WO2005023222A1 - Pharmaceutical composition with improved solubility and fluidity - Google Patents

Pharmaceutical composition with improved solubility and fluidity Download PDF

Info

Publication number
WO2005023222A1
WO2005023222A1 PCT/JP2004/012827 JP2004012827W WO2005023222A1 WO 2005023222 A1 WO2005023222 A1 WO 2005023222A1 JP 2004012827 W JP2004012827 W JP 2004012827W WO 2005023222 A1 WO2005023222 A1 WO 2005023222A1
Authority
WO
WIPO (PCT)
Prior art keywords
water
pharmaceutical composition
weight
soluble
composition according
Prior art date
Application number
PCT/JP2004/012827
Other languages
French (fr)
Japanese (ja)
Inventor
Hideyoshi Kanbe
Toshiaki Kurazumi
Teiji Murata
Original Assignee
Ssp 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 Ssp Co., Ltd. filed Critical Ssp Co., Ltd.
Publication of WO2005023222A1 publication Critical patent/WO2005023222A1/en
Priority to HK06113473A priority Critical patent/HK1092711A1/en

Links

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
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K9/14—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
    • A61K9/1611—Inorganic compounds

Definitions

  • composition with improved solubility and flowability
  • the present invention relates to a pharmaceutical composition having improved solubility and fluidity of a poorly water-soluble drug.
  • a solid dispersion obtained by pulverizing a poorly water-soluble drug together with a hydrophilic polymer and a solubility improving agent in the presence of an aqueous solvent and then removing water has a dissolution behavior different from that of a normal solid dispersion. That is, it is known that fine droplets containing a poorly water-soluble drug are generated in water and dispersed and rapidly dissolved (Patent Document 1).
  • Patent Document 2 a method in which crystal particles of a poorly water-soluble drug are dispersed in the air, and a water-soluble polymer solution is sprayed and coated.
  • the spraying mechanism is composed of a jetting portion of the crystalline drug particles in the center and a water-soluble polymer solution in the outside.
  • Special equipment called a jet coating device equipped with a concentric triple nozzle (Patent Document 3) with a compressed air ejection part disposed outside of it and a compressed air ejection part is required, and it is compatible with mass production. It is difficult.
  • Patent Document 4 an easily absorbable solid composition containing a poorly water-soluble propionic acid-based non-steroidal anti-inflammatory agent, a water-soluble polymer base material and a nonionic surfactant is known (Patent Document 4). .
  • Patent Document 2 JP-A-6-128147
  • Patent Document 3 JP-A-3-270598
  • Patent Document 4 JP-A-2000-95682
  • an object of the present invention is to provide a pharmaceutical composition which can be applied to a wider range of poorly water-soluble drugs and has improved solubility and flowability of the poorly water-soluble drug obtained by a simple production method. It is in.
  • the inventors of the present invention have conducted intensive studies to achieve this object. As a result, a poorly water-soluble drug and a fluidizing agent are mixed in advance, and this is mixed with a water-soluble or water-containing alcohol solution of a water-soluble polymer. The present inventors have found that the granulation by granulation improves the solubility and fluidity of the drug, and completed the present invention. That is, the present invention provides a mixture of a poorly water-soluble drug and a superplasticizer with a water-soluble polymer The present invention provides a pharmaceutical composition containing a granulated product obtained by granulating using a hydroalcoholic solution.
  • the present invention also provides a solid pharmaceutical preparation obtained by using the above pharmaceutical composition.
  • the pharmaceutical composition of the present invention is excellent in solubility and flowability of a poorly water-soluble drug in water. Further, since it has excellent fluidity, direct tableting is possible, and a solid pharmaceutical preparation such as a fast-dissolving tablet containing a poorly water-soluble drug can be easily obtained.
  • FIG. 1 is a view showing a dissolution test result of a pharmaceutical composition.
  • FIG. 2 is a view showing a dissolution test result of a pharmaceutical composition.
  • the poorly water-soluble drug used in the present invention is not particularly limited as long as it is a drug that is hardly soluble in water.
  • the term “slightly water-soluble” means that the solubility in water at 36 ° C. is equal to or less than lg / 100 mL in view of the effect of improving the solubility.
  • poorly water-soluble drugs include gastrointestinal analgesics, antacids, analgesics, anti-inflammatory drugs, and anti-inflammatory drugs.
  • Formulation peptic ulcer treatment, coronary vasodilator, peripheral and cerebral vasodilator, antiinfective, anxiolytic, neuroleptic, central nervous system stimulant, antidepressant, antihistamine, diarrhea, laxative , Nutritional supplements, cholesterol lowering agents, caliber reducing agents, anti-agonist agents, cardiac rhythm agonists, drugs for treating arterial hypertension, anti-migraine drugs, blood clotting drugs, drugs for treating thyroid dysfunction, diuretics , Appetite suppressants, antiasthmatics, expectorants, analgesics, expectorants, mucus regulators, antiemetics, uric acid excretions, gout treatments, arrhythmia treatments, hyperlipidemia treatments, bronchodilators , Antidiabetic agents, oral contraceptives, motion sickness treatment, prostatic hypertrophy treatment, knee inflammation treatment, hypnosis inducer Hypnotic sedatives, antirheumatics, anti-epileptic drugs, cerebral metabolism improving agents, anti
  • Particularly preferred and poorly water-soluble drugs include ibuprofen, ketoprofen, and spironolatatatone
  • Examples of the fluidizing agent used in the present invention include light caustic anhydride, hydrous caustic acid, talc, magnesium stearate, lactose and the like.
  • these fluidizers commercially available ones may be used.
  • light silicic anhydride such as Ad Solida 101 (manufactured by Freund Corporation) and AEROSIL 200 (manufactured by Nippon Aerogenore Co., Ltd.), Ad Solida 102 (manufactured by Freund Corporation), Carplex # 6a, # 80, # 100, # 1120 (manufactured by Shionogi Pharmaceutical Co., Ltd.) and the like.
  • the fluidizing agent As the fluidizing agent, light silicic anhydride and hydrous silicon dioxide are preferred, and light silicic anhydride is particularly preferred.
  • the fluidizing agent may be used alone, but may be used in combination if necessary.
  • the compounding amount of the superplasticizer in the pharmaceutical composition of the present invention is preferably 0.01 to 5 parts by weight, more preferably 0.03 to 4 parts by weight, especially 0 to 5 parts by weight based on 100 parts by weight of the poorly water-soluble drug. 05—3 parts by weight are preferred.
  • Examples of the water-soluble polymer used in the present invention include hydroxypropylmethylcellulose (hereinafter, may be described as HPMC), hydroxypropylcellulose (hereinafter, may be described as HPC), borobulpyrrolidone (hereinafter sometimes referred to as HPC).
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • HPC borobulpyrrolidone
  • PVP methylcellulose
  • punorelane polyvinylinolenoreconore
  • canoleboxymethinoresenorelose sodium hydroxyshethylcellulose, methylhydroxyethylcellulose, and the like.
  • water-soluble polymers commercially available ones may be used.
  • hydroxypropylmethylcellulose such as trade names TC-5E, TC-5M, TC-5R, TC-5S, Metrolose 90SH, Metrolose 65SH (manufactured by Shin-Etsu Chemical Co., Ltd.); HPC_L, HPC_SL, HPC Hydroxypropyl cellulose such as -SSL, HPC_M, and HPC-H (manufactured by Nippon Soda Co., Ltd.); and polyvinylinole pyrrolidone such as PVP_K30 and PVP-K90 (manufactured by BSF TF Takeda Vitamin Co., Ltd.).
  • water-soluble polymer hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvierpyrrolidone are preferred, and hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly preferred.
  • the water-soluble polymer may be used alone, or may be used in combination if necessary.
  • the compounding amount of the water-soluble polymer in the pharmaceutical composition of the present invention is preferably 0.1 to 50% by weight, and more preferably 0.3 to 40% by weight, based on 100% by weight of the poorly water-soluble drug. 0.5 to 30 parts by weight, preferably.
  • the pharmaceutical composition of the present invention contains, in addition to a poorly water-soluble drug, a fluidizing agent, and a water-soluble polymer, a drug other than the poorly water-soluble drug, and a component usually used in a solid preparation as appropriate. May be blended according to the conditions.
  • excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder, and the like, coloring agents, flavoring agents, flavoring agents, light blocking agents, flavoring agents, sweetening agents and the like can be mentioned.
  • the pharmaceutical composition of the present invention is produced by mixing a poorly water-soluble drug and a fluidizing agent, and granulating using a solution in which a water-soluble polymer is dissolved in water or hydrous alcohol.
  • a water-soluble polymer is dissolved in water or hydrous alcohol.
  • hydrous alcohol hydrous alcohol containing 10 to 90% by weight of a lower alcohol such as ethanol or isopropanol is preferable, and especially hydrous ethanol is preferable.
  • the water-soluble polymer is preferably used as a 1 to 30% by weight solution, more preferably a 520% by weight solution, particularly preferably a 5 to 15% by weight solution.
  • the granulating apparatus to be used is not particularly limited, and examples thereof include a stirring-type granulating apparatus (Perch Caldera Doubler), a fluidized bed apparatus, and a tumbling fluidizing apparatus.
  • a fluidized bed granulator is preferred, for example, a fluidized bed granulator (multiplex fine particle coating apparatus SPC-01).
  • particles having a particle size of 63 to 500 ⁇ m are preferably fine particles of 85% by weight or more from the viewpoint of improvement in solubility and fluidity.
  • the particle size of the particles is measured by a screening test method.
  • the particulate pharmaceutical composition produced as described above has good flowability and improved solubility, so that the particulate pharmaceutical composition can be used as it is as a powder or the like. Capable of making capsules, etc., as well as being capable of easily manufacturing tablet-type pharmaceutical preparations with rapid dissolution by direct compression. Therefore, examples of the solid pharmaceutical preparation obtained using the pharmaceutical composition of the present invention include granules, powders, tablets, capsules and the like. In preparing these solid pharmaceutical preparations, ingredients usually used in solid preparations further include excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder, coloring agents, flavoring agents, and odorants. Agents, light blocking agents, flavoring agents, sweetening agents, and the like.
  • Ibuprofen BASF IBUPROFEN25 particle size: 20-33 ⁇ m
  • Example 2 In the same manner as in Example 1, granulation was carried out with 10% by weight of an aqueous HPMC solution (IOOg) to obtain granules of 63-500 x m particles of 98.2% by weight.
  • IOOg aqueous HPMC solution
  • a mixture of 1000 g of ibuprofen (IBUPROFEN25 from BASF, particle size: 20-30 ⁇ m) and 10 g of Adsolida-1 101 is mixed with a vertical granulator VG-10, and 99.7% by weight of particles with a particle size of 63 ⁇ m or less is 99.7% by weight.
  • the elution amount of the poorly water-soluble drug in the pharmaceutical compositions produced in Examples 13 and 13 and Comparative Example 1 was determined according to the following test method.
  • Dissolution test method JP Dissolution test method (2) Method 2 (Paddle method) Test solution: When a pharmaceutical composition containing 65 mg of ibupufen is added to 900 mL of water and stirred at a rotation speed of 100 r / min. The elution amount of the poorly water-soluble drug was measured by a UV method. The evaluation was made based on the percentage of the dissolution amount relative to the amount of the poorly water-soluble drug incorporated in the pharmaceutical composition.
  • FIG. 1 shows the measurement results.
  • the dissolution rate of ibuprofen (a poorly water-soluble drug) was high, and 80% or more was dissolved in 30 minutes, and the dissolution was excellent.
  • Ibuprofen BASF IBUPROFEN50 particle size: 45-60 ⁇ m
  • lOOOOg Adsolida-101 10g
  • Adsolida-101 10g
  • VG-10 vertical granulator
  • lC ⁇ i% HPMC Particle Coating Equipment (SPC-01 type)
  • SPC-01 type particle Coating Equipment
  • TC-5E fine granulated with TC-5E solution LOOOg
  • Example 4 10 wt% 1 ⁇ 1 ⁇ ⁇ (Ding ⁇ _5 £) aqueous lOOOg 10 wt% 1 «3 Rei_0« 3 ⁇ _3 SL) Aqueous solution: A granulated product of fine particles having a particle power of 98.7% by weight of 98.7% by weight was obtained in the same manner as in Example 4 except that the temperature was changed to lOOOOg.
  • Ibuprofen (BASF's IBUPROFEN50 particle size: 45-60 ⁇ m) 10 g of lOOOOg and Adsolida-1 101 are mixed with a vertical granulator VG-10, and 97.5% by weight of granules with a particle size of 63 ⁇ m or less are 97.5% by weight.
  • VG-10 vertical granulator
  • the particle power of 63-500 zm was obtained in the same manner as in Example 4 except that the aqueous solution of 10% by weight of 1!? 1 ⁇ ⁇ (TC-5E) in Example 4 was replaced with 10000 g of a 10% by weight aqueous solution of lactose. A granulated product of fine particles of weight% was obtained.
  • FIG. 2 shows the results of dissolution tests of the pharmaceutical compositions of Examples 4 and 5 and Comparative Examples 2 and 3 in the same manner as in Test Example 1.
  • Ketoprofen manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.
  • lOOOOg and ADSOLIDA-1 101 10g were mixed with a vertical granulator VG-10, and then 10% by weight HPMC (TC_5E) aqueous solution lOOOg with a fine particle coating device (SPC-01 type)
  • HPMC TC_5E
  • SPC-01 type fine particle coating device
  • a granulated product was obtained by mixing 10 g of ketoprofen lOOOOg and 10 g of Adsolida 101 with Vertical Granulator VG-10 (manufactured by Baurek).
  • Spironolataton manufactured by Koa Shoji Co., Ltd. 1000 g, Adsolida 101 5 g and 10 weight 0 / oH PMC (TC-5E) aqueous solution lOOOOg were used, and the particle power of 63 500 ⁇ m was obtained in the same manner as in Example 6. A granulated product of 7% by weight of fine particles was obtained.
  • Comparative Example 5 A granulated product was obtained in the same manner as in Comparative Example 4 using Spironolataton 100 g and Adsolida 101 5 g.
  • Furosemide (manufactured by Shizuoka Caffeine Industry Co., Ltd.), 1000 g, Adsolida 101 5 g and 10 weight 0 / oHPMC (TC-5E) aqueous solution lOOOOg were used. A granulated product of 3% by weight of fine particles was obtained.
  • a granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of furosemide and 5 g of Adsolida 101.
  • Mefuenamu acid (Ltd. Shizuoka caffeine Industries Ltd.) 1000g
  • Adosorida one 101 3 g and 10 weight 0 / oHPMC (TC- 5E) use an aqueous solution 1000g Rere, in the same manner as in Example 6 63- 500 mu m of the particles Obtained 99.6% by weight of fine particles.
  • a granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of mefenamic acid and 103 g of Adsolida-1.
  • Trichlormethiazide manufactured by Japan SiberHegner Co., Ltd.
  • ADSORIDA 101 0.5 g
  • lC ⁇ i% HPMC aqueous solution 1000 g, 63-500 ⁇ m as in Example 6 Of 97.9% by weight of fine particles were obtained.
  • a granulated product was obtained in the same manner as in Comparative Example 4, using 1,000 g of trichloronmethiazide and 0.5 g of Adsolida-1 101.
  • Pindolol manufactured by Daito (Ltd.) 1000g
  • Test Example 4 Table 2 shows the measurement results of the orifice diameter (mm) and the particle size distribution of the pharmaceutical compositions produced in Example 113 and Comparative Example 111.
  • Difficult 9 5.0 0.9 2.5 4.0 3.5 33.0 13.4 9.1 Difficult 10 5.0 0.3 2.7 46.8 33.7 14.8 0.7 0.4 Jong 11 11 0.4 0.4 3.2 8.2 16.9 36.6 13.9 8.1 Sick 12 12 0.4 0.4 1.8 5.5 15.1 38.8 15.0 11. Difficult 13 5.0 0.2 1.6 5.6 14.7 36.5 16.4 10.Rev. 1 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 ai 2 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Ver. 3 6.3 0.2 1.6 5.6 14.7 36.5 16.4 ⁇ 0.
  • Orifice diameter The diameter (mm) of the hole from which the powder flowed out was measured using an orifice diameter measuring device (manufactured by Konishi Medical Instruments Co., Ltd.).
  • Particle size distribution 500, 355, 300, 250, 177, 150, 125, 75, 63 / im sieve, using a micro-type electromagnetic vibration sieve (M-2, Tsutsui Physical and Chemical Co., Ltd.) was measured.
  • the pharmaceutical composition of the present invention (Examples 1-113) had a smaller orifice diameter and better fluidity than the pharmaceutical compositions produced in Comparative Examples 1-111.
  • all of the pharmaceutical compositions of the present invention contained 85% by weight or more in the particle diameter range of 63 to 500 ⁇ m.
  • V-type mixer (V-10, manufactured by Tokuju Seisakusho), 1998 g of the granulated product of Example 3 and 720 g of crospopidone CL (trade name: Kollidon CL, manufactured by BSF) were mixed for 15 minutes. 28 g of talc and 14 g of magnesium stearate were added and mixed for another 3 minutes, and a rotary tableting machine (RT-S15-T35, manufactured by Kikusui Seisakusho Co., Ltd.) was used to obtain tablets 8.5 mm in diameter and 230 mg per tablet.
  • V-10 manufactured by Tokuju Seisakusho
  • Example 6 The granulated product of Example 6 (1998 g) and crospovidone CL720 g were mixed for 15 minutes using a V-type mixer (V-10 type), 28 g of talc and 14 g of magnesium stearate were added, and the mixture was further mixed for 3 minutes. With a tableting machine (RT-S15-T35), tablets of 8.5 mg in diameter and 230 mg per tablet were obtained.
  • V-10 type V-type mixer
  • R-S15-T35 tableting machine
  • Hardness Measured using a tablet hardness tester (TH-303RP, manufactured by Toyama Sangyo Co., Ltd.). In addition, the value shows the average value of 10 times.
  • Disintegration time Measured using a disintegration tester (NT-6H, manufactured by Toyama Sangyo Co., Ltd.). The values are shown as the average of 6 measurements (test solution: water).
  • Ibuprofen (BASF IBUPROFEN50 particle size: 45-60 m) and 10 g of hydrated silicon dioxide (Adsolida-1 102 by Freund Corporation) are mixed with a vertical granulator VG-10, and then a fine particle coating device (SPC-01 type) ) At 10 weight. / oPV P (BFSF Takeda Vitamin Co., Ltd. PVP-K30) aqueous solution Granulated with lOOOOg and 85 particles of 63-500 ⁇ m. /. A granulated product of the above fine particles was obtained.
  • oPV P BFSF Takeda Vitamin Co., Ltd. PVP-K30
  • Table 5 shows the results of measuring the dissolution property of the poorly water-soluble drug in the same manner as in Test Example 1.
  • the pharmaceutical composition of the present invention had a significantly improved dissolution property as compared with the comparative example.

Abstract

Disclosed is a pharmaceutical composition which is applicable with various hardly water-soluble drugs and can be produced by a simple method. In this pharmaceutical composition, the solubility and fluidity of a hardly water-soluble drug are improved. Specifically, disclosed is a pharmaceutical composition which contains granules obtained by granulating a mixture of a hardly water-soluble drug and a plasticizer using a water solution or a water-containing alcohol solution of a water-soluble polymer.

Description

明 細 書  Specification
溶解性と流動性を改善した医薬組成物  Pharmaceutical composition with improved solubility and flowability
技術分野  Technical field
[0001] 本発明は、難水溶性薬物の溶解性と流動性が改善された医薬組成物に関する。  The present invention relates to a pharmaceutical composition having improved solubility and fluidity of a poorly water-soluble drug.
背景技術  Background art
[0002] 近年、医薬品として開発される薬物は、水に難溶性であることが多い。この難水溶 性薬物は、ノくィォアベイラビリティ一に問題があり、吸収性を向上させる必要がある。 従来から、難水溶性薬物の溶解性は、微細化、非晶化、固体分散化、包接化等によ つて改善されていた。  [0002] In recent years, drugs developed as pharmaceuticals are often poorly soluble in water. This poorly water-soluble drug has a problem in terms of no availability, and it is necessary to improve absorption. Conventionally, the solubility of poorly water-soluble drugs has been improved by miniaturization, amorphization, solid dispersion, inclusion, and the like.
[0003] 難水溶性薬物を親水性高分子及び溶解性改善剤と共に水性溶媒の存在下で粉 砕後水分を除去して得た固体分散体は、通常の固体分散体とは異なる溶解挙動を 示すこと、すなわち、水中で難水溶性薬物を含む微細な液滴を生じて分散して急速 に溶解することが知られている（特許文献 1)。  [0003] A solid dispersion obtained by pulverizing a poorly water-soluble drug together with a hydrophilic polymer and a solubility improving agent in the presence of an aqueous solvent and then removing water has a dissolution behavior different from that of a normal solid dispersion. That is, it is known that fine droplets containing a poorly water-soluble drug are generated in water and dispersed and rapidly dissolved (Patent Document 1).
また、難水溶性薬物の結晶粒子を気中に分散させ水溶性高分子溶液を噴霧しコ 一ティングする方法が知られている（特許文献 2)。しかし、この方法は、結晶薬物を 気中に分散させた状態で噴霧処理を行う必要があり、実質的には噴霧機構として、 中央に結晶薬物粒子の噴出部、その外側に水溶性高分子溶液の噴出部、さらにそ の外側に圧縮空気の噴出部を配置した同心 3重構造のノズル (特許文献 3)を装着し たジェットコーティング装置という特殊な装置が必要であって、大量生産には対応し 難いものである。  Further, a method is known in which crystal particles of a poorly water-soluble drug are dispersed in the air, and a water-soluble polymer solution is sprayed and coated (Patent Document 2). However, in this method, it is necessary to perform the spraying process in a state where the crystalline drug is dispersed in the air, and in effect, the spraying mechanism is composed of a jetting portion of the crystalline drug particles in the center and a water-soluble polymer solution in the outside. Special equipment called a jet coating device equipped with a concentric triple nozzle (Patent Document 3) with a compressed air ejection part disposed outside of it and a compressed air ejection part is required, and it is compatible with mass production. It is difficult.
また、難水溶性のプロピオン酸系非ステロイド系抗炎症剤と水溶性高分子基材及 び非イオン性界面活性剤を含有する易吸収性固形組成物が知られている（特許文 献 4)。  Also, an easily absorbable solid composition containing a poorly water-soluble propionic acid-based non-steroidal anti-inflammatory agent, a water-soluble polymer base material and a nonionic surfactant is known (Patent Document 4). .
[0004] し力しながら、これらの方法では、適用可能な薬物が限定されることと、溶解性を改 善した組成物は流動性が必ずしも良くない。その為、錠剤、カプセル剤、顆粒剤、散 剤等の固形製剤を調製するにあたっては、再度造粒し流動性を上げる必要があり、 複雑な工程になると同時に、溶解性を改善した難水溶性薬物を再び造粒することに より溶解性を低下させてしまう場合もあって、より広範囲にしかも簡単に難水溶性薬 物の溶解性を改善すると同時に流動性を改善する方法の開発が強く望まれている。 特許文献 1 :特開平 7 - 291854号公報 [0004] However, in these methods, the applicable drugs are limited, and the composition having improved solubility does not always have good flowability. Therefore, when preparing solid preparations such as tablets, capsules, granules, powders, etc., it is necessary to re-granulate and increase the fluidity. To re-granulate the drug In some cases, the solubility may be further reduced. Therefore, it is strongly desired to develop a method for improving the solubility of a poorly water-soluble drug in a wider range and easily and at the same time improving the flowability. Patent Document 1: JP-A-7-291854
特許文献 2 :特開平 6 - 128147号公報  Patent Document 2: JP-A-6-128147
特許文献 3：特開平 3 - 270598号公報  Patent Document 3: JP-A-3-270598
特許文献 4 :特開 2000— 95682号公報  Patent Document 4: JP-A-2000-95682
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] すなわち、本発明の目的は、より広範囲な難水溶性薬物に適用でき、しかも簡単な 製造法で得られる難水溶性薬物の溶解性と流動性が改善された医薬組成物を提供 することにある。 [0005] That is, an object of the present invention is to provide a pharmaceutical composition which can be applied to a wider range of poorly water-soluble drugs and has improved solubility and flowability of the poorly water-soluble drug obtained by a simple production method. It is in.
課題を解決するための手段  Means for solving the problem
[0006] 本発明者等は、この目的を達成する為に鋭意研究を重ねた結果、難水溶性薬物と 流動化剤を予め混合し、これを水溶性高分子の水又は含水アルコール溶液を用い て造粒すると該薬物の溶解性と流動性が改善されることを見出し、本発明を完成した すなわち、本発明は、難水溶性薬物と流動化剤の混合物を、水溶性高分子の水又 は含水アルコール溶液を用いて造粒することにより得られる造粒物を含有する医薬 組成物を提供するものである。 [0006] The inventors of the present invention have conducted intensive studies to achieve this object. As a result, a poorly water-soluble drug and a fluidizing agent are mixed in advance, and this is mixed with a water-soluble or water-containing alcohol solution of a water-soluble polymer. The present inventors have found that the granulation by granulation improves the solubility and fluidity of the drug, and completed the present invention. That is, the present invention provides a mixture of a poorly water-soluble drug and a superplasticizer with a water-soluble polymer The present invention provides a pharmaceutical composition containing a granulated product obtained by granulating using a hydroalcoholic solution.
また、本発明は上記医薬組成物を用いて得られる固形医薬製剤を提供するもので める。  The present invention also provides a solid pharmaceutical preparation obtained by using the above pharmaceutical composition.
発明の効果  The invention's effect
[0007] 本発明の医薬組成物は、難水溶性薬物の水への溶解性及び流動性が優れる。ま た、流動性に優れるので直接打錠が可能で、難水溶性薬物を含有する速溶性の錠 剤等の固形医薬製剤が容易に得られる。  [0007] The pharmaceutical composition of the present invention is excellent in solubility and flowability of a poorly water-soluble drug in water. Further, since it has excellent fluidity, direct tableting is possible, and a solid pharmaceutical preparation such as a fast-dissolving tablet containing a poorly water-soluble drug can be easily obtained.
図面の簡単な説明  Brief Description of Drawings
[0008] [図 1]図 1は、医薬組成物の溶出試験結果を示す図である。 [図 2]図 2は、医薬組成物の溶出試験結果を示す図である。 FIG. 1 is a view showing a dissolution test result of a pharmaceutical composition. FIG. 2 is a view showing a dissolution test result of a pharmaceutical composition.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0009] 本発明で使用する難水溶性薬物は、水に溶け難い薬物であれば特に限定されな レ、。ここで、難水溶性とは、 36°Cにおいて水に対する溶解量が lg/lOOmL以下の ものが溶解性改善効果の発現の点から好ましい。 [0009] The poorly water-soluble drug used in the present invention is not particularly limited as long as it is a drug that is hardly soluble in water. Here, the term “slightly water-soluble” means that the solubility in water at 36 ° C. is equal to or less than lg / 100 mL in view of the effect of improving the solubility.
一般的に、難水溶性薬物としては胃腸鎮痛薬、制酸薬、鎮痛薬、抗炎症剤、抗炎 症 *鎮痛 ·解熱剤、消炎剤、抗菌剤、抗真菌剤、抗狭心症薬、無機質製剤、消化性 潰瘍治療薬、冠状血管拡張薬、末梢および脳血管拡張薬、抗感染剤、抗不安剤、 神経弛緩薬、中枢神経系刺激薬、抗鬱薬、抗ヒスタミン剤、下痢止め剤、緩下薬、栄 養補給剤、コレステロール低下剤、鎮徑剤、抗苦悶剤、心臓律動作動薬、動脈高血 圧の治療薬、抗偏頭痛薬、血液凝固作用薬、甲状腺機能不全の治療薬、利尿剤、 食欲抑制薬、抗ぜん息剤、去痰薬、鎮該剤、鎮痰剤、粘液調整薬、制吐剤、尿酸排 泄剤、痛風治療剤、不整脈治療剤、高脂血症治療剤、気管支拡張剤、糖尿病用剤 、経口避妊薬、乗り物酔い治療剤、前立腺肥大症治療剤、膝炎治療剤、催眠導入剤 、催眠鎮静剤、抗リウマチ薬、抗てんかん薬、脳代謝改善剤、抗血小板剤、ビタミン 剤等が挙げられる。難水溶性薬物は、単独で用いても良いが、必要により併用しても 良い。  Generally, poorly water-soluble drugs include gastrointestinal analgesics, antacids, analgesics, anti-inflammatory drugs, and anti-inflammatory drugs. * Analgesic drugs, antipyretics, anti-inflammatory drugs, antibacterial drugs, antifungal drugs, anti-anginal drugs, and mineral substances. Formulation, peptic ulcer treatment, coronary vasodilator, peripheral and cerebral vasodilator, antiinfective, anxiolytic, neuroleptic, central nervous system stimulant, antidepressant, antihistamine, diarrhea, laxative , Nutritional supplements, cholesterol lowering agents, caliber reducing agents, anti-agonist agents, cardiac rhythm agonists, drugs for treating arterial hypertension, anti-migraine drugs, blood clotting drugs, drugs for treating thyroid dysfunction, diuretics , Appetite suppressants, antiasthmatics, expectorants, analgesics, expectorants, mucus regulators, antiemetics, uric acid excretions, gout treatments, arrhythmia treatments, hyperlipidemia treatments, bronchodilators , Antidiabetic agents, oral contraceptives, motion sickness treatment, prostatic hypertrophy treatment, knee inflammation treatment, hypnosis inducer Hypnotic sedatives, antirheumatics, anti-epileptic drugs, cerebral metabolism improving agents, antiplatelet agents, vitamins and the like. The poorly water-soluble drug may be used alone, or may be used in combination if necessary.
[0010] 特に好ましレ、難水溶性薬物として、イブプロフェン、ケトプロフェン、スピロノラタトン [0010] Particularly preferred and poorly water-soluble drugs include ibuprofen, ketoprofen, and spironolatatatone
、フロセミド、ジピリダモール、メフエナム酸、ピロキシカム、トリクロルメチアジド、ビンド ロール等の薬物を挙げることができる。 , Furosemide, dipyridamole, mefenamic acid, piroxicam, trichlormethiazide, vindolol and the like.
[0011] 本発明で使用する流動化剤としては、例えば、軽質無水ケィ酸、含水ケィ酸、タル ク、ステアリン酸マグネシウム、乳糖等が挙げられる。これらの流動化剤は、市販のも のを使用しても良い。例えば、アドソリダ一 101 (フロイント産業 (株)製）、ァエロジル 2 00 (日本ァエロジノレ (株）製）等の軽質無水ケィ酸、アドソリダ一 102 (フロイント産業（ 株)製）、カープレックス # 6ァ、 # 80、 # 100、 # 1120 (シオノギ製薬 (株)製）等の含 水二酸化ケイ素等が挙げられる。流動化剤としては、軽質無水ケィ酸、含水二酸化 ケィ素が好ましぐ特に軽質無水ケィ酸が好ましい。流動化剤は、単独で用いても良 レ、が、必要により併用しても良い。 本発明の医薬組成物における流動化剤の配合量は、難水溶性薬物 100重量部に 対して 0. 01— 5重量部であるのが好ましぐ更に 0. 03— 4重量部、特に 0. 05— 3 重量部であるのが好ましい。 [0011] Examples of the fluidizing agent used in the present invention include light caustic anhydride, hydrous caustic acid, talc, magnesium stearate, lactose and the like. As these fluidizers, commercially available ones may be used. For example, light silicic anhydride such as Ad Solida 101 (manufactured by Freund Corporation) and AEROSIL 200 (manufactured by Nippon Aerogenore Co., Ltd.), Ad Solida 102 (manufactured by Freund Corporation), Carplex # 6a, # 80, # 100, # 1120 (manufactured by Shionogi Pharmaceutical Co., Ltd.) and the like. As the fluidizing agent, light silicic anhydride and hydrous silicon dioxide are preferred, and light silicic anhydride is particularly preferred. The fluidizing agent may be used alone, but may be used in combination if necessary. The compounding amount of the superplasticizer in the pharmaceutical composition of the present invention is preferably 0.01 to 5 parts by weight, more preferably 0.03 to 4 parts by weight, especially 0 to 5 parts by weight based on 100 parts by weight of the poorly water-soluble drug. 05—3 parts by weight are preferred.
[0012] 本発明で使用する水溶性高分子としては、ヒドロキシプロピルメチルセルロース（以 下、 HPMCと記載することがある）、ヒドロキシプロピルセルロース（以下、 HPCと記載 することがある）、ボリビュルピロリドン (以下、 PVPと記載することがある)、メチルセル ロース、プノレラン、ポリビニノレアノレコーノレ、カノレボキシメチノレセノレロースナトリウム、ヒド ロキシェチルセルロース、メチルヒドロキシェチルセルロース等が挙げられる。 [0012] Examples of the water-soluble polymer used in the present invention include hydroxypropylmethylcellulose (hereinafter, may be described as HPMC), hydroxypropylcellulose (hereinafter, may be described as HPC), borobulpyrrolidone (hereinafter sometimes referred to as HPC). Hereinafter, it may be referred to as PVP), methylcellulose, punorelane, polyvinylinolenoreconore, canoleboxymethinoresenorelose sodium, hydroxyshethylcellulose, methylhydroxyethylcellulose, and the like.
これらの水溶性高分子は、市販のものを使用しても良い。例えば、商品名（以下同様 )TC— 5E、 TC— 5M、 TC— 5R、 TC— 5S、メトローズ 90SH、メトローズ 65SH (信越 化学工業 (株）製）等のヒドロキシプロピルメチルセルロース； HPC_L、 HPC_SL、 H PC-SSL, HPC_M、 HPC—H (日本曹達 (株）製）等のヒドロキシプロピルセルロー ス； PVP_K30、 PVP-K90 (ビーエーエスエフ武田ビタミン（株）製）等のポリビニノレ ピロリドン等が挙げられる。  As these water-soluble polymers, commercially available ones may be used. For example, hydroxypropylmethylcellulose such as trade names TC-5E, TC-5M, TC-5R, TC-5S, Metrolose 90SH, Metrolose 65SH (manufactured by Shin-Etsu Chemical Co., Ltd.); HPC_L, HPC_SL, HPC Hydroxypropyl cellulose such as -SSL, HPC_M, and HPC-H (manufactured by Nippon Soda Co., Ltd.); and polyvinylinole pyrrolidone such as PVP_K30 and PVP-K90 (manufactured by BSF TF Takeda Vitamin Co., Ltd.).
水溶性高分子としては、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセ ノレロース、ポリビエルピロリドンが好ましぐ特にヒドロキシプロピルメチルセルロース、 ヒドロキシプロピルセルロースが好ましい。水溶性高分子は、単独で用いても良いが、 必要により併用しても良い。  As the water-soluble polymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvierpyrrolidone are preferred, and hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly preferred. The water-soluble polymer may be used alone, or may be used in combination if necessary.
本発明の医薬組成物における水溶性高分子の配合量は、難水溶性薬物 100重量 咅に対して好ましく ίま 0. 1一 50重量咅 Βであって、更に 0. 3一 40重量咅 特に 0. 5一 30重量部であるのが好ましレ、。  The compounding amount of the water-soluble polymer in the pharmaceutical composition of the present invention is preferably 0.1 to 50% by weight, and more preferably 0.3 to 40% by weight, based on 100% by weight of the poorly water-soluble drug. 0.5 to 30 parts by weight, preferably.
[0013] 本発明の医薬組成物には、難水溶性薬物、流動化剤及び水溶性高分子の他に、 難水溶性薬物以外の薬物、更に固形製剤に通常使用される成分を適宜その目的に 応じて配合してもよい。例えば、デンプン、炭酸カルシウム、硫酸カルシウム、結晶セ ルロース、植物末等の賦形剤、着色剤、矯味剤、矯臭剤、光線遮断剤、香味剤、甘 味剤等が挙げられる。 [0013] The pharmaceutical composition of the present invention contains, in addition to a poorly water-soluble drug, a fluidizing agent, and a water-soluble polymer, a drug other than the poorly water-soluble drug, and a component usually used in a solid preparation as appropriate. May be blended according to the conditions. For example, excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder, and the like, coloring agents, flavoring agents, flavoring agents, light blocking agents, flavoring agents, sweetening agents and the like can be mentioned.
[0014] 本発明の医薬組成物は、難水溶性薬物と流動化剤とを混合し、水溶性高分子を水 又は含水アルコールに溶解した溶液を用いて造粒することにより製造される。ここで 使用する含水アルコールとしては、エタノール、イソプロパノール等の低級アルコー ルを 10— 90重量％含有する含水アルコールが好ましぐ特に含水エタノールが好ま しい。この場合、水溶性高分子は 1一 30重量％溶液として使用するのが好ましぐ更 に 5 20重量％溶液、特に 5— 15重量％溶液として使用するのが好ましい。 [0014] The pharmaceutical composition of the present invention is produced by mixing a poorly water-soluble drug and a fluidizing agent, and granulating using a solution in which a water-soluble polymer is dissolved in water or hydrous alcohol. here As the hydrous alcohol to be used, hydrous alcohol containing 10 to 90% by weight of a lower alcohol such as ethanol or isopropanol is preferable, and especially hydrous ethanol is preferable. In this case, the water-soluble polymer is preferably used as a 1 to 30% by weight solution, more preferably a 520% by weight solution, particularly preferably a 5 to 15% by weight solution.
[0015] 使用する造粒装置としては、特に限定はないが、例えば、攪拌型造粒装置 (パーチ カルダラ二ユレター）、流動層装置、転動流動装置等が挙げられる。特に、流動層造 粒装置が好ましぐ例えば、流動層造粒機（マルチプレックス 微粒子コーティング装 置 SPC—01型）が挙げられる。  [0015] The granulating apparatus to be used is not particularly limited, and examples thereof include a stirring-type granulating apparatus (Perch Caldera Doubler), a fluidized bed apparatus, and a tumbling fluidizing apparatus. In particular, a fluidized bed granulator is preferred, for example, a fluidized bed granulator (multiplex fine particle coating apparatus SPC-01).
[0016] 造粒物は、粒径 63— 500 μ mの粒子が 85重量％以上の微粒子であるのが溶解性 及び流動性の改善の点で好ましい。なお、粒子の粒径はふるい分け試験法で測定 する。  In the granulated product, particles having a particle size of 63 to 500 μm are preferably fine particles of 85% by weight or more from the viewpoint of improvement in solubility and fluidity. In addition, the particle size of the particles is measured by a screening test method.
[0017] このようにして製造された粒子状の医薬組成物は、流動性が良ぐしかも溶解性が 改善されているので、粒子状医薬組成物をそのまま散剤等として使用できるが、顆粒 剤、カプセル剤等にできる他、直接打錠して速溶性の錠剤型医薬製剤を容易に製 造すること力 Sできる。従って、本発明の医薬組成物を用いて得られる固形医薬製剤と しては、顆粒剤、散剤、錠剤、カプセル剤等が挙げられる。これらの固形医薬製剤を 調製するにあたっては、更に固形製剤に通常使用される成分、例えば、デンプン、炭 酸カルシウム、硫酸カルシウム、結晶セルロース、植物末等の賦形剤、着色剤、矯味 剤、矯臭剤、光線遮断剤、香味剤、甘味剤等を配合しても良い。  [0017] The particulate pharmaceutical composition produced as described above has good flowability and improved solubility, so that the particulate pharmaceutical composition can be used as it is as a powder or the like. Capable of making capsules, etc., as well as being capable of easily manufacturing tablet-type pharmaceutical preparations with rapid dissolution by direct compression. Therefore, examples of the solid pharmaceutical preparation obtained using the pharmaceutical composition of the present invention include granules, powders, tablets, capsules and the like. In preparing these solid pharmaceutical preparations, ingredients usually used in solid preparations further include excipients such as starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powder, coloring agents, flavoring agents, and odorants. Agents, light blocking agents, flavoring agents, sweetening agents, and the like.
実施例  Example
[0018] 次に、実施例を挙げて本発明を具体的に説明するが、本発明はこれに限定される ものではない。  Next, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
[0019] 実施例 1 Example 1
イブプロフェン（BASF製 IBUPROFEN25 粒径： 20— 33 μ m) lOOOgと軽質 無水ケィ酸 (フロイント産業 (株)製 アドソリダ一 101) 10gを、バーチカルグラ二ユレ 一ター VG—10 (パゥレック製）で混合後、流動層造粒機（マルチプレックス製：微粒子 コーティング装置 SPC-01型）で 10重量％HPMC (信越化学工業 (株）製 TC-5E )水溶液 50gで造粒し、 63— 500 /i mの粒子力 99. 6重量％の微粒子の造粒物を得 た。 Ibuprofen (BASF IBUPROFEN25 particle size: 20-33 μm) After mixing lOOOOg and 10 g of light anhydrous silicic acid (Adsolida-1 101 manufactured by Freund Corporation) with Vertical Granulator VG-10 (made by Perek) Granulated with 50 g of 10% by weight aqueous solution of HPMC (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) using a fluidized bed granulator (Multiplex: fine particle coating equipment SPC-01 type), 63-500 / im particles 99.6% by weight of fine particles were obtained. It was.
[0020] 実施例 2  Example 2
実施 f列 1と同様に、 10重量0 /oHPMC水溶 ί夜 400gで造粒し、 63— 500 μ ΐηの 粒子が 96. 2重量％の微粒子の造粒物を得た。 In the same manner as in row f 1, and granulated with a 10 weight 0 / oHPMC water ί night 400g, 63- 500 μ ΐη particles to obtain a granulated product 96. 2% by weight of the microparticles.
[0021] 実施例 3 Example 3
実施例 1と同様に、 10重量％HPMC水溶液 lOOOgで造粒し、 63— 500 x mの粒 子が 98. 2重量％の微粒子の造粒物を得た。  In the same manner as in Example 1, granulation was carried out with 10% by weight of an aqueous HPMC solution (IOOg) to obtain granules of 63-500 x m particles of 98.2% by weight.
[0022] 比較例 1 Comparative Example 1
イブプロフェン 1000g (BASF製 IBUPROFEN25 粒径： 20— 30 μ m)とアドソ リダ一 101 10gを、バーチカルグラニュレーター VG— 10で混合し、粒径 63 μ m以 下が 99. 7重量％の造粒物を得た。  A mixture of 1000 g of ibuprofen (IBUPROFEN25 from BASF, particle size: 20-30 μm) and 10 g of Adsolida-1 101 is mixed with a vertical granulator VG-10, and 99.7% by weight of particles with a particle size of 63 μm or less is 99.7% by weight. Got.
[0023] 試験例 1 Test Example 1
実施例 1一 3及び比較例 1で製造した医薬組成物の難水溶性薬物の溶出量を次の 試験法に従って行った。  The elution amount of the poorly water-soluble drug in the pharmaceutical compositions produced in Examples 13 and 13 and Comparative Example 1 was determined according to the following test method.
溶出試験法：日局 溶出試験法（2)第 2法 (パドル法)試験液：水 900mLにイブプ 口フェンとして 65mg含有量の医薬組成物を入れ、 100r/minの回転数で攪拌した とき、難水溶性薬物の溶出量を UV法で測定した。医薬組成物に配合した難水溶性 薬物量に対する溶出量の百分率で評価を行った。  Dissolution test method: JP Dissolution test method (2) Method 2 (Paddle method) Test solution: When a pharmaceutical composition containing 65 mg of ibupufen is added to 900 mL of water and stirred at a rotation speed of 100 r / min. The elution amount of the poorly water-soluble drug was measured by a UV method. The evaluation was made based on the percentage of the dissolution amount relative to the amount of the poorly water-soluble drug incorporated in the pharmaceutical composition.
[0024] 測定結果を図 1に示す。 FIG. 1 shows the measurement results.
本発明の医薬組成物（実施例 1一 3)はイブプロフェン (難水溶性薬物）の溶出速度 が速ぐ 30分で 80%以上が溶出し溶出性が優れたものであった。  In the pharmaceutical composition of the present invention (Examples 13 to 13), the dissolution rate of ibuprofen (a poorly water-soluble drug) was high, and 80% or more was dissolved in 30 minutes, and the dissolution was excellent.
[0025] 実施例 4 Example 4
イブプロフェン（BASF製 IBUPROFEN50 粒径： 45— 60 μ m) lOOOgとアドソ リダ一 101 10gを、バーチカルグラニュレーター VG—10で混合後、微粒子コーティ ング装置（SPC—01型）で lC^i%HPMC (TC-5E)水溶液 lOOOgで微粒子造粒 し、 63— 500 z mの粒子力 S97. 7重量0 /0の微粒子の造粒物を得た。 Ibuprofen (BASF IBUPROFEN50 particle size: 45-60 μm) After mixing lOOOOg and Adsolida-101 10g with a vertical granulator VG-10, use lC ^ i% HPMC (Particle Coating Equipment (SPC-01 type)) and fine granulated with TC-5E) solution LOOOg, to obtain a granulated product 63- 500 zm particle force of S97. 7 weight 0/0 of the microparticles.
[0026] 実施例 5 Example 5
実施例 4の 10重量％1^1^〇（丁〇_5£)水溶液 lOOOgを 10重量％1«3〇0«3〇_3 SL)水溶 ί夜 lOOOgに代えた他は実施 ί列 4と同様にして、 63— 500 /i mの粒子力 98 . 7重量％の微粒子の造粒物を得た。 Example 4 10 wt% 1 ^ 1 ^ 〇 (Ding 〇_5 £) aqueous lOOOg 10 wt% 1 «3 Rei_0« 3 〇_3 SL) Aqueous solution: A granulated product of fine particles having a particle power of 98.7% by weight of 98.7% by weight was obtained in the same manner as in Example 4 except that the temperature was changed to lOOOOg.
[0027] 比較例 2 Comparative Example 2
イブプロフェン（BASF製 IBUPROFEN50 粒径： 45— 60 μ m) lOOOgとアドソ リダ一 101 10gを、バーチカルグラニュレーター VG— 10で混合し、粒径 63 μ m以 下が 97. 5重量％の造粒物を得た。  Ibuprofen (BASF's IBUPROFEN50 particle size: 45-60 μm) 10 g of lOOOOg and Adsolida-1 101 are mixed with a vertical granulator VG-10, and 97.5% by weight of granules with a particle size of 63 μm or less are 97.5% by weight. Got.
[0028] 比較例 3 Comparative Example 3
実施例 4の 10重量％1!?1^〇 (TC-5E)水溶液 1 OOOgを 10重量％乳糖水溶液 10 00gに代えた他は実施例 4と同様にして、 63— 500 z mの粒子力 2重量％の微 粒子の造粒物を得た。  The particle power of 63-500 zm was obtained in the same manner as in Example 4 except that the aqueous solution of 10% by weight of 1!? 1 ^ 〇 (TC-5E) in Example 4 was replaced with 10000 g of a 10% by weight aqueous solution of lactose. A granulated product of fine particles of weight% was obtained.
[0029] 試験例 2 Test Example 2
試験例 1と同様にして実施例 4、 5及び比較例 2、 3医薬組成物の溶出試験を行つ た結果を図 2に示す。  FIG. 2 shows the results of dissolution tests of the pharmaceutical compositions of Examples 4 and 5 and Comparative Examples 2 and 3 in the same manner as in Test Example 1.
本発明の医薬組成物（実施例 4、 5)は、イブプロフェンの溶出性が顕著に改善され ていた。  In the pharmaceutical compositions of the present invention (Examples 4 and 5), the dissolution of ibuprofen was remarkably improved.
[0030] 実施例 6 [0030] Example 6
ケトプロフェン (米沢浜理薬品工業 (株)製） lOOOgとアドソリダ一 101 10gを、バー チカルグラニュレーター VG-10で混合後、微粒子コーティング装置（SPC-01型）で 10重量％HPMC (TC_5E)水溶液 lOOOgで微粒子造粒し、 63— 500 μ ΐηの粒 子が 97. 4重量％の微粒子の造粒物を得た。  Ketoprofen (manufactured by Yonezawa Hamari Yakuhin Kogyo Co., Ltd.) lOOOOg and ADSOLIDA-1 101 10g were mixed with a vertical granulator VG-10, and then 10% by weight HPMC (TC_5E) aqueous solution lOOOg with a fine particle coating device (SPC-01 type) The particles of 63-500 μΐη were obtained as 97.4% by weight of fine particles.
比較例 4  Comparative Example 4
ケトプロフェン lOOOgとアドソリダ一 101 10gを、バーチカルグラ二ユレ一ター VG— 10 (バウレック製）で混合して造粒物を得た。  A granulated product was obtained by mixing 10 g of ketoprofen lOOOOg and 10 g of Adsolida 101 with Vertical Granulator VG-10 (manufactured by Baurek).
[0031] 実施例 7 Example 7
スピロノラタトン（コーァ商事（株）製） 1000g、アドソリダ一 101 5g及び 10重量0 /oH PMC (TC— 5E)水溶液 lOOOgを用レ、、実施例 6と同様にして 63 500 μ mの粒子 力 5. 7重量％の微粒子の造粒物を得た。 Spironolataton (manufactured by Koa Shoji Co., Ltd.) 1000 g, Adsolida 101 5 g and 10 weight 0 / oH PMC (TC-5E) aqueous solution lOOOOg were used, and the particle power of 63 500 μm was obtained in the same manner as in Example 6. A granulated product of 7% by weight of fine particles was obtained.
比較例 5 スピロノラタトン lOOOgとアドソリダ一 101 5gを用い、比較例 4と同様にして造粒物 を得た。 Comparative Example 5 A granulated product was obtained in the same manner as in Comparative Example 4 using Spironolataton 100 g and Adsolida 101 5 g.
[0032] 実施例 8 Example 8
フロセミド（(株)静岡カフヱイン工業所製） 1000g、アドソリダ一 101 5g及び 10重 量0 /oHPMC (TC— 5E)水溶液 lOOOgを用レヽ、実施例 6と同様にして 63 500 μ m の粒子が 96. 3重量％の微粒子の造粒物を得た。 Furosemide (manufactured by Shizuoka Caffeine Industry Co., Ltd.), 1000 g, Adsolida 101 5 g and 10 weight 0 / oHPMC (TC-5E) aqueous solution lOOOOg were used. A granulated product of 3% by weight of fine particles was obtained.
比較例 6  Comparative Example 6
フロセミド 1000gとアドソリダ一 101 5gを用レ、、比較例 4と同様にして造粒物を得 た。  A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of furosemide and 5 g of Adsolida 101.
[0033] 実施例 9  Example 9
ジピリダモール（日本シィベルヘグナー（株）製） 1000g、ァエロジル 200 10g及び 10重量0 /oHPMC (TC— 5E)水溶液 1000gを用レヽ、実施例 6と同様にして 63 500 μ mの粒子が 94. 2重量％の微粒子の造粒物を得た。 Dipyridamole (Japan Consequences Bell Heguna (Ltd.)) 1000g, Aerojiru 200 10 g and 10 weight 0 / oHPMC (TC- 5E) use an aqueous solution 1000g Rere, particles to 63 500 mu m in the same manner as in Example 6 is 94.2 A granulated product of fine particles of weight% was obtained.
比較例 7  Comparative Example 7
ジピリダモーノレ 1000gとァエロジノレ 200 10gを用レヽ、 匕較 ί列 4と同様にして造粒物 を得た。  Using 1000 g of dipyridamone and 200 g of aerodine, a granulated product was obtained in the same manner as in the dangling line 4.
[0034] 実施例 10 Example 10
メフエナム酸（(株）静岡カフェイン工業所製） 1000g、アドソリダ一 101 3g及び 10 重量0 /oHPMC (TC— 5E)水溶液 1000gを用レヽ、実施例 6と同様にして 63— 500 μ mの粒子が 99. 6重量％の微粒子の造粒物を得た。 Mefuenamu acid (Ltd. Shizuoka caffeine Industries Ltd.) 1000g, Adosorida one 101 3 g and 10 weight 0 / oHPMC (TC- 5E) use an aqueous solution 1000g Rere, in the same manner as in Example 6 63- 500 mu m of the particles Obtained 99.6% by weight of fine particles.
比較例 8  Comparative Example 8
メフエナム酸 1000gとアドソリダ一 101 3gを用レ、、比較例 4と同様にして造粒物を 得た。  A granulated product was obtained in the same manner as in Comparative Example 4 using 1000 g of mefenamic acid and 103 g of Adsolida-1.
[0035] 実施例 11 Example 11
ピロキシカム（尼崎化学合成 (株）製） 1000g、アドソリダ一 101 1. 0g及び 10重量 %HPMC (TC— 5E)水溶液 1000gを用レ、、実施例 6と同様にして 63 500 μ mの 粒子が 96. 2重量％の微粒子の造粒物を得た。 ピロキシカム lOOOgとアドソリダ一 101 lgを用い、比較例 4と同様にして造粒物を 得た。 Using 1000 g of piroxicam (manufactured by Amagasaki Chemical Synthesis Co., Ltd.), 1.01.0 g of Adsolida-1 and 1000 g of a 10% by weight aqueous solution of HPMC (TC-5E), particles of 63 500 μm were 96 in the same manner as in Example 6. A granulated product of 2% by weight of fine particles was obtained. A granulated product was obtained in the same manner as in Comparative Example 4 using piroxicam lOOOOg and Adsolida-1 101 lg.
[0036] 実施例 12 Example 12
トリクロルメチアジド（日本シィベルヘグナー（株）製） lOOOg、アドソリダ一 101 0. 5 g及び lC^i%HPMC (TC_5E)水溶液 1000gを用レ、、実施例 6と同様にして 63 一 500 μ mの粒子が 97. 9重量％の微粒子の造粒物を得た。  Trichlormethiazide (manufactured by Japan SiberHegner Co., Ltd.) lOOOOg, ADSORIDA 101 0.5 g and lC ^ i% HPMC (TC_5E) aqueous solution 1000 g, 63-500 μm as in Example 6 Of 97.9% by weight of fine particles were obtained.
比較例 10  Comparative Example 10
トリクロノレメチアジド 1000gとアドソリダ一101 0. 5gを用レ、、比較例 4と同様にして 造粒物を得た。  A granulated product was obtained in the same manner as in Comparative Example 4, using 1,000 g of trichloronmethiazide and 0.5 g of Adsolida-1 101.
[0037] 実施例 13 Example 13
ピンドロール（ダイト（株）製） 1000g、アドソリダ一 101 10g及び 10重量0 /oHPMC (TC— 5E)水溶液 1000gを用レヽ、実施例 6と同様にして 63 500 x mの粒子力 2重量％の微粒子の造粒物を得た。 Pindolol (manufactured by Daito (Ltd.)) 1000g, Adosorida one 101 10 g and 10 weight 0 / oHPMC (TC- 5E) use an aqueous solution 1000g Rere, particle strength 2% by weight of the fine particles of the to 63 500 xm in the same manner as in Example 6 A granulated product was obtained.
比較例 11  Comparative Example 11
ピンドロール 1000gとアドソリダ一 101 10gを、比較例 4と同様にして造粒物を得 [0038] 試験例 3  A granulated product was obtained from 1000 g of pindolol and 10 g of Adsolida 101 in the same manner as in Comparative Example 4. [0038] Test Example 3
本発明の医薬組成物（実施例 6— 13)の難水溶性薬物の溶出性を試験例 1と同様 にして測定した結果を表 1に示す。  The dissolution property of the poorly water-soluble drug of the pharmaceutical composition of the present invention (Examples 6 to 13) was measured in the same manner as in Test Example 1, and the results are shown in Table 1.
本発明の医薬組成物は、比較例に比していずれも顕著に改善された溶出性を有し ていた [0039] [表 1]
Figure imgf000011_0001
Each of the pharmaceutical compositions of the present invention had remarkably improved dissolution properties as compared with Comparative Examples. [0039] [Table 1]
Figure imgf000011_0001
[0040] 試験例 4 実施例 1一 13及び比較例 1一 11で製造された医薬組成物のオリフィス径（mm)及 び粒度分布の測定結果を表 2に示す。 Test Example 4 Table 2 shows the measurement results of the orifice diameter (mm) and the particle size distribution of the pharmaceutical compositions produced in Example 113 and Comparative Example 111.
[0041] [表 2] [Table 2]
才リフィス径 (%) Year orifice diameter (%)
(ran) 500 imt 355 m† 300 /im† 250^mT 177/im† 150 /zmt 125 ii 難例 1 8.0 0.3 0.7 0.4 0.4 2.7 46.8 33. 難例 2 6.3 2.6 9.8 16.0 13.3 27.2 9.4 10. 雄例 3 5.0 0.9 1.5 5.4 7.3 45.4 22.9 7.5 難例 4 4.0 1.1 1.1 3.8 3.5 25.3 24.9 15. 細列 5 4.0 1.2 1.8 8.9 23.6 39.8 12.1 5.5 難例 6 5.0 1.8 10.8 18.3 16.7 30.4 8.9 5.8 麵例 7 5.0 0.6 1.2 2.9 5.8 30.0 19.8 17.1
Figure imgf000013_0001
纖例 8 5.0 0.7 6.7 9.2 15.2 . 27.5 14.2 9.7 (ran) 500 imt 355 m † 300 / im † 250 ^ mT 177 / im † 150 / zmt 125 ii Difficult 1 8.0 0.3 0.7 0.4 0.4 2.7 46.8 33. Difficult 2 6.3 2.6 9.8 16.0 13.3 27.2 9.4 10.Male 3 5.0 0.9 1.5 5.4 7.3 45.4 22.9 7.5 Difficult 4 4.0 1.1 1.1 3.8 3.5 25.3 24.9 15.Narrow 5 4.0 1.2 1.8 8.9 23.6 39.8 12.1 5.5 Difficult 6 5.0 1.8 10.8 18.3 16.7 30.4 8.9 5.8 麵 Ex 75.0 0.6 1.2 2.9 5.8 30.0 19.8 17.1
Figure imgf000013_0001
Fiber 8 5.0 0.7 6.7 9.2 15.2. 27.5 14.2 9.7
難例 9 5.0 0.9 2.5 4.0 3.5 33.0 13.4 9.1 難例 10 5.0 0.3 2.7 46.8 33.7 14.8 0.7 0.4 鍾例 11 5.0 0.4 3.2 8.2 16.9 36.6 13.9 8.1 鎌例 12 5.0 0.4 1.8 5.5 15.1 38.8 15.0 11. 難例 13 5.0 0.2 1.6 5.6 14.7 36.5 16.4 10. 翻 1 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 a i 2 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 翻 3 6.3 0.2 1.6 5.6 14.7 36.5 16.4 】0. Difficult 9 5.0 0.9 2.5 4.0 3.5 33.0 13.4 9.1 Difficult 10 5.0 0.3 2.7 46.8 33.7 14.8 0.7 0.4 Jong 11 11 0.4 0.4 3.2 8.2 16.9 36.6 13.9 8.1 Sick 12 12 0.4 0.4 1.8 5.5 15.1 38.8 15.0 11. Difficult 13 5.0 0.2 1.6 5.6 14.7 36.5 16.4 10.Rev. 1 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 ai 2 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Ver. 3 6.3 0.2 1.6 5.6 14.7 36.5 16.4】 0.
1：賴 4 16.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 a i 5 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 i»j6 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.01: 賴 4 16.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 a i 5 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 i »j6 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
1WJ7 20.0 0.0 0.0 0.0 0.0 " 0.0 0.0 0.0 1WJ7 20.0 0.0 0.0 0.0 0.0 "0.0 0.0 0.0
25.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 25.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
25.0 0.0 0.0 0.0 0.0 0.0 0.0 0.025.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 比翻 11 20.0 0.0 0,0 0.0 0.0 0.0 0.0 0.0 20.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Comparative 11 20.0 0.0 0,0 0.0 0.0 0.0 0.0 0.0
オリフィス径：オリフィス径測定器 (小西医療器 (株)製）を用いて粉体の流れ出る穴 の径 (mm)を測定した。 Orifice diameter: The diameter (mm) of the hole from which the powder flowed out was measured using an orifice diameter measuring device (manufactured by Konishi Medical Instruments Co., Ltd.).
粒度分布： 500、 355, 300、 250、 177, 150、 125、 75, 63 /i mのふるレヽを用レヽ て、ミクロ型電磁振動ふるい器 (M - 2型、筒井理化学器 (株)製)で測定した。  Particle size distribution: 500, 355, 300, 250, 177, 150, 125, 75, 63 / im sieve, using a micro-type electromagnetic vibration sieve (M-2, Tsutsui Physical and Chemical Co., Ltd.) Was measured.
[0043] 本発明の医薬品組成物（実施例 1一 13)は、比較例 1一 11で製造した医薬品組成 物よりオリフィス径が小さぐ流動性が優れていた。また、本発明の医薬組成物は、い ずれも 63— 500 μ mの粒径範囲に 85重量％以上が入っていた。 [0043] The pharmaceutical composition of the present invention (Examples 1-113) had a smaller orifice diameter and better fluidity than the pharmaceutical compositions produced in Comparative Examples 1-111. In addition, all of the pharmaceutical compositions of the present invention contained 85% by weight or more in the particle diameter range of 63 to 500 μm.
[0044] 実施例 14 Example 14
実施例 3の造粒物 1998g、クロスポピドン CL (商品名：コリドン CL、ビーエーエスェ フ (株)製） 720gを V型混合機 (V-10型、徳寿製作所製)を用いて 15分混合し、タル ク 28gとステアリン酸マグネシウム 14gを添加しさらに 3分混合し、ロータリー打錠機（ RT-S15-T35,菊水製作所 (株)製）で、直径 8. 5mm、 1錠 230mgの錠剤を得た  Using a V-type mixer (V-10, manufactured by Tokuju Seisakusho), 1998 g of the granulated product of Example 3 and 720 g of crospopidone CL (trade name: Kollidon CL, manufactured by BSF) were mixed for 15 minutes. 28 g of talc and 14 g of magnesium stearate were added and mixed for another 3 minutes, and a rotary tableting machine (RT-S15-T35, manufactured by Kikusui Seisakusho Co., Ltd.) was used to obtain tablets 8.5 mm in diameter and 230 mg per tablet.
[0045] 実施例 15 Example 15
実施例 6の造粒物 1998g、クロスポピドン CL720gを V型混合機 (V— 10型）を用い て 15分混合し、タルク 28gとステアリン酸マグネシウム 14gを添カ卩しさらに 3分混合し、 ロータリー打錠機（RT— S15— T35)で、直径 8. 5mm、 1錠 230mgの錠剤を得た。  The granulated product of Example 6 (1998 g) and crospovidone CL720 g were mixed for 15 minutes using a V-type mixer (V-10 type), 28 g of talc and 14 g of magnesium stearate were added, and the mixture was further mixed for 3 minutes. With a tableting machine (RT-S15-T35), tablets of 8.5 mg in diameter and 230 mg per tablet were obtained.
[0046] 試験例 5 Test Example 5
実施例 14及び 15で製造した錠剤の試験例 1と同じ試験法での溶出試験結果 (表 3 )及び錠剤の物性 (表 4)を示す。  The results of the dissolution test (Table 3) and the physical properties (Table 4) of the tablets produced in Examples 14 and 15 by the same test method as in Test Example 1 are shown.
[0047] [表 3] [Table 3]
(¾)
Figure imgf000014_0001
(¾)
Figure imgf000014_0001
[0048] 実施例 14及び 15で製造した錠剤は、 V、ずれも難水溶性薬物の溶出性が優れてレ ' た。  [0048] The tablets produced in Examples 14 and 15 were excellent in the dissolution of the poorly water-soluble drug in V and deviation.
[0049] [表 4] 赚 （N) 腳寺間 （秒） 厚さ Olll) [Table 4] 赚 (N) 腳 Temple (seconds) Thickness Olll)
難例 14 46.00 10〜20 5. 23  Difficult case 14 46.00 10〜20 5.23
麵例 15 52.00 8-18 5. 25  麵 Example 15 52.00 8-18 5.25
[0050] なお、測定は次の方法に従った。 [0050] The measurement was performed according to the following method.
硬度：錠剤硬度計 (TH— 303RP、富山産業 (株)製）を用いて測定した。なお、値は 10回の平均値を示す。  Hardness: Measured using a tablet hardness tester (TH-303RP, manufactured by Toyama Sangyo Co., Ltd.). In addition, the value shows the average value of 10 times.
崩壊時間：崩壊試験器 (NT— 6H、富山産業 (株)製）を用いて測定した。なお、値 は 6回の平均値で示す (試験液：水）。  Disintegration time: Measured using a disintegration tester (NT-6H, manufactured by Toyama Sangyo Co., Ltd.). The values are shown as the average of 6 measurements (test solution: water).
[0051] 実施例 16 Example 16
イブプロフェン 1000g (BASF製 IBUPROFEN50 粒径： 45— 60 m)と含水 二酸化ケイ素（フロイント産業 (株)製 アドソリダ一 102) 10gを、バーチカルグラニュ レーター VG— 10で混合後、微粒子コーティング装置（SPC— 01型）で 10重量。 /oPV P (ビーエーエスエフ武田ビタミン (株）製 PVP— K30)水溶液 lOOOgで微粒子造粒 し、 63— 500 μ mの粒子が 85。 /。以上の微粒子の造粒物を得た。  1000 g of Ibuprofen (BASF IBUPROFEN50 particle size: 45-60 m) and 10 g of hydrated silicon dioxide (Adsolida-1 102 by Freund Corporation) are mixed with a vertical granulator VG-10, and then a fine particle coating device (SPC-01 type) ) At 10 weight. / oPV P (BFSF Takeda Vitamin Co., Ltd. PVP-K30) aqueous solution Granulated with lOOOOg and 85 particles of 63-500 μm. /. A granulated product of the above fine particles was obtained.
[0052] 比較例 12 [0052] Comparative Example 12
イブプロフェン 1000g (BASF製 IBUPROFEN50 粒径： 45— 60 /i m)とアドソ リダ一 102 10gを、バーチカルグラニュレーター VG-10で混合し、混合物を得た。  1000 g of ibuprofen (IBUPROFEN50 particle size: 45-60 / im, manufactured by BASF) and 10 g of Adsolida 102 were mixed with a vertical granulator VG-10 to obtain a mixture.
[0053] 試験例 6 [0053] Test Example 6
難水溶性薬物の溶出性を試験例 1と同様にして測定した結果を表 5に示す。本発 明の医薬組成物は、比較例に比して顕著に改善された溶出性を有していた。  Table 5 shows the results of measuring the dissolution property of the poorly water-soluble drug in the same manner as in Test Example 1. The pharmaceutical composition of the present invention had a significantly improved dissolution property as compared with the comparative example.
[0054] [表 5] 時間 （分） [Table 5] Time (minutes)
0 2 4 12 20 30 40 50 60 90 120 鎌例 16 0.00 9.54 18.98 43.76 58.38 70.05 77.87 83.55 88.02 95.43 99. 19 膽列 12 0.00 1.22 3.84 15.63 27.66 41. 12 51.30 62.30 67.60 82. 22 92.36  0 2 4 12 20 30 40 50 60 90 120 Sickle case 16 0.00 9.54 18.98 43.76 58.38 70.05 77.87 83.55 88.02 95.43 99.19 Roughness 12 0.00 1.22 3.84 15.63 27.66 41.12 51.30 62.30 67.60 82.22 92.36

Claims

請求の範囲 The scope of the claims
[1] 難水溶性薬物と流動化剤の混合物を、水溶性高分子の水又は含水アルコール溶 液を用いて造粒することにより得られる造粒物を含有する医薬組成物。  [1] A pharmaceutical composition containing a granulated substance obtained by granulating a mixture of a poorly water-soluble drug and a fluidizing agent using a water-soluble or water-containing alcohol solution of a water-soluble polymer.
[2] 流動化剤が軽質無水ケィ酸又は含水二酸化ケイ素である請求項 1記載の医薬組 成物。  [2] The pharmaceutical composition according to claim 1, wherein the superplasticizer is light caustic anhydride or hydrous silicon dioxide.
[3] 水溶性高分子が、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロー ス及びポリビニルピロリドンから選ばれるものである請求項 1又は 2記載の医薬組成物  3. The pharmaceutical composition according to claim 1, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone.
[4] 難水溶性薬物がイブプロフェン、ケトプロフェン、フロセミド、スピロノラタトン、ジピリ ダモール、ピロキシカム、メフエナム酸、トリクロルメチアジド及びピンドロールから選ば れる薬物である請求項 1一 3のいずれ力 1項記載の医薬組成物。 [4] The pharmaceutical composition according to any one of [1] to [13], wherein the poorly water-soluble drug is a drug selected from ibuprofen, ketoprofen, furosemide, spironolatone, dipyridamole, piroxicam, mefenamic acid, trichlormethiazide and pindolol. .
[5] 造粒物の 85重量％以上が粒子径 63— 500 μ ΐηである請求項 1一 4のいずれか 1 項記載の医薬組成物。  [5] The pharmaceutical composition according to any one of [14] to [14], wherein 85% by weight or more of the granulated product has a particle size of 63 to 500 µΐη.
[6] 難水溶性薬物 100重量部に対して流動化剤を 0. 01— 5重量部含有する請求項 1 一 5のいずれか 1項記載の医薬組成物。  [6] The pharmaceutical composition according to any one of [15] to [15], which contains 0.01 to 5 parts by weight of a fluidizing agent based on 100 parts by weight of the poorly water-soluble drug.
[7] 難水溶性薬物 100重量部に対して水溶性高分子を 0. 1 50重量部含有する請求 項 1一 6のいずれか 1項記載の医薬組成物。 [7] The pharmaceutical composition according to any one of [16] to [16], which comprises 0.150 parts by weight of a water-soluble polymer per 100 parts by weight of a poorly water-soluble drug.
[8] 請求項 1一 7のいずれ力 4項記載の医薬組成物を用いて得られる固形医薬製剤。 [8] A solid pharmaceutical preparation obtained by using the pharmaceutical composition according to [4] of [11].
PCT/JP2004/012827 2003-09-05 2004-09-03 Pharmaceutical composition with improved solubility and fluidity WO2005023222A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HK06113473A HK1092711A1 (en) 2003-09-05 2006-12-07 Pharmeceutical composition with improved solubility and fluidity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003313853A JP4575654B2 (en) 2003-09-05 2003-09-05 Pharmaceutical composition with improved solubility and fluidity
JP2003-313853 2003-09-05

Publications (1)

Publication Number Publication Date
WO2005023222A1 true WO2005023222A1 (en) 2005-03-17

Family

ID=34269778

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/012827 WO2005023222A1 (en) 2003-09-05 2004-09-03 Pharmaceutical composition with improved solubility and fluidity

Country Status (6)

Country Link
JP (1) JP4575654B2 (en)
KR (1) KR20060119860A (en)
CN (1) CN100389750C (en)
HK (1) HK1092711A1 (en)
TW (1) TWI344376B (en)
WO (1) WO2005023222A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010508851A (en) * 2006-11-13 2010-03-25 エシコン・インコーポレイテッド In vitro expansion of postpartum-derived cells using microcarriers

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20130135994A (en) * 2005-06-27 2013-12-11 다이이찌 산쿄 가부시키가이샤 Pharmaceutical preparation containing an angiotensin ii receptor antagonist and a calcium channel blocker
JP5201819B2 (en) * 2006-11-22 2013-06-05 エスエス製薬株式会社 Solid composition
JP5817715B2 (en) * 2010-03-03 2015-11-18 ライオン株式会社 Solid pharmaceutical composition, pharmaceutical preparation and method for producing solid pharmaceutical composition
CN105343006B (en) * 2015-12-02 2019-05-14 北京大学 A kind of nanometer shell system and its preparation method and application carrying insoluble drug
CN105832680B (en) * 2016-05-12 2018-12-25 沈阳药科大学 A kind of pharmaceutical composition improving spirolactone In Vitro Dissolution and mobility
JP6918392B2 (en) * 2021-01-13 2021-08-11 築野食品工業株式会社 Yield improvement in powder production or generation, scattering or solidification inhibitor of fine powder in powder use

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01283219A (en) * 1988-03-25 1989-11-14 Ciba Geigy Ag Solid rapid collapsible administration form
JPH04159222A (en) * 1990-10-22 1992-06-02 Taisho Yakuhin Kogyo Kk Production of solid preparation for oral administration
WO1992009275A1 (en) * 1990-11-30 1992-06-11 Yamanouchi Pharmaceutical Co., Ltd. Quick release coated preparation
JPH0776517A (en) * 1993-09-07 1995-03-20 Yamanouchi Pharmaceut Co Ltd Composition for medicine
JPH09183728A (en) * 1987-06-24 1997-07-15 Bayer Ag Preparation of solid medicine
JPH10180080A (en) * 1996-11-01 1998-07-07 Fujisaki Denki Kk Granulating method of powder and device therefor
JPH10218761A (en) * 1997-02-07 1998-08-18 Taisho Pharmaceut Co Ltd Multiple unit type sustained release tablet
JPH10298111A (en) * 1997-03-10 1998-11-10 Basf Ag Use of re-dispersible polymeric powder or polymeric granule as binder and solid pharmaceutical dosage form
JPH11506432A (en) * 1995-05-17 1999-06-08 大正製薬株式会社 Bisacodyl dosage form for colon delivery
JPH11506433A (en) * 1995-05-17 1999-06-08 大正製薬株式会社 Bisacodyl dosage form with multiple enteric polymer coatings for colon delivery
JP2000016930A (en) * 1998-04-27 2000-01-18 Taisho Pharmaceut Co Ltd Oral rapid disintegration tablet and its production
JP2000026292A (en) * 1998-01-29 2000-01-25 Kissei Pharmaceut Co Ltd Rapid release oral pharmaceutical composition
WO2000078292A1 (en) * 1999-06-18 2000-12-28 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations
JP2002522377A (en) * 1998-08-05 2002-07-23 ザ ブーツ カンパニー ピーエルシー Pharmaceutical composition comprising ibuprofen and domperidone

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU84875A1 (en) * 1983-06-27 1985-03-29 Oreal TINCTORIAL COMPOSITIONS FOR KERATINIC FIBERS BASED ON DIRECT DYES AND XANTHANE GUM

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09183728A (en) * 1987-06-24 1997-07-15 Bayer Ag Preparation of solid medicine
JPH01283219A (en) * 1988-03-25 1989-11-14 Ciba Geigy Ag Solid rapid collapsible administration form
JPH04159222A (en) * 1990-10-22 1992-06-02 Taisho Yakuhin Kogyo Kk Production of solid preparation for oral administration
WO1992009275A1 (en) * 1990-11-30 1992-06-11 Yamanouchi Pharmaceutical Co., Ltd. Quick release coated preparation
JPH0776517A (en) * 1993-09-07 1995-03-20 Yamanouchi Pharmaceut Co Ltd Composition for medicine
JPH11506433A (en) * 1995-05-17 1999-06-08 大正製薬株式会社 Bisacodyl dosage form with multiple enteric polymer coatings for colon delivery
JPH11506432A (en) * 1995-05-17 1999-06-08 大正製薬株式会社 Bisacodyl dosage form for colon delivery
JPH10180080A (en) * 1996-11-01 1998-07-07 Fujisaki Denki Kk Granulating method of powder and device therefor
JPH10218761A (en) * 1997-02-07 1998-08-18 Taisho Pharmaceut Co Ltd Multiple unit type sustained release tablet
JPH10298111A (en) * 1997-03-10 1998-11-10 Basf Ag Use of re-dispersible polymeric powder or polymeric granule as binder and solid pharmaceutical dosage form
JP2000026292A (en) * 1998-01-29 2000-01-25 Kissei Pharmaceut Co Ltd Rapid release oral pharmaceutical composition
JP2000016930A (en) * 1998-04-27 2000-01-18 Taisho Pharmaceut Co Ltd Oral rapid disintegration tablet and its production
JP2002522377A (en) * 1998-08-05 2002-07-23 ザ ブーツ カンパニー ピーエルシー Pharmaceutical composition comprising ibuprofen and domperidone
WO2000078292A1 (en) * 1999-06-18 2000-12-28 Takeda Chemical Industries, Ltd. Quickly disintegrating solid preparations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010508851A (en) * 2006-11-13 2010-03-25 エシコン・インコーポレイテッド In vitro expansion of postpartum-derived cells using microcarriers

Also Published As

Publication number Publication date
TW200514571A (en) 2005-05-01
JP2005082503A (en) 2005-03-31
JP4575654B2 (en) 2010-11-04
HK1092711A1 (en) 2007-02-16
CN100389750C (en) 2008-05-28
TWI344376B (en) 2011-07-01
CN1842324A (en) 2006-10-04
KR20060119860A (en) 2006-11-24

Similar Documents

Publication Publication Date Title
JP6092936B2 (en) Method for producing orally disintegrating tablets
AU737738B2 (en) Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient
ES2205000T3 (en) PHARMACEUTICAL COMPOSITION CONTAINING IRBESARTAN.
JP4868695B2 (en) Oral preparation with good disintegration
TWI228414B (en) Pharmaceutical composition comprising carvedilol and hydrochlorothiazide, solid dosage form comprising it, and process for the production of the same
CN1747723B (en) Composition comprising a mixture of active principles, and method of preparation
EP2098225B1 (en) Taste masking system for non-plasticizing drugs
WO2005023222A1 (en) Pharmaceutical composition with improved solubility and fluidity
EP0599767B1 (en) Process to prepare water-dispersable tablets containing diclofenac
JP5275815B2 (en) Orally disintegrating tablets and bitterness-suppressing preparations containing risperidone
EP0200252B1 (en) Tablets comprising trimethoprim and a sulfonamide
JP7264711B2 (en) Method for producing pharmaceutical composition containing levetiracetam
JP6328138B2 (en) Of N- [5- [2- (3,5-dimethoxyphenyl) ethyl] -2H-pyrazol-3-yl] -4-[(3R, 5S) -3,5-dimethylpiperazin-1-yl] benzamide Pharmaceutical formulation
EP0319074A1 (en) Pharmaceutical composition and process for its preparation
WO2011040195A1 (en) Unpleasant taste-masking particles and an oral preparation containing same
JP5825686B2 (en) Method for producing slightly water-soluble drug-containing fine particle granulated product
EP1729735B1 (en) Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby
KR20180098282A (en) Compression-molded preparation
EP2848259B1 (en) Sustained release pharmaceutical formulations of Thiocolchicoside
EP1438961B1 (en) Bioequivalent composition of itraconazole dispersed in a hydrophilic polymer
KR20060058415A (en) Pharmceutical compositions containing the mixture of amoxicillin and clavulanic acid or salts and processes for preparing the same

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480024528.7

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1020067002247

Country of ref document: KR

122 Ep: pct application non-entry in european phase
WWP Wipo information: published in national office

Ref document number: 1020067002247

Country of ref document: KR