WO2012144592A1 - Composition pharmaceutique solide - Google Patents

Composition pharmaceutique solide Download PDF

Info

Publication number
WO2012144592A1
WO2012144592A1 PCT/JP2012/060701 JP2012060701W WO2012144592A1 WO 2012144592 A1 WO2012144592 A1 WO 2012144592A1 JP 2012060701 W JP2012060701 W JP 2012060701W WO 2012144592 A1 WO2012144592 A1 WO 2012144592A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
solid pharmaceutical
crystal
proline
known compound
Prior art date
Application number
PCT/JP2012/060701
Other languages
English (en)
Japanese (ja)
Inventor
啓介 坂浦
田村　哲哉
片川　好史
迫　和博
Original Assignee
アステラス製薬株式会社
壽製薬株式会社
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 アステラス製薬株式会社, 壽製薬株式会社 filed Critical アステラス製薬株式会社
Priority to KR1020137022811A priority Critical patent/KR101841087B1/ko
Priority to JP2013511052A priority patent/JP6063379B2/ja
Priority to CN201280018783.5A priority patent/CN103687596B/zh
Publication of WO2012144592A1 publication Critical patent/WO2012144592A1/fr

Links

Images

Classifications

    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 maintains good dissolution properties and dissolution stability of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol It is related with the solid pharmaceutical composition formed.
  • the present invention relates to (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol having good dissolution property and dissolution stability. It is related with the manufacturing method of the solid pharmaceutical composition formed by maintaining.
  • C-glycoside derivative A Is a Na + -glucose cotransporter inhibitor created by Astellas Pharma Inc. and Sakai Pharmaceutical Co., Ltd., for example, insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), etc. It has been reported as a compound useful for the treatment of insulin resistance disease and obesity, and prevention thereof (Patent Document 1).
  • Patent Document 2 a co-crystal of known compound A and L-proline, as a drug substance crystal used in the manufacture of a pharmaceutical, a co-crystal of L-proline having a certain quality and excellent storage stability, and An invention relating to a pharmaceutical composition containing as an active ingredient and particularly useful as a therapeutic agent for diabetes has been disclosed (Patent Document 2).
  • the crystal of known compound A forms clathrate hydrate and reversibly changes from an anhydride to a non-stoichiometric hydrate depending on the temperature and humidity environment, the drug substance used for pharmaceuticals Since it was difficult to maintain a certain quality, the known compound A was obtained as a co-crystal with L-proline as a crystal of a drug substance having a certain quality and excellent storage stability. Is provided.
  • an object of the present invention is to provide a pharmaceutical composition having a good dissolution property produced from a co-crystal of a known compound A and L-proline, and a method for producing the pharmaceutical composition.
  • Another object of the present invention is to provide a pharmaceutical composition having a good dissolution property produced from a free form of known compound A and a method for producing the pharmaceutical composition.
  • the present inventors prepared a granulated product containing a co-crystal of a known compound A and L-proline by a wet granulation method using a known agitation granulator, and then tableted from the granulated product. As a result, it was found that the tablets had good drug dissolution immediately after the manufacture, but there were problems such as changes in disintegration characteristics and a decrease in dissolution over time. .
  • the present inventors have found that the co-crystal of the known compound A and L-proline is released from the co-crystal structure by water used during the preparation production. As a result, it was found that the known compound A becomes a free form, and the drug dissolution properties are temporarily improved, but aggregates are formed over time.
  • the present inventors can maintain good elution if it can prevent the known compound A, which has become a free form by detachment of L-proline from the co-crystal structure, from reforming the co-crystal. I thought. As a result of intensive studies, it has been found that, when a pharmaceutical composition containing a specific cellulose derivative is applied to a co-crystal of a known compound A and L proline, it achieves good dissolution properties and the present invention is completed. I came to let you.
  • the present invention [1] (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and crystalline cellulose and / or croscarmellose sodium
  • a solid pharmaceutical composition comprising (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol which does not form a co-crystal object; [2] The solid pharmaceutical composition according to [1], further comprising L-proline; [3] The solid pharmaceutical composition according to [1] or [2], wherein the amount of crystalline cellulose and / or croscarmellose sodium is 5% by weight or more and 90% by weight or less in the pharmaceutical composition; [4] In the dissolution test described in the 15th revision Japanese Pharmacopoeia, (1S) -1,5-anhydro-1- [3- (1-benzothien-2
  • the characteristics of the present invention are as follows: (1) a pharmaceutical preparation containing the known compound A exhibits good dissolution properties, (2) the dissolution rate does not change with time, and a stable pharmaceutical preparation can be provided. 3) Since it exhibits a good dissolution property, the bioavailability (BA) is improved, and an effect such as a sufficient pharmacological therapeutic effect is obtained.
  • FIG. 1 shows X-ray powder of co-crystal of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L-proline It is a diffractogram (measurement conditions: Cu ⁇ K ⁇ line 50 kV, 5 ° / min, 0 ° to 40 °, peak position: diffraction angle (2 ⁇ ) 8.9 °, 12.3 °, 17.4 °, 20.5 °).
  • FIG. 2 is a powder X-ray diffraction pattern of a crystal of (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol (measurement) Conditions: Cu K ⁇ ray 50 kV, 5 ° / min, 0 ° to 40 °, peak position: diffraction angle (2 ⁇ ) 9.8 °, 11.8 °, 15.1 °, 19.8 °).
  • 3 is a powder X-ray diffraction pattern of the solid pharmaceutical composition produced in Example 1.
  • FIG. FIG. 4 is a view showing an elution profile of Test Example 2.
  • FIG. 5 is a view showing an elution profile of Test Example 3.
  • FIG. 6 is a graph showing the change in plasma concentration of the known compound A in Test Example 5 over time.
  • FIG. 7 is a view showing an elution profile of Test Example 6.
  • the “free form of the known compound A” means a state in which the known compound A exists without forming a co-crystal in the solid pharmaceutical composition.
  • co-crystal of known compound A and L-proline means a co-crystal formed of known compound A and L-proline in a molar ratio of 1: 1.
  • Identification of the co-crystal structure is shown from results such as differential scanning calorimetry analysis (DSC analysis) and / or powder X-ray diffraction.
  • DSC analysis differential scanning calorimetry analysis
  • Patent Document 2 discloses that in the case of powder X-ray diffraction, a co-crystal of a known compound A and L-proline is characterized by a spectral diffraction angle (2 ⁇ (°)) and a relative intensity. (Table 1, Table 2).
  • Powder X-ray diffraction is based on the nature of the data, and the crystal lattice spacing and overall pattern are important in identifying the identity of the crystal.
  • the relative intensity depends somewhat on the crystal growth direction, particle size, and measurement conditions. Since it can change, it should not be interpreted strictly.
  • a peak peculiar to the structure of the known compound A appears in X-ray diffraction, it is defined as a co-crystal of the known compound A and L-proline if it is negligibly small.
  • Powder X-ray diffraction was measured under the following conditions. Standard measurement: using “MAC Science MXP18TAHF22”, tube: Cu, tube current: 200 mA, tube voltage: 40 kV, sampling width: 0.020 °, scanning speed: 3 ° / min, wavelength: 1.54056 mm, measurement times Folding angle range (2 ⁇ ): Measured under conditions of 3 to 40 °.
  • “good dissolution” means that the dissolution is equivalent to or equivalent to that of the immediate-release preparation.
  • the dissolution rate of the known compound A after 30 minutes is defined as 60% or more.
  • “elution stability” means that BA does not substantially change in the elution of the known compound A from the pharmaceutical composition.
  • dissolution rate of the known compound A is less changed with time than when the storage was started.
  • difference in dissolution rate 30 minutes after the start of the dissolution test after storage is within ⁇ 15% compared to that before storage. Examples of the storage conditions include 40 weeks at 2 weeks, 1 month, 2 months, 3 months, or 6 months.
  • the solid pharmaceutical composition of the present invention comprises the known compound A and crystalline cellulose and / or croscarmellose sodium as essential components.
  • known compound A and L-proline, and crystalline cellulose and / or croscarmellose sodium are essential components.
  • the known compound A does not form a co-crystal.
  • “the known compound A does not form a co-crystal with L-proline” means that when a powder X-ray diffraction of a solid pharmaceutical composition is measured, a peak derived from the co-crystal is hardly observed. To do. Specifically, when the powder X-ray diffraction is measured under the conditions of Cu K ⁇ ray 50 kV, ⁇ 5 ° / min, 0 ° to 40 °, the diffraction angle (2 ⁇ ) is 8.9 °, 12.3 °, 17.4 °, It is defined that no characteristic peak is observed around 20.5 °.
  • diffraction angle (2 ⁇ ) is 9.8 °, 11.8 °, 15.1 ° Or a characteristic peak of the crystal of the known compound A around 19.8 °.
  • the DSC has an endothermic peak around 145 to 150 ° C. derived from the known compound A when the DSC is measured at a temperature rising rate of 20 ° C./min.
  • DSC when DSC is measured at a temperature rising rate of 20 ° C./min, it means an embodiment that does not show an endothermic peak around 209 ° C. derived from a co-crystal of known compound A and L-proline. .
  • C-glycoside derivative A The chemical name is (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol (hereinafter referred to as “C-glycoside derivative A”). Or simply “known compound A”).
  • the known compound A can form a co-crystal structure with L-proline as shown by the following formula (II).
  • the co-crystal has an endothermic peak at 201 to 213 ° C. by DSC analysis and / or 2 ⁇ (°) 4.14, 8.98, 12.4, 16.5, 17.5 by powder X-ray diffraction. , 18.7, 20.5, and 21.5.
  • the known compound A and the co-crystal of known compound A and L-proline can be characterized by the diffraction angle (2 ⁇ (°)) and relative intensity in the powder X-ray diffraction spectrum, or the peak position by the DSC spectrum.
  • the clinical dose (therapeutically effective amount) of the known compound A to humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to be applied. It is ⁇ 500 mg, which is administered once or divided into several times. Since the dosage varies depending on various conditions, an amount smaller than the above dosage range may be sufficient.
  • the crystalline cellulose used in the present invention is obtained by partially depolymerizing and purifying ⁇ -cellulose obtained as a pulp from a fibrous plant with an acid (15th revised Japanese Pharmacopoeia). And if it is pharmacologically acceptable and can maintain the favorable elution property and elution stability of the well-known compound A, crystalline cellulose can be used without a restriction
  • the shape of crystalline cellulose is not particularly limited, such as granular or acicular. Needle-shaped ones can also be crushed and used.
  • As the crystalline cellulose a commercially available mixture as a mixture with other additives (carrageenan, sodium carboxymethyl cellulose, guar gum, etc.) can be used.
  • the average particle size is preferably 20 to 200 ⁇ m when measured by the second method (sieving method) of the powder particle size measurement method described in the Japanese Pharmacopoeia.
  • the crystalline cellulose ones having different grades, shapes, average particle sizes and the like can be used alone or in combination of two or more.
  • the blending amount of the crystalline cellulose is not particularly limited as long as the known compound A can usually exhibit good dissolution properties. For example, it is 5% by weight to 90% by weight in the pharmaceutical composition of the present invention. 20 wt% or more and 70 wt% or less, 20 wt% or more and 1500 wt% or less with respect to the weight of the known compound A, another embodiment is 50 wt% or more and 1100 wt% or less, and yet another embodiment is 40 wt% or more and 350 wt% or less. % Or less.
  • Croscarmellose sodium is a sodium salt of a crosslinked polyvalent carboxymethyl ether of cellulose (15th revised Japanese Pharmacopoeia). And croscarmellose sodium will not be restrict
  • the amount of croscarmellose sodium is not particularly limited as long as the known compound A can usually exhibit good dissolution properties. For example, it is 5% by weight to 90% by weight in the pharmaceutical composition of the present invention. As an aspect, 20 weight% or more and 70 weight% or less, 20 weight% or more and 1500 weight% or less with respect to the weight of the well-known compound A, As another aspect, 50 weight% or more and 1100 weight% or less, Furthermore, as another aspect, 40 weight% or more 350% by weight or less.
  • the total amount is 5% by weight to 90% by weight in the pharmaceutical composition, and in another embodiment, 5% by weight to 70% by weight. Used.
  • various pharmaceutical additives are appropriately used in the solid pharmaceutical composition of the present invention as desired.
  • a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
  • excipients, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, coating agents, etc. used.
  • Excipients include D-mannitol, lactose and the like.
  • binder examples include hydroxypropylmethylcellulose, hydroxypropylcellulose, gum arabic and the like.
  • disintegrant examples include corn starch, potato starch, carmellose calcium, carmellose sodium, partially pregelatinized starch, crospovidone, and sodium starch glycolate.
  • sour agent examples include citric acid, tartaric acid, malic acid and the like.
  • foaming agents examples include baking soda.
  • artificial sweetener examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
  • fragrances include lemon, lemon lime, orange and menthol.
  • lubricant examples include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
  • Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
  • Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
  • antioxidants examples include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
  • surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
  • Coating agents include talc, polyethylene glycol, hypromellose, titanium oxide and the like.
  • an appropriate amount can be appropriately added in combination of one or more kinds.
  • the blending amount of the pharmaceutical additive is 0.1 to 70% by weight in the pharmaceutical composition of the present invention.
  • the solid pharmaceutical composition of the present invention comprises (1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol, and crystals.
  • a step of obtaining a granulated product comprising —benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol can be included.
  • the solid pharmaceutical composition of the present invention comprises (1) (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol and L A step of mixing a co-crystal with proline and crystalline cellulose and / or croscarmellose sodium, and (2) a state in which the resulting mixture is wet granulated to form no co-crystal with L-proline To obtain a granulated product containing (1S) -1,5-anhydro-1- [3- (1-benzothien-2-ylmethyl) -4-fluorophenyl] -D-glucitol. be able to. Furthermore, the obtained granulated product can be compression molded (step (3)) to obtain a desired form.
  • wet granulation is a granulation method performed by adding a solvent during granulation, and various granulation methods such as stirring granulation method, fluidized bed granulation method, rolling granulation method and kneading granulation method are known. It has been.
  • the pharmaceutical additives are used in the step (1), between the steps (1) and (2), in the step (2), and ( It can be added at any stage such as between step 2) and step (3).
  • the co-crystal of the known compound A and L-proline, the cellulose derivative, and any pharmaceutical additive can be adjusted to any size by subjecting them to a pulverization step before the mixing step.
  • the pulverization step is not particularly limited to any device and means as long as the drug and / or pharmaceutical additive can be pharmaceutically pulverized normally.
  • the mixing step of each component continuous with the pulverization is not particularly limited to any device or means as long as it is a method that can generally uniformly mix each component pharmaceutically.
  • granulation is performed by adding a solvent to a mixture of a cocrystal of a known compound A and L-proline and a cellulose derivative.
  • the solvent include water, ethanol, methanol, or a mixed solvent thereof.
  • the solvent may contain a binder (ie, a binder solution).
  • the rate of addition of the solvent (or binder solution) varies depending on the granulation method or the scale to be produced. For example, when producing a 1 kg scale by the wet granulation method, the solvent (or binder solution) is 1 to It can be added at a rate of 30 g / min, in other embodiments 5-20 g / min.
  • a mode in which a binder is added in advance to a mixture of a co-crystal of a known compound A and L-proline and a cellulose derivative, followed by granulation while adding a solvent can also be employed.
  • a solvent of 50 parts by weight or more and 400 parts by weight or less is used with respect to 100 parts by weight of the co-crystal of the known compound A and L-proline. it can.
  • the known compound A and L-proline do not form a co-crystal in the solid pharmaceutical composition. That is, by wet granulation under the above conditions, L-proline is released from the co-crystal structure during granulation, whereby the known compound A becomes a free body and the state of the free body is maintained.
  • Granulation is preferably performed by stirring granulation from the viewpoint of promoting the separation of L-proline during granulation. Agitation granulation gives a strong shearing force to the material to be granulated, and it is presumed that the strong shearing force promotes the detachment of L-proline.
  • the granulated product prepared as described above can be made into various preparations such as tablets, capsules, powders, granules, and dry syrup.
  • the solid pharmaceutical composition of the present invention is a tablet.
  • preparations can be produced by known methods.
  • various preparations can be produced by a known method including steps such as drying, tableting and film coating.
  • the prepared granulated product can be dried by any means.
  • drying apparatuses such as a fluidized bed dryer, a multiplex, and a shelf dryer can be used.
  • the drying temperature is, for example, 40 to 90 ° C.
  • the dried granulated product can be tableted to produce a tablet.
  • the tableting method is not particularly limited as long as it is a method in which a compression-molded product is usually produced pharmaceutically.
  • a method of tableting by mixing a disintegrant and a lubricant into the granulated product.
  • the tableting device is not particularly limited as long as it is a method in which a compression-molded product is usually produced pharmaceutically, and examples thereof include a rotary tableting machine and a single tableting machine.
  • the tablet hardness is, for example, 40 to 250 N, and in another embodiment, 50 to 200 N.
  • the tablet surface may be coated with a film.
  • the method is not particularly limited as long as it is a pharmaceutically coating method.
  • pan coating and the like can be mentioned.
  • the film coating agent is not particularly limited as long as it is a pharmaceutical additive that is usually pharmaceutically coated.
  • As the film coating agent one or a combination of two or more can be added as appropriate.
  • the coating rate is not particularly limited as long as the tablet surface can be normally coated. For example, it is 1.0 wt% or more and 5.0 wt% or less with respect to the weight of the uncoated tablet which is a tablet before coating.
  • the method for producing the solid pharmaceutical composition of the present invention or the pharmaceutical formulation thereof is not particularly limited as long as it is a method for producing a pharmaceutical formulation having the desired effect of the present invention by appropriately combining the above-described methods or methods known per se. Not.
  • Example 1 After mixing 1.8 g of co-crystal of known compound A and L-proline and 1.8 g of crystalline cellulose (product name: Theolas PH101, manufactured by Asahi Kasei, the same shall apply hereinafter), about 3 g of water is added and wet stirring granulation is performed. (A granulator (small agitator, manufactured by Kyoritsu Riko Co., Ltd., granulation time: about 1 minute)). The obtained granulated product was dried (40 ° C., 12 hours) to prepare a solid pharmaceutical composition of the present invention.
  • a granulator small agitator, manufactured by Kyoritsu Riko Co., Ltd., granulation time: about 1 minute
  • Example 2 The solid of the present invention was the same as in Example 1 except that 1.8 g of croscarmellose sodium (product name: Ac-Di-Sol, manufactured by FMC Biopolymer Co., Ltd., hereinafter the same) was used instead of crystalline cellulose. A pharmaceutical composition was prepared.
  • Example 1 Evaluation of crystallinity
  • Example 2 Evaluation of crystallinity
  • Comparative Examples 1 to 7 immediately after production (at the start of storage) and 1 at 40 ° C. and 75% relative humidity
  • Powder X-ray diffraction measurement was performed after storage for months.
  • Example 1 and Example 2 In the solid pharmaceutical compositions of Example 1 and Example 2, no peak corresponding to the co-crystal of the known compound A and L-proline was observed immediately after production and after storage, while the peak corresponding to the crystal of the known compound A was observed. Peaks were observed at folding angles (2 ⁇ ) of 9.8 °, 11.8 °, 15.1 °, and 19.8 °.
  • the powder X-ray diffraction pattern of Example 1 is shown in FIG. Therefore, in Example 1 and Example 2, it is considered that L-proline was released from the co-crystal structure during granulation, so that known compound A became a free form.
  • Example 3 Tablets were prepared based on the formulation in Table 3 (numbers in the table are the weight (mg) of each ingredient used).
  • Co-crystal of known compound A and L-proline, croscarmellose sodium, D-mannitol, and hydroxypropylcellulose product name: HPC-SL, manufactured by Nippon Soda Co., Ltd.
  • Water was added and granulated by wet stirring to 100 parts by weight with 100 parts by weight of co-crystal with proline (granulating device (small agitator, manufactured by Kyoritsu Riko Co., Ltd., granulation time: about 2 minutes)) .
  • the obtained granulated product was dried (40 ° C., 12 hours), mixed with magnesium stearate and tableted to obtain a solid pharmaceutical composition of the present invention (inguinal diameter: 9.5 mm).
  • L-HPC low-substituted hydroxypropylcellulose
  • a solid pharmaceutical composition of a comparative example was prepared in the same manner as in Example 3 except that crospovidone (substance name: KollidonCL, manufactured by BASF Japan Ltd.) was used instead of croscarmellose sodium.
  • crospovidone substance name: KollidonCL, manufactured by BASF Japan Ltd.
  • Example 2 Evaluation of dissolution property
  • the solid pharmaceutical compositions of Example 3, Comparative Example 8, and Comparative Example 9 were subjected to a tablet dissolution test immediately after the preparation of the preparation.
  • the dissolution test was performed by the paddle method described in the 15th revised Japanese Pharmacopoeia.
  • the test solution was 900 mL (0.1N hydrochloric acid) of the first dissolution test solution.
  • the rotation speed of the paddle was 50 rotations / minute.
  • Table 4 shows the dissolution rate of the known compound A 30 minutes after the start of the test. The elution profile is shown in FIG.
  • Example 4 Tablets were prepared based on the formulation in Table 5 (the numbers in the table are the weight (mg) of each ingredient used).
  • a co-crystal of a known compound A and L-proline, croscarmellose sodium, crystalline cellulose, and hydroxypropyl cellulose are put into a stirring granulator (VG01, manufactured by POWREC), and stirring granulation is performed while spraying water. It was.
  • the obtained granulated product was dried (40 ° C., 12 hours), passed through a sieve having a sieve opening of 710 ⁇ m, and sized to obtain granules.
  • the granules were mixed with magnesium stearate and tableted to obtain a solid pharmaceutical composition of the present invention.
  • Example 10 A solid pharmaceutical composition of a comparative example was obtained in the same manner as in Example 4 using a known compound A and L-proline co-crystal, D-mannitol, hydroxypropyl cellulose and magnesium stearate.
  • Example 3 Evaluation of Dissolution
  • the solid pharmaceutical compositions of Example 4 and Comparative Example 10 were subjected to a tablet dissolution test immediately after production (initial) in the same manner as Test Example 2.
  • the elution profile is shown in FIG.
  • Example 4 the elution profile after leaving still at 40 degreeC for 2 weeks (40 degreeC2W) is shown.
  • Example 5 A solid pharmaceutical composition was prepared based on the formulation of Table 6 (the numbers in the table are the weight (mg) of each component used).
  • Example 5 Oral Administration Test for Dogs
  • the solid pharmaceutical composition produced in Example 5 and a methylcellulose suspension composition: 128.5 mg of co-crystal of known compound A and L-proline in 10 mL of 0.5% aqueous methylcellulose solution
  • the results are shown in FIG. 6 (in the figure, “Tab” indicates the absorbability of the solid pharmaceutical composition, and “MCsus” indicates the absorbability of the methylcellulose suspension).
  • the AUC of the solid pharmaceutical composition of Example 5 was 121% compared to the AUC of the methylcellulose suspension. Therefore, it was shown that the solid pharmaceutical composition of the present invention exhibits good absorbability even in an in vivo test.
  • the known compound A and L-proline, and crystalline cellulose and / or croscarmellose sodium are contained, and the known compound A and L-proline form a co-crystal.
  • the solid pharmaceutical composition not shown showed good dissolution properties and dissolution stability. Since known compound A is considered to have a co-crystal structure with L-proline due to hydrogen bonding by an OH group, formation of hydrogen bond between known compound A and L-proline is inhibited, so that known compound A Guess that the free body will be maintained.
  • Example 6 Tablets were prepared based on the formulation in Table 8 (the numbers in the table are the weight (mg) of each ingredient used).
  • a known compound A, crystalline cellulose and croscarmellose sodium were mixed and then molded with a single tableting machine to prepare a tablet of the present invention.
  • Example 6 Evaluation of dissolution property The tablet manufactured in Example 6 was subjected to the dissolution test of the composition immediately after the manufacture in the same manner as in Test Example 2. The test results are shown in FIG.

Abstract

L'invention concerne une composition pharmaceutique solide comprenant du (1S)-1,5-anhydro-1-[3-(1-benzothién-2-ylméthyl)-4-fluorophényl]-D-glucitol et de la cellulose cristalline et/ou de la croscarmellose sodique, le (1S)-1,5-anhydro-1-[3-(1-benzothién-2-ylméthyl)-4-fluorophényl]-D-glucitol ne formant pas de cocristaux. L'invention concerne également un procédé pour la préparation de la composition.
PCT/JP2012/060701 2011-04-22 2012-04-20 Composition pharmaceutique solide WO2012144592A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
KR1020137022811A KR101841087B1 (ko) 2011-04-22 2012-04-20 고형 의약 조성물
JP2013511052A JP6063379B2 (ja) 2011-04-22 2012-04-20 固形医薬組成物
CN201280018783.5A CN103687596B (zh) 2011-04-22 2012-04-20 固态医药组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161478188P 2011-04-22 2011-04-22
US61/478,188 2011-04-22

Publications (1)

Publication Number Publication Date
WO2012144592A1 true WO2012144592A1 (fr) 2012-10-26

Family

ID=47041696

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/060701 WO2012144592A1 (fr) 2011-04-22 2012-04-20 Composition pharmaceutique solide

Country Status (4)

Country Link
JP (1) JP6063379B2 (fr)
KR (1) KR101841087B1 (fr)
CN (1) CN103687596B (fr)
WO (1) WO2012144592A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015199115A1 (fr) * 2014-06-24 2015-12-30 アステラス製薬株式会社 Composition pharmaceutique à administration orale
WO2019098259A1 (fr) 2017-11-17 2019-05-23 塩野義製薬株式会社 Préparation pharmaceutique présentant d'excellentes propriétés de photostabilité et de libération de médicament

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106924206A (zh) * 2015-12-31 2017-07-07 深圳翰宇药业股份有限公司 一种依格列净口服固体制剂及其制备方法
KR102097250B1 (ko) * 2019-11-09 2020-04-03 유니셀랩 주식회사 신규한 이프라글리플로진의 결정형, 이의 제조방법 또는 용도

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5441386A (en) * 1977-09-02 1979-04-02 Kyowa Hakko Kogyo Co Ltd Preparation of l-proline by fermentation
WO2004080990A1 (fr) * 2003-03-14 2004-09-23 Astellas Pharma Inc. Derives de c-glycoside et sels correspondants
JP2006514044A (ja) * 2002-12-19 2006-04-27 アキュスフィア， インコーポレイテッド 脱凝集微粒子を含む医薬製剤を製造する方法
WO2007114475A1 (fr) * 2006-04-05 2007-10-11 Astellas Pharma Inc. Cocristal du derive de c-glycoside et de l-proline
WO2009096455A1 (fr) * 2008-01-31 2009-08-06 Astellas Pharma Inc. Composition pharmaceutique pour le traitement de stéatoses hépatiques
JP2010536734A (ja) * 2007-08-16 2010-12-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄｐｐｉｖ阻害剤と併用するｓｇｌｔ２阻害剤を含む医薬組成物
WO2011049191A1 (fr) * 2009-10-23 2011-04-28 アステラス製薬株式会社 Composition pharmaceutique pour administration orale

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5441386A (en) * 1977-09-02 1979-04-02 Kyowa Hakko Kogyo Co Ltd Preparation of l-proline by fermentation
JP2006514044A (ja) * 2002-12-19 2006-04-27 アキュスフィア， インコーポレイテッド 脱凝集微粒子を含む医薬製剤を製造する方法
WO2004080990A1 (fr) * 2003-03-14 2004-09-23 Astellas Pharma Inc. Derives de c-glycoside et sels correspondants
WO2007114475A1 (fr) * 2006-04-05 2007-10-11 Astellas Pharma Inc. Cocristal du derive de c-glycoside et de l-proline
JP2010536734A (ja) * 2007-08-16 2010-12-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｄｐｐｉｖ阻害剤と併用するｓｇｌｔ２阻害剤を含む医薬組成物
WO2009096455A1 (fr) * 2008-01-31 2009-08-06 Astellas Pharma Inc. Composition pharmaceutique pour le traitement de stéatoses hépatiques
WO2011049191A1 (fr) * 2009-10-23 2011-04-28 アステラス製薬株式会社 Composition pharmaceutique pour administration orale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NANZANDO CO., YAKUZAIGAKU MANUAL, 1989, pages 88 - 89, 112 TO 113 *
YAKUJI NIPPO LTD., IYAKUHIN TENKABUTSU JITEN, 1994, pages 93, 100 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015199115A1 (fr) * 2014-06-24 2015-12-30 アステラス製薬株式会社 Composition pharmaceutique à administration orale
JPWO2015199115A1 (ja) * 2014-06-24 2017-04-20 アステラス製薬株式会社 経口投与用医薬組成物
US9775832B2 (en) 2014-06-24 2017-10-03 Astellas Pharma Inc. Pharmaceutical composition for oral administration
WO2019098259A1 (fr) 2017-11-17 2019-05-23 塩野義製薬株式会社 Préparation pharmaceutique présentant d'excellentes propriétés de photostabilité et de libération de médicament
KR20200089290A (ko) 2017-11-17 2020-07-24 시오노기세야쿠 가부시키가이샤 광안정성 및 용출성이 우수한 의약 제제

Also Published As

Publication number Publication date
CN103687596A (zh) 2014-03-26
JPWO2012144592A1 (ja) 2014-07-28
JP6063379B2 (ja) 2017-01-18
KR101841087B1 (ko) 2018-03-23
KR20140022002A (ko) 2014-02-21
CN103687596B (zh) 2016-08-17

Similar Documents

Publication Publication Date Title
CN110944638A (zh) 尼拉帕尼组合物
TWI382838B (zh) 錠劑及其製造方法
TW201827049A (zh) 含二胺衍生物之口腔崩散錠
JP6063379B2 (ja) 固形医薬組成物
JP4759102B2 (ja) 経口投与用医薬組成物
JP6455611B2 (ja) 経口投与用医薬組成物
TW201609194A (zh) 含有托格列淨（Ｔｏｆｏｇｌｉｆｌｏｚｉｎ）之固體製劑及其製造方法
JP5381978B2 (ja) アミド誘導体含有医薬組成物
TW200922546A (en) Galenical formulations of organic compounds
KR20190007896A (ko) 솔리페나신 또는 이의 약제학적으로 허용가능한 염을 포함하는 구강 붕해정 및 이의 제조방법
JP6116847B2 (ja) シクロデキストリンとの混合体を含有する錠剤
WO2019230937A1 (fr) Forme galénique solide pour la voie orale possédant d'excellentes propriétés de dissolution
WO2013147135A1 (fr) Composition pharmaceutique à libération contrôlée
JP5900702B2 (ja) 経口投与用医薬組成物
WO2023238929A1 (fr) Composition pharmaceutique contenant du pimitespib
JPWO2015199115A1 (ja) 経口投与用医薬組成物
WO2016059192A1 (fr) Composition comprenant de l'odanacatib
TW200810759A (en) Oral pharmaceutical composition of a poorly water-soluble active substance

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12773560

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013511052

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20137022811

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12773560

Country of ref document: EP

Kind code of ref document: A1