monovalent groups derived from trimellitic acid).
  • hydroxypropylmethylcellulose trimeritols is hydroxypropylmethylcellulose having 1.1 to 1.6 methoxy groups per glucose ring. It is a hydroxypropylmethylcellulose trimellitate in which 0.2 to 1.0 trimellityl groups per glucose ring are substituted.
  • hydroxypropylmethylcellulose having 1.3 to 1.5 methoxy groups per glucose ring is added to 0.4 to 0.8 (more preferably 0.5 (From 0.7 to 0.7) of the trimethyllicyl group.
  • the starting pH for dissolution of the hydroxypropyl methylcellulose trimellitate is 3. 5 to 4.5, and does not dissolve at a pH lower than that.
  • hydroxypropyl methylcellulose has less than 1.1 methoxy groups, it becomes difficult to dissolve hydroxypropylmethylcellulose in an organic solvent, and it becomes difficult to prepare a coating solution.
  • the number of methoxy groups exceeds 1.6 and the number of trimeric groups is 0.5 or more, the dissolution starting pH becomes 4.5 or more.
  • the number of trimeric groups is less than 0.2, the hydrophobicity by the trimeric groups becomes insufficient, so that moisture easily penetrates and the acid resistance as a coating base is insufficient.
  • the number of trimellityl groups exceeds 1.0, the pH at which dissolution starts is 4.5 or more.
  • hydroxypropylmethyl cellulose trimellitate as a coating base used in the present invention is a water-soluble compound having from 1.7 to 2.1 methoxy groups per glucose group. This is hydroxypropyl methylcellulose trimellitate in which 0.2 to 0.5 trimellityl groups per glucose ring are substituted with hydroxypropylmethylcellulose.
  • a water-soluble hydroxypropylmethylcellulose having 1.8 to 2.0 methoxy groups per glucose ring is substituted with 0.3 to 0.4 trimellityl groups per glucose ring.
  • Hydroxypropyl methylcellulose trimester is preferably used.
  • the starting pH for dissolution of the hydroxypropyl methylcellulose trimellitate is between 3.5 and 4.5, below which pH does not dissolve:
  • the hydroxypropinolemethylcellulose contains more than 2.1 methoxy groups, it will not be suitable for medical use. Further, when the number of trimeric groups is less than 0.2, the hydrophobicity by the trimeric groups becomes insufficient, so that moisture easily penetrates and the acid resistance as a coating base is insufficient. When the content of trimellityl groups exceeds 0.5, the dissolution starting pH is 4.5 or more.
  • the hydroxypropyl methylcellulose having a thiol group is substituted with 0.4 to 0.6 (optimally 0.5) trimellityl groups per glucose ring, and the dissolution start pH Hydroxypropyl methylcellulose trimellitate, 3.5 to 4.5;
  • the viscosity of a 2% by weight aqueous solution of hydroxypropylmethylcellulose which is a raw material used for the above-mentioned hydroxypropynolemethylcellulose trimellitate, is preferably from 30 to 10 cP at 20 C. Below 3 cP, the strength of the finally obtained coating film is insufficient. On the other hand, if it exceeds 10 cP, the viscosity when reacting by dissolving in a solvent is too high, and handling becomes inconvenient.
  • “dissolution start pH” described in (1) and (2) above means that when the pH of the dissolving solvent is gradually increased from a low pH, the coating film is applied to the dissolving solvent. Means the pH of the dissolving solvent that is first dissolved.
  • the starting pH for dissolution is measured by the method described below. Dissolve the coating base in an organic solvent, etc. to make a coating solution, and cast it onto a glass plate to make a ⁇ ⁇ ⁇ ⁇ finolem. This film is cut into lcm x lcm, and the film is dissolved in a solvent for dissolution using an auxiliary cylinder according to the disintegration test method of the 13th revision of the Japanese Pharmacopoeia. I do.
  • McValin buffers with different pH are used for the dissolution solvent. Cellulose acetate maleates and hydroxypropinolemethylcellulose trimellitate are described in JP-A-8-133899 or JP-A-8-310790, respectively, as described above. It can be manufactured by the method described above.
  • the cellulose acetate maleates first react maleic anhydride and acetic anhydride with a water-soluble cellulose derivative at a specific ratio.
  • Purified water is added to the reaction product and cooled to stop the substitution reaction.
  • an acid for example, a mineral acid such as hydrochloric acid or sulfuric acid
  • the reaction solution is poured into a large excess of water to form a base for coating. Is sufficiently precipitated.
  • the coating base is washed with purified water until the washing liquid is no longer acidic, and dried with a fluidized bed drier, etc. Is obtained. Grinding and sieving may be performed if necessary.
  • hydroxypropyl methylcellulose trimellitate first, hydroxypropylmethylcellulose is reacted with trimellitic anhydride at a specific ratio. Purified water is added to this reaction product and cooled to stop the substitution reaction. After the reaction is completed, if necessary, an acid (for example, a mineral acid such as hydrochloric acid or sulfuric acid) is added, and the reaction solution is poured into a large excess of water, and the hydroxypropyl methylcellulose trimethylate is added. Is sufficiently precipitated. After washings with purified water to wash the hydroxycarboxylic propyl methylation cellulose Application Benefits main retail preparative until no show acidity, P H 3 and dried in a fluidized bed dryer or the like. 5 to 4..
  • an acid for example, a mineral acid such as hydrochloric acid or sulfuric acid
  • a coating base that dissolves in the solvent is obtained. If necessary, grinding and sieving may be performed. Next, the coating liquid of the above base is obtained as follows. That is, the coating base obtained by the above production method is dissolved in an organic solvent such as acetone, methylene chloride alcohol, or alcohol / water, or the coating base is dispersed in water.
  • an organic solvent such as acetone, methylene chloride alcohol, or alcohol / water
  • the coating base is dispersed in water as a fine product having an average particle diameter of 1 ⁇ or less, preferably 2 ⁇ m to 7 m to form a coating liquid. If the average particle diameter of the fine products exceeds 10 m, a large amount of coating liquid is required to form a film.
  • the lower limit of the average particle diameter is not particularly limited. However, if the average particle diameter is less than 2 / im, it is difficult to substantially disperse the particles into primary particles under ordinary stirring conditions, and a uniform coating liquid may not be obtained.
  • the dispersion contains 3 to 15 weight of cellulose acetate maleates or hydroxypropyl methylcellulose trimellitate. / 0 , preferably 5 to 10 weight. / 0 is desirable. 3% by weight of cellulose acetate maleates or hydroxypropinolemethyl cenorellose trimethylate If the amount is less than 15% by weight, the coating takes a long time, and if the amount exceeds 15% by weight, it is accompanied by agglomeration of senorate acetate maleates or hydroxypropinolemethylcellulose trimeric particles in the dispersion. Problems such as blockage of the spray gun are liable to occur.
  • a plasticizer (a film-forming auxiliary agent) may be added to the coating liquid dispersed in water as required.
  • the plasticizer to be added include triethyl citrate, triacetin, polyethylene glycol, fatty acid esters of glycerin, sucrose fatty acid esters, and phthalate esters such as dimethyl phthalate, getyl phthalate, and dibutyl phthalate.
  • the amount of the plasticizer to be added is 20 to 60% by weight, preferably 25 to 50% by weight, based on cellulose acetate maleates or hydroxypropinolemethylcellulose trimellitate. Desirably. If the amount of the plasticizer is less than 20% by weight, it is difficult to form a coating film.
  • the amount of plasticizer added was 60% by weight. /. Exceeding may cause sticking of the preparations during the coating operation or sticking during storage.
  • a fine product of cellulose acetate maleate or hydroxypropyl methylcellulose trimellitate is added to an aqueous solution containing a plasticizer or the like under ordinary stirring. Should be dispersed. If necessary, a plasticizer may be added after dispersing cellulose acetate acetate or hydroxypropinolemethinolecellulose fine trimer in water.
  • the coating liquid used in the present invention may contain a surfactant such as polysorbate 80, a light-shielding agent such as titanium oxide and iron sesquioxide, a coloring agent, a pigment, an anti-adhesive, a talc, a suspending agent and the like. Achieving partial improvement, for example, by including a coating solution or an antioxidant in the coating solution is included in the scope of the present invention.
  • the coating method can be applied to any method such as a spraying method, a spraying method, a coating method or a dipping method, and the coating apparatus is a method using a pan, a method using a fluidized bed apparatus, and a stirring fluidized bed coating apparatus.
  • the method used is a method using a rolling coating device, a method using a ventilation rotary drum, or the like.
  • Community Before coating apply a coating with another coating base in advance, including the underlay described below, and after Z or coating, apply a gloss coating, sugar coating or other coating base. May do c
  • an existing coating base may be added to the coating base used in the present invention for use.
  • the preparations obtained by the present invention for example, coated pills, granules or fine granules, etc. are added to a pill and compressed into tablets, or coated tablets, pills, condyles or fine granules, etc. Is also included in the present invention.
  • the HMG-CoA reductase inhibitors used in the present invention include, for example, pravastatin sodium, simvastatin, lovastatin, fluvastatin sodium, cerivastatin sodium, atorvastatin canolecidium.
  • nisvastatin, such as lucidum and calpastatin preferably pravastatin sodium, simvastatin and lovastatin, and more preferably pravastatin sodium.
  • the uncoated preparation contains one or more commonly used additives in addition to the HMG-CoA reductase inhibitor.
  • the additives include various excipients such as lactose, sucrose, mannite, starch, and crystalline cellulose; various binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.
  • Corn starch carboxymethinoresenorelose, carboxymethinoresorenol — sucrose, low-substituted hydroxypropylcellulose, croscarmonas sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone And various lubricants such as metal stearate, stearate or talc; see, for example, Vol. 12 of "Development of Pharmaceuticals" published by Hirokawa Shoten.
  • one or more basifying agents may be added so that the pH of the aqueous dispersion of the preparation becomes 7 or more.
  • Formulations that can be included and are preferred in the present invention are those that include a basifying agent.
  • the mixing amount of the basifying agent is about 1 to 75 ° / in the total amount of the composition. , Preferably in the range of 2 to 70%.
  • the basifying agent preferably, metal oxides such as magnesium oxide and aluminum oxide; sodium hydroxide, potassium hydroxide, lithium hydroxide and the like metal hydroxide metal compounds: calcium hydroxide, magnesium hydroxide Alkaline earth metal hydroxide compounds; magnesium aluminate metasilicate; ammonium hydroxide; aluminum hydroxide; and Z or Magalldrate.
  • magnesium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium metasilicate aluminate, ammonium hydroxide, aluminum hydroxide and Z or Magalldrate It is. Most preferably, it is magnesium oxide, sodium hydroxide and / or magnesium aluminate metasilicate.
  • the HMG-CoA reductase inhibitor of the present invention may be coated in the form of tablets, capsules, pills, granules or fine granules, which can be administered orally. The form of the preparation does not matter. In addition, these preparations can be manufactured by a conventional method.
  • an HMG-CoA reductase inhibitor and an excipient selected from the above additives, a disintegrant, etc. are added and mixed according to a conventional method, and a binder solution is added and kneaded to perform wet granulation.
  • a method for producing uncoated tablets by condensing granules, drying and sizing the granules, adding a lubricant and the like to the obtained granules and mixing the obtained granules, and compressing the obtained granules. (For example, see “Development of Pharmaceuticals,” Vol. 11, published by Hirokawa Shoten).
  • the above-mentioned cellulose acetate maleates or hydroxypropyl methylcellulose trimellitate may be used.
  • Coating (hereinafter referred to as “undercoat”) between the coating film and the uncoated product.
  • the preferred formulation in the present invention is a submerged formulation:
  • the undergarment uses a water-soluble polymer having a neutral or basic pH of an aqueous solution or dispersion.
  • the undercoat is made by dissolving or dispersing the water-soluble polymer in an organic solvent or an aqueous solvent (water or a uniform mixture of water and an organic solvent) to form an undercoat, and then coating according to the coating method described above.
  • An additive such as a plasticizer may be added to the undercoat liquid.
  • Preferred examples of the water-soluble polymer used for the undercoat include hydroxypropylmethylcellulose, hydroxypropylcellulose, and Z or polyvinylpyrrolidone, and more preferably, hydroxypropylmethylcellulose. .
  • the amount to be multiplied should be such that the disintegration time is almost the same as the uncoated product.
  • the content of the HMG-CoA reductase inhibitor used in the preparation of the present invention is, for example, 0.1 mg to 500 mg per tablet in the case of tablets, and preferably 1 mg per tablet. To 10 ⁇ mg. Note that these
  • Cellulose acetate maleates are water-soluble cellulose derivatives substituted with 0.2 to 0.5 acetyl groups and 0.3 to 0.6 maleyl groups per glucose ring ( The preparation containing the HMG-CoA reductase inhibitor according to 1) and (2),
  • Cellulose acetate maleates are water-soluble cell derivatives substituted with 0.2 to 0.4 acetyl groups and 0.5 to 0.6 maleyl groups per glucose ring.
  • HMG—CoA according to any one of (1) to (3) Reductase inhibitor-containing preparations
  • Cellulose acetate maleates are water-soluble cellulose derivatives substituted with 0.3 acetyl groups and 0.6 maleyl groups per glucose ring (1) to (4).
  • the HMG-CoA reductase inhibitor-containing preparation according to any one of the above,
  • the water-soluble cellulose derivative is characterized in that it is at least one selected from the group consisting of methinolecellulose, hydroxypropynolecinolose, hydroxypropylmethylcellulose and hydroxyxetinoresenolole.
  • the preparation containing the HMG-CoA reductase inhibitor according to any one of (1) to (5),
  • Hydroxypropyl methylcellulose is formed by substituting 2 to 0.4 acetyl groups and 0.5 to 0.6 maleyl groups per glucose ring, and its dissolution starting pH is 3
  • the HMG-CoA reductase inhibitor-containing preparation according to any one of (1) to (9), wherein the preparation is coated with hydroxypropyl methylcellulose acetate maleate between
  • a hydroxypropylmethylcell having 1.1 to 1.6 methoxy groups per glucose ring has 0.2 to 1.0 trimethylyl groups per glucose ring.
  • the dissolution start pH of the coating membrane is between 3.5 and 4.5, and it does not dissolve at a pH lower than that, using hydroxypropyl methylcellulose trimethylate.
  • the coated HMG-CoA reductase inhibitor-containing preparation according to any one of (1) and (12) to (19),
  • HMG-CoA reductase inhibitor-containing preparation according to any one of (1) to (23), wherein the plasticizer is triethyl citrate, (25) Any one of (1) to (24) wherein one or more basic agents are added to the uncoated preparation so that the pH of the aqueous dispersion is 7 or more.
  • the basifying agent is a metal oxide, an alkali metal hydroxide compound, an alkali metal hydroxide compound, an alkaline earth metal compound, magnesium metasilicate aluminate, ammonium hydroxide, aluminum hydroxide, and magnesium or magnesium chloride.
  • the HMG-CoA reductase inhibitor-containing preparation according to any one of (1) to (25),
  • the basifying agent is selected from the group consisting of magnesium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium metasilicate aluminate, ammonium hydroxide, aluminum hydroxide and Or an HMG-CoA reductase inhibitor-containing preparation according to any one of (1) to (26),
  • reaction solution was cooled, and the reaction was stopped by adding 1633 g of purified water.
  • a solution obtained by adding 300 g of concentrated hydrochloric acid to this solution was poured into a large excess of purified water with stirring to precipitate a product.
  • the product is washed with purified water, and after the washings no longer show acidity, the product is dried for 2 hours with 6 O 'in a fluidized bed drier, and hydroxypropyl methyl cenorellose acetate is added.
  • Heat mud viscosity of a 2 weight 0 I solution is 7. 0 c P at 2 0 C carboxypropyl methyl cellulose (main butoxy group 2 3. ⁇ weight 0/0, hydroxycarboxylic propoxy group 5.5 wt 0 / : Shin-Etsu Chemical Co., Ltd.) (660 g) and acetic acid (230 g) were charged into a 5-L twin-screw ladder and dissolved at 70. After completion of the dissolution, 528 g of trimellitic anhydride was added as an esterifying agent, and 208 g of sodium acetate was further added as a catalyst, followed by reaction at 85 to 90 ° C.
  • reaction solution was cooled and 140 g of purified water was added to stop the reaction. This solution was poured into a large excess of purified water with stirring to precipitate a product. The product was washed with purified water, and after the washing liquid showed no acidity, the product was dried in a fluidized bed drier 6 (TC for 2 hours to obtain hydroxypropylmethylcellulose trimellitate.
  • the average particle diameter was measured using a dry laser single light diffractometer (He1os & Rodos, manufactured by JASCO Corporation).
  • Hydroxypropyl methylcellulose (TC 5 ⁇ 'IW, Shin-Etsu Chemical Co., Ltd.) was prepared by dissolving 8 parts of sterilized purified water in 92 parts of a coating solution.
  • C 1 tablet an undercoated tablet
  • Pravastatin sodium 20 parts and crystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Kogyo Co., Ltd.) 5 9 parts and low-substituted hydroxypropylcellulose (LH21, Shin-Etsu Chemical Co., Ltd.) 3 0 parts and 6 parts of magnesium aluminate metasilicate (Neusilin FL2, manufactured by Fuji Chemical Industry Co., Ltd.) mixed with Hensur Mixer (Mitsui Mining Co., Ltd.) Then, 50 parts of a 10% aqueous solution of hydroxypropylcellulose and an appropriate amount of water are added to the mixture, and the mixture is kneaded with a Henschel mixer. The obtained kneaded mixture is dome granulated with a ⁇ lmm screen. After extruding and granulating with Fuji Padal,
  • the spheroidized product (produced by Fuji Electric Industries Co., Ltd.) is dried with a through-air dryer at 60 C for 1 hour to obtain an uncoated pill.
  • Hydroxypropyl methylcellulose (TC 5MW, Shin-Etsu Chemical Co., Ltd.) 8 parts sterilized purified water 92
  • a coating liquid was prepared by dissolving it in 2 parts, and the air inlet temperature was 60 ° C, spray rate about 8 minutes, and coated with the conditions of a spray pressure 1. 5 k gZ cm 2, coated with about 5 parts of a substantially solid increase per un Kotopiru 1 2 0 parts under seat pills (hereinafter Later, "C pill" is obtained.)
  • a coating solution 8 parts of hydroxypropinolemethylcellulose acetate prepared in Production Example 1 was dissolved in 92 parts of 70% ethanol water to prepare a coating solution.
  • Ventilation rotation Use a drum coating device (DRIA-200), air inlet temperature 70 ° C, air volume 30 m 3 / h, spray speed about 3 gZ, spray pressure 0.8 K g / cm 2 , and coated in 1 tablet (1 tablet weight: about 14.5 mg) manufactured in Reference Example 1 so that the solid increase per tablet is about 15 mg.
  • a coating tablet was obtained by coating with the above-mentioned coating solution (hereinafter referred to as “AM one tablet”).
  • T1 tablets J 8 parts of hydroxypropyl methylcellulose trimellitate prepared in Production Example 2 and 0.8 parts of triethyl citrate (Citroflex, manufactured by Carter Food Science Co., Ltd.) were replaced with 701.2% ethanol water 91.2 parts
  • a coating solution 8 parts of hydroxypropyl methylcellulose trimellitate prepared in Production Example 2 and 0.8 parts of triethyl citrate (Citroflex, manufactured by Carter Food Science Co., Ltd.) were replaced with 701.2% ethanol water 91.2 parts
  • a coating solution Using a ventilated rotary drum coating device (Doriacoater DRC-200), air inlet temperature 70 C, air volume 30 m 3 / h, spray speed about 3 g / min, spray pressure 0.8 kg / cm Under the conditions of 2 , coating with the above coating solution was performed so that the amount of the actual solid content per tablet (1 tablet per tablet, weight of about 1 45 mg) of Reference Example 1 was about 1 O mg. Coating tablets were obtained (hereinafter
  • vent rotating drum coating apparatus (Doriako one coater the DRC-2 ⁇ ⁇ ), inlet air temperature 7 0: 'C, when the air volume 4 0 m 3 /, about 3 g / min spray rate, spray Ichi ⁇ 0.8 in terms of kg / cm 2, C tablets (1 tablet weight about 1 5 5 mg) of reference example 2 so that the actual quality solids increase per tablet of about 1 O mg, co one above coating solution
  • ⁇ ⁇
  • Example 5 Production of tablets in which one C tablet was coated with an aqueous dispersion coating solution of hydroxypropylmethylcellulose trimellitate
  • the water dispersion co One coating solution is coated with the above coating solution so that the actual solid content increase per 125 parts of C pill of Reference Example 3 is about 30 parts to obtain a coating pill. (Hereafter referred to as “T-pill”).
  • Example 6 135 parts of pill obtained in Example 6, microcrystalline cellulose (Avicel 101, manufactured by Asahi Kasei Kogyo Co., Ltd.) 124 parts and crospovidone 18 parts and magnesium stearate (Nippon Oil & Fats) Mix 3 parts with V-type mixer (manufactured by Tokuju Seisakusho Co., Ltd.). The mixture is tableted to produce uncoated tablets having a diameter of 9.0 mm and a double R surface.
  • Vicel 101 manufactured by Asahi Kasei Kogyo Co., Ltd.
  • crospovidone 18 parts and magnesium stearate Nippon Oil & Fats
  • a CME C fine product 10 was produced in the same manner as in Example 2 of the publication.
  • Parts a mixture of mono- and dicaprylates of glycerin (MGK, manufactured by Nikko Chemicals Co., Ltd.) 3 parts, Polysorbate 80 (Leodol, manufactured by Kao Corporation) 0.5 parts CM EC 5 out of 10 parts.
  • a coating solution comprising sodium hydroxide in an amount capable of neutralizing / o and water in such an amount that the total amount becomes 100 parts was prepared.
  • CMEC fine products manufactured by the same method as described in JP-A-59-1933832 10 parts of CMEC fine products were produced in the same manner as in Example 2 of the gazette.
  • a coating solution composed of sodium hydroxide in an amount capable of neutralizing 5% of the solution and water in such an amount that the total amount was 100 parts was prepared.
  • CME C 2 tablets coated tablets
  • a coating solution was prepared by dispersing 8 parts of a fine product of hydroxypropylmethyl cell per phthalate and 3.2 parts of talc under stirring.
  • an insufflation rotating drum coating apparatus (Doriako one coater DRC 2 0 0)
  • inlet air temperature 6 0 ° C
  • air flow rate 3 8 m 3 about 4 g Z min spray rate
  • spray pressure 1. 0 kg / cm
  • the above coating solution was applied to the water-dispersed coating liquid so that the amount of solid increase per 1 tablet (1 tablet, about 14.5 mg) of Reference Example 1 was about 35 mg.
  • Coating tablets were obtained (hereinafter referred to as “HPMC P tablets”).
  • AM 1 tablet JP1 solution > 120 > 120 > 120 > 120> 120> 120> 120> 120 p H4.5 Buffer 10 13 13 11 12 11 12
  • HPMCP tablet JP1 solution > 120 > 120 * 1 97 48
  • one CMEC tablet and one HPMCP tablet had a longer disintegration time in pH 4.5 buffer than one AM tablet and one T tablet.
  • the AM I and T 1 tablets do not disintegrate for more than 120 minutes in the JP 1 solution assuming the inside of the stomach in the above time-lapse test, and can be stored in the pH 4.5 buffer assuming the upper small intestine. It collapsed quickly.
  • the preparation of the present invention is a preparation that gives a stable absorption of pravastatin even with time.
  • Blood was collected at each time using a syringe prepared by treating 4 ml of venous blood at a time with heparin, and immediately centrifuged (4 C, 300 rpm, 15 minutes) to measure the obtained plasma Until time-2 (frozen and stored in TC.
  • the measurement of 3 ⁇ -hydroxy-sopravastatin in plasma was performed using a liquid mouth mass spectrometer (LC / MS / S) under the following conditions.
  • the value of AUC (0— ⁇ : area under the blood concentration curve) is model-independent of the drug pharmacokinetic analysis software Wi ⁇ c ⁇ ⁇ 1 in (registered trademark, manufactured by Scientific Consulting INC.). It was calculated using the analytical method.
  • Retention time 3 ⁇ -hydroxy-isopravastatin about 2.5 minutes.
  • Ion mode Atmospheric pressure chemical ionization (negative ion mode) Monitoring ion (ra / z):
  • HMG-CoA reductase inhibitors by coating formulations containing HMG-CoA reductase inhibitors with cellulose acetate maleates or hydroxypropyl methylcellulose trimellitate It is a preparation of an HMG-CoA reductase inhibitor that does not form a body and has excellent stability over time with respect to the absorption amount of the drug.
  • the preparation has a uniform drug release behavior.
  • the formulation does not require addition of components other than the plasticizer and the solvent to the coating base, and is particularly effective in the use of an aqueous solvent (a homogeneous mixed solvent of water and an organic solvent) in cellulose acetate maleates.
  • the coating solution can be prepared without adding any components other than the aqueous solvent, so that the formulation can be formulated more easily than a formulation containing an HMG-CoA reductase inhibitor using a conventional coating base. The number of processes can be reduced.
  • the preparation is capable of sustained release of a drug contained in the drug and has excellent sustainability.

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  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne la mise au point de préparations à base d'inhibiteur de HMG-CoA destinées à l'administration par voie orale, exemptes de sous-produits des médicaments, et capable de grande stabilité dans le temps. On utilise dans ce cadre des préparations à base d'inhibiteur de HMG-CoA enduites de cellulose acétates maléates ou d'hydroxypropylméthylcellulose trimellitate.
PCT/JP1999/005200 1998-09-25 1999-09-22 PREPARATIONS A BASE D'INHIBITEUR DE HMG-CoA Ceased WO2000018396A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57587/99A AU5758799A (en) 1998-09-25 1999-09-22 Hmg-coa reductase inhibitor-containing preparations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/271695 1998-09-25
JP27169598 1998-09-25

Publications (1)

Publication Number Publication Date
WO2000018396A1 true WO2000018396A1 (fr) 2000-04-06

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PCT/JP1999/005200 Ceased WO2000018396A1 (fr) 1998-09-25 1999-09-22 PREPARATIONS A BASE D'INHIBITEUR DE HMG-CoA

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin

Citations (12)

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US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
US4438091A (en) * 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
JPS59193832A (ja) * 1983-04-18 1984-11-02 Sankyo Co Ltd 腸溶性製剤の製法
US4661162A (en) * 1983-04-18 1987-04-28 Sankyo Company, Limited Enteric-soluble preparations
US4997658A (en) * 1988-11-21 1991-03-05 Merck & Co., Inc. Method for enhancing the lowering of plasma cholesterol levels
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5376383A (en) * 1988-11-21 1994-12-27 Merck & Co., Inc. Method for enhancing the lowering of plasma-cholesterol levels
EP0754452A2 (fr) * 1995-07-20 1997-01-22 Tanabe Seiyaku Co., Ltd. Préparation pharmaceutique sous forme d'une capsule enrobée pour la libération dans la partie inférieure du tube digestif
US5700929A (en) * 1995-05-01 1997-12-23 Shin-Etsu Chemical Co., Ltd. Base for coating solid enteric pharmaceutical preparations
WO1998011879A1 (fr) * 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
WO1998015264A1 (fr) * 1996-10-08 1998-04-16 Astra Aktiebolag COMPOSITIONS PHARMACEUTIQUES POUR LA LIBERATION PROLONGEE DE FLUVASTATINE INHIBANT LA REDUCTASE DE HMG-CoA
US5776501A (en) * 1994-11-07 1998-07-07 Shin-Etsu Chemical Co., Ltd. Coating base for solid enteric pharmaceutical preparations

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4367217A (en) * 1980-01-12 1983-01-04 Boehringer Ingelheim Gmbh Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof
US4438091A (en) * 1981-07-07 1984-03-20 Dr. Karl Thomae Gmbh Bromhexine delayed-release pharmaceutical form
JPS59193832A (ja) * 1983-04-18 1984-11-02 Sankyo Co Ltd 腸溶性製剤の製法
US4661162A (en) * 1983-04-18 1987-04-28 Sankyo Company, Limited Enteric-soluble preparations
US4997658A (en) * 1988-11-21 1991-03-05 Merck & Co., Inc. Method for enhancing the lowering of plasma cholesterol levels
US5376383A (en) * 1988-11-21 1994-12-27 Merck & Co., Inc. Method for enhancing the lowering of plasma-cholesterol levels
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5776501A (en) * 1994-11-07 1998-07-07 Shin-Etsu Chemical Co., Ltd. Coating base for solid enteric pharmaceutical preparations
US5700929A (en) * 1995-05-01 1997-12-23 Shin-Etsu Chemical Co., Ltd. Base for coating solid enteric pharmaceutical preparations
EP0754452A2 (fr) * 1995-07-20 1997-01-22 Tanabe Seiyaku Co., Ltd. Préparation pharmaceutique sous forme d'une capsule enrobée pour la libération dans la partie inférieure du tube digestif
WO1998011879A1 (fr) * 1996-09-19 1998-03-26 Depomed, Inc. Formes galeniques orales retenues dans l'estomac, pour la liberation controlee de medicaments faiblement solubles et de substance insoluble
WO1998015264A1 (fr) * 1996-10-08 1998-04-16 Astra Aktiebolag COMPOSITIONS PHARMACEUTIQUES POUR LA LIBERATION PROLONGEE DE FLUVASTATINE INHIBANT LA REDUCTASE DE HMG-CoA

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin
US10363238B2 (en) 2011-06-06 2019-07-30 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin

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