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WO1996019239A1 - Composition solide a solubilite et absorbabilite ameliorees - Google Patents

Composition solide a solubilite et absorbabilite ameliorees Download PDF

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Publication number
WO1996019239A1
WO1996019239A1 PCT/JP1995/002611 JP9502611W WO9619239A1 WO 1996019239 A1 WO1996019239 A1 WO 1996019239A1 JP 9502611 W JP9502611 W JP 9502611W WO 9619239 A1 WO9619239 A1 WO 9619239A1
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WO
WIPO (PCT)
Prior art keywords
solid composition
powder
water
soluble drug
poorly water
Prior art date
Application number
PCT/JP1995/002611
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English (en)
Japanese (ja)
Inventor
Katsuhiko Yano
Atsushi Kajiyama
Shigeru Yamazaki
Naoki Itoh
Kazuhiro Sako
Original Assignee
Yamanouchi Pharmaceutical 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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU43141/96A priority Critical patent/AU4314196A/en
Publication of WO1996019239A1 publication Critical patent/WO1996019239A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to a solid composition
  • a solid composition comprising a polymer base and a nonionic surfactant, wherein an extremely poorly water-soluble drug having a solubility of less than 10 / g Zm 1 is made amorphous.
  • an extremely poorly water-soluble drug having a solubility of less than 10 / g Zm 1 is made amorphous.
  • the solid composition is dispersed in a liquid such as water or a buffer solution, it forms stable fine particles having a particle diameter of 1 m or less, thereby improving the solubility of a very poorly water-soluble drug and This makes it possible to improve the absorption of the drug from the digestive tract.
  • a liquid such as water or a buffer solution
  • poorly water-soluble drugs have low solubility in the digestive tract, they are generally difficult to be absorbed from the digestive tract such as the gastrointestinal tract.
  • the solubility of some poorly water-soluble drugs depends on the pH. For example, some have high solubility in the acidic region (gastric pH), but low solubility in the weakly acidic to weakly alkaline region (intestinal pH).
  • the pH in the gastrointestinal tract varies among individuals (particularly the acidity in the stomach) and is influenced by the diet, so that the bioavailability of poorly water-soluble drugs may vary greatly.
  • poorly water-soluble drugs often have low bioavailability (bioavailability), so that the solubility of the drug in a wide pH region corresponding to the gastrointestinal tract, for example, in the region of pH 1 to 8 can be reduced. Improved formulation processing is required.
  • the complex formation depends on the structure of the drug and the like, and therefore, the complex may not be formed depending on the drug.
  • the present inventors have conducted intensive studies on the solubility and absorbability of a very poorly water-soluble drug, and have found that a very poorly water-soluble drug having a solubility of less than 10 g Zm 1 was made amorphous, a high molecular weight base and When a solid composition containing a nonionic surfactant is dispersed in a liquid such as water, stable ultrafine water-soluble drugs are kept amorphous for a long time, and stable fine particles with a particle size of 1 m or less are formed. As a result, they have found that a solid composition excellent in gastrointestinal absorption can be provided, thereby completing the present invention.
  • the solid composition according to the present invention improves the reduction in the dissolution rate of a solid dispersion and the reduction in solubility associated with the precipitation of a drug after a certain period of time, as observed in a conventional solid dispersion.
  • the present invention will be described in detail.
  • liquids such as gastric juice and intestinal juice penetrate into the solid composition in the gastrointestinal tract, and fine particles 12 are formed as the solid composition is dissolved. . Thereafter, the very poorly water-soluble drug contained in the fine particles 12 elutes into liquids such as gastric juice and intestinal juice.
  • the very sparingly water-soluble drug eluted is absorbed from gastrointestinal mucosa such as gastric mucosa and intestinal mucosa.
  • the solubility of each of the very poorly water-soluble drug, the polymer base, and the surfactant is different, so that the composition of the fine particles 12 is different from the composition of the solid composition 10. That is, in the fine particles 12, the ratio of the very poorly water-soluble drug is increased and the ratios of the polymer base and the surfactant are decreased as compared with the solid composition 10.
  • the composition of the very poorly water-soluble drug is so high that the very poorly water-soluble drug cannot be dispersed in the polymer base, it can exist as fine particles.
  • whether the poorly water-soluble drug contained in the fine particles is crystalline or amorphous can be determined by the presence of a diffraction peak by powder X-ray crystal diffraction of the fine particles.
  • the solid composition 10 was powdered or granular. However, it is not necessary that the solid composition be a powder or granule.
  • the step of forming fine particles includes disintegration of the solid preparation for internal use.
  • disintegration refers to a phenomenon in which a molded preparation for internal use collapses in a liquid such as the digestive tract and is dispersed at least to its constituent particles. Disintegration does not necessarily imply complete dissolution of the active ingredient, eg, the poorly water-soluble drug.
  • the ultra-poorly water-soluble drug used in the present invention is not particularly limited as long as its solubility is less than 10 g / m 1 in water, the first solution or the second solution having a temperature of 37.
  • the solubility may be any one of water, the first solution and the second solution under the conditions of 37.
  • the solubility is less than 5 ⁇ g / m1 And more preferably less than 2 gZmI.
  • a drug having a solubility in the second liquid of less than 10 gZm1 is preferable, a drug of less than 5 gZm1 is more preferable, and a drug of less than 2 gZml is preferable. Even more preferred.
  • the solid composition when a solid composition composed of a polymer base and a nonionic surfactant in a state where the ultra-slightly soluble drug is in an amorphous state is dispersed in a liquid, the solid composition has a particle diameter of 1 m or less. Are formed. At this time, those having a solubility of less than 10 ⁇ g / 1 are preferable because they maintain the amorphous state.
  • ultra-poorly water-soluble drug used in the present invention may be a salt generally used for production.
  • water is a model for gastric acidity of the stomach or the elderly
  • gastric fluid of the first is normal human gastric juice
  • liquid of the normal is intestinal fluid of normal human.
  • the first and second liquids are prescribed in the Japanese Pharmacopoeia 12th Revised Disintegration Test Method.
  • the first solution is an aqueous solution having a pH of about 1.2, which is obtained by adding water to 2 g of sodium chloride and 7.Om1 of hydrochloric acid to obtain 100 OmI.
  • the second solution was prepared by adding water to 250 ml of a 0.2 M aqueous solution of potassium dihydrogen phosphate and 11.8 m 1 of a 0.2 N aqueous solution of sodium hydroxide to adjust the pH to 100 O m 1. About 6.8 aqueous solution.
  • the solubility refers to the degree to which the drug dissolves within 30 minutes when the drug is put into a solvent, shaken every 5 minutes for 30 seconds, and shaken.
  • the type of the very poorly water-soluble drug used in the present invention is not particularly limited.
  • Preferred specific examples of the very poorly water-soluble drug include a benzodiazepine derivative having a gastrin antagonism and acting as an anti-ulcer agent.
  • examples include benzodiazepine derivatives described in PCT / JP91 / 01720 (International Publication No. WO9211246), PCT / JP94 / 01094, and the like.
  • benzazepine derivatives that is a vasopressin antagonist.
  • condensed benzazepine derivatives PCTZ JP 94/01 1183, etc.
  • benzazepine derivatives PCTZ JP 94 01 409, etc.
  • benzodiazepine derivatives PC TJP 91Z0 1720 (International Publication No. WO 9271 1246)).
  • the polymer base used in the present invention is not particularly limited as long as it is pharmaceutically acceptable and can disperse the extremely poorly water-soluble drug in an amorphous state.
  • a water-soluble polymer or an enteric polymer can be used.
  • water-soluble polymer examples include hydroxypropyl methylcellulose (for example, Shin-Etsu Chemical Co., Ltd., trade name: TC-15, Methorose 90, Methorose 65 SH), hydroxypropyl cellulose (for example, Nippon Soda, trade name: Nisso HPC), Methylcellulose (for example, Shin-Etsu Chemical, trade name METROLONE SM), hydroxyethyl cellulose (for example, Hercules' Japan, trade name NATRO SOL), polyvinylpyrrolidone (for example, BSF Japan, trade name corridone), Macrogol (for example, Nippon Soda, trade name Nisso Polyethylene Glycol # 6000) and the like.
  • hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxyshethylcellulose are mentioned.
  • enteric polymers examples include hydroxypropylcellulose phthalate (for example, Shin-Etsu Chemical, trade name HPMC P), hydroxypropyl methylcellulose (for example, Shin-Etsu Chemical, trade name Shin-Etsu AQOAT), carboxymethylethylcellulose (for example, Freund) Uto Sangyo, trade name CME C), phthalic acid acetate cell Loose (for example, Wako Pure Chemicals, trade name CAP), methacrylic acid copolymers (for example, Rohm Pharma, trade names Eudragit L, Eudragit S, Eudragit L 30D-55) and the like. .
  • hydroxypropylcellulose phthalate for example, Shin-Etsu Chemical, trade name HPMC P
  • hydroxypropyl methylcellulose for example, Shin-Etsu Chemical, trade name Shin-Etsu AQOAT
  • carboxymethylethylcellulose for example, Freund
  • phthalic acid acetate cell Loose for
  • the amount of the polymer base is 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, and more preferably 1 to 5 parts by weight based on 1 part by weight of the very poorly water-soluble drug. .
  • the reason is that if the amount is less than 0.5 part by weight, the drug often does not become amorphous. On the other hand, if it exceeds 20 parts by weight, it is difficult to take the drug due to the large capacity of the preparation, which is not practically preferable.
  • the high molecular base can be used alone or as a mixture of two or more if necessary.
  • nonionic surfactant used in the present invention examples include fatty acid esters and ethers. However, it is not limited to these.
  • fatty acid ester examples include sucrose fatty acid ester (sugar ester), polyethylene glycol fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and glycerin fatty acid ester. And polyoxyethylene glycerin fatty acid esters and polyoxyethylene sorbitol fatty acid esters.
  • the ether examples include a polyoxyethylene alkyl ether, a block polymer type ether, and a polyoxyethylene alkylaryl ether. Among these, polyoxetylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and block polymer ether are particularly preferable.
  • polyoxyethylene hydrogenated castor oil examples include hydrogenated castor oil polyoxyethylene ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil (20E.II), and polyoxyethylene hydrogenated castor oil (5E 0), polyoxyethylene hydrogenated castor oil 50 (HCO-50), and polyoxyethylene hydrogenated castor oil 60.
  • polyoxyethylene sorbitan fatty acid esters include polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 65, polysorbate 80 (Tween 80), polyoxyethylene sorbitan monolaurate (20 E . 0) Power.
  • block polymer type ether examples include polyoxyethylene [160] polyoxypropylene [30] glycol (pull nick F 68) and polyoxyethylene oxypropylene cetyl ether (20E.04P.0). , '.
  • the amount of the nonionic surfactant is from 1 to 3 parts by weight, preferably from 0.2 to 1.5 parts by weight, more preferably from 0.25 to 1 part by weight based on 1 part by weight of the very poorly water-soluble drug. ⁇ 1.25 parts by weight. This is because if the amount is less than 0.1 part by weight or more than 3 parts by weight, it is difficult to form fine particles when dispersed in a liquid.
  • the nonionic surfactants can be used alone or as a mixture of two or more if necessary.
  • the nonionic surfactant may be added when forming a solid dispersion together with the very poorly water-soluble drug and the polymer base. Further, a nonionic surfactant may be added after forming a solid dispersion of the very poorly water-soluble drug and the polymer base.
  • the composition ratio of the very poorly water-soluble drug, the polymer base and the nonionic surfactant is expressed as a weight ratio of the very poorly water-soluble drug: high.
  • Molecular base: nonionic surfactant 1: (0.01-1): (0.1 to 0.5).
  • a more preferable composition ratio is a weight ratio of a very poorly water-soluble drug: a polymer base: a nonionic surfactant-1: (0.
  • the solid composition of the present invention is obtained by dissolving or suspending a very poorly water-soluble drug, a polymer base and a nonionic surfactant in a solvent, and removing the solvent from the obtained solution by vacuum drying, freeze drying, spray drying, or the like. Obtained by removal.
  • the obtained powder or granules can be used as they are, but pharmaceutically acceptable excipients are added, and fine granules, granules, tablets, capsules, etc. commonly known as oral preparations are added. It may be formulated into
  • the solid composition of the present invention can be dispersed in water, and an excipient can be added as needed to obtain a liquid preparation for oral use.
  • FIG. 1 shows the mechanism until the drug contained in the solid composition of the present invention is absorbed.
  • FIG. 2 shows the particle size distribution when the solid composition of Example 1 was dispersed in water.
  • FIG. 3 shows the particle size distribution when the solid composition of Comparative Example 1 was dispersed in water.
  • FIG. 4 shows the particle size distribution when the solid composition of Control Sample 1 was dispersed in water.
  • FIG. 5 shows the drug concentration in plasma when the solid compositions of Example 1 and Control Sample 1 were orally administered to dogs.
  • FIG. 6 shows the drug concentration in plasma when the solid compositions of Example 1 and Control Sample 2 were orally administered to dogs.
  • FIG. 7 shows the particle size distribution when the solid composition of Comparative Example 5 was dispersed in water.
  • FIG. 8 shows the particle size distribution when the solid composition of Comparative Example 6 was dispersed in water.
  • the particle diameter was measured using a particle size distribution analyzer A-910 manufactured by Horiba, Ltd.
  • Table 1 summarizes the solubilities (g / m 1) of the drugs used in Examples, Comparative Examples, and Experimental Examples in the second solution, which is a buffer having a pH of about 6.8.
  • FIG. 2 shows the particle size distribution.
  • FIG. 2 a bar graph shows the relative distribution of the volume average diameter of particles having a specific particle diameter, and a cumulative distribution is shown by a curve.
  • the relative distribution of the volume average diameter of the particle is Shown on the axis.
  • the cumulative distribution of the volume average diameter of the particles is shown on the right vertical axis.
  • the notation method of the cumulative distribution is the same for FIGS. 3, 4, 7, and 8 as in FIG.
  • the solid composition of Comparative Example 1 differs from the solid composition of Example 1 in that it does not contain a nonionic surfactant.
  • YM022 and 3.5 g of hydroxypropylmethylcellulose were dissolved in a mixture of dichloromethane and methanol (8: 2), and the resulting solution was spray-dried to obtain a powder of a solid composition.
  • YM022 in the powder was amorphous.
  • the obtained powder was dispersed in purified water and the particle size was measured.
  • Fig. 3 shows the particle size distribution. The particle size was distributed between 2 and 100, and no fine particles of 1 m or less were produced.
  • YM087 [(2-Methyl-1,4,5,6-tetrahydromidazo [4,5-d] [1] benzazepine-1-yl) carbonyl] -12-phenylbenzanilide (hereinafter referred to as YM087)
  • 1 g, hydroxypropyl methylcellulose 3 g, and polyoxyethylene hydrogenated castor oil 0.5 g were dissolved in a dichloromethane / methanol mixture (8: 2), and the solution was spray-dried. A powder of the solid composition was obtained.
  • the solid composition of Comparative Example 2 is different from the solid composition of Example 2 in that it does not contain a nonionic surfactant.
  • Example 1 Using the powder of the solid composition obtained in Example 1 and the powder of a control sample shown below, the absorbability upon oral administration was compared.
  • the powder of the solid composition of Control Sample 1 differs from Example 1 only in that the powder containing YM022, ', YM022 is crystalline and not amorphous.
  • a disintegrant was added to the powder obtained in Comparative Example 1.
  • YM022 in the powder was a crystal.
  • the obtained powder was dispersed in purified water and the particle size was measured. The result was 0.1 to 1 m (Fig. 4).
  • the obtained powder (10 g) and a disintegrant (8 g) were mixed, and a tablet of 18 Omg containing 4 Omg of YM022 was produced by a conventional method.
  • the powder of the solid composition of Example 1 or Control Sample 1 was orally administered to dogs so as to contain 120 mg of YM022.
  • Three tablets of 600 mg of the powder of the solid composition obtained in Example 1 or a tablet of control sample 1 were orally administered to five beagle dogs, and blood was collected at predetermined time intervals.
  • the YM022 concentration in the plasma was measured by high performance liquid chromatography, and the pharmacokinetic parameters were calculated. The results for the average of the five cases are shown in Table 2 and FIG. In FIG. 5, bars indicate standard errors.
  • Cmax refers to the maximum plasma concentration
  • AUC refers to the area under the plasma concentration curve.
  • N.D. means below the detection limit.
  • the control sample 1 using YM022 in a crystalline state became fine particles of 1 m or less.
  • drug concentrations in plasma are below the detection limit. Therefore, it was confirmed that simply miniaturizing YM022 in a crystalline state did not improve absorption from the digestive tract.
  • Capsules were filled with the powder of Example 1 or Control Sample 2 so that YM022 contained 1 Omg, and orally administered to four beagle dogs. Then, blood was collected at predetermined time intervals, the concentration of YM022 in plasma was measured by GCZMS, and pharmacokinetic parameters were calculated. The results for the average of the four cases are shown in Table 3 and FIG. In FIG. 6, bars indicate standard errors. Table 3
  • Example 1 is a solid composition of the present invention.
  • Control Sample 2 was prepared by a conventional solid dispersion method with a polymer, and did not contain a nonionic surfactant.
  • Example 1 showed a value 4 times or more in Cmax (maximum plasma concentration) and 3 times or more in AUC (area under the plasma concentration curve) as compared to control sample 2. In other words, it was shown that the absorption was significantly improved by containing a nonionic surfactant.
  • Experimental example 3 Maintaining absorbency (suspension of suspension)
  • Example 4 Maintaining solubility
  • Example 1 50 ml of purified water was added to the powder obtained in Example 1 or Comparative Example 1 in an amount equivalent to 0.1 g in terms of YM022, and the mixture was shaken with a shaker for 1 hour, and then subjected to an ultracentrifuge (50 000 rpm, 30 ) And the supernatant was collected. Next, 50 ml of purified water was added to the obtained precipitate, shaken with a shaker for 30 minutes, and then subjected to an ultracentrifuge (50,000 rpm, 30 minutes), and the supernatant was collected. Further, the same treatment was applied to the obtained precipitate, and the supernatant was collected. The concentration of YM022 was measured for each of the collected supernatants by high performance liquid chromatography. Table 4
  • the concentration of YM022 in the supernatant after the second time decreases.
  • the solid composition of Example 1 has almost no decrease in the concentration of YMO22.
  • Example 2 2.5 g of the powder of the solid composition obtained in Example 1 was added to 200 ml of purified water and stirred for 1 hour with a magnetic stirrer to obtain a suspension. The suspension was centrifuged at 3,000 rpm for 5 minutes using a centrifuge to separate a precipitate. Further, the remaining suspension was centrifuged at 5,000 rpm for 30 minutes in an ultracentrifuge to separate a precipitate. Similarly, the precipitate was centrifuged under the centrifugation conditions shown in Table 5 to collect the precipitate.
  • the ratio indicates the weight ratio of each precipitate to the very poorly water-soluble drug (YM022) contained.
  • G means gravitational acceleration
  • 1 G is equivalent to 9.8 mZs 2 .
  • Each of the obtained precipitates is a mixture of three components.
  • the weight of the precipitate was 1.5 to 2.4 times that of YM022.
  • the above-mentioned force, TC-5E, is hydroxypropylmethyl cellulose acting as a polymer base
  • HCO-60 is a polyoxyethylene hydrogenated castor oil acting as a nonionic surfactant.
  • a powder having the following composition was prepared based on the measurement result of the composition ratio of the fine particles of Experimental Example 5, and the particle diameter in the dispersion was measured.
  • YM022 in the powder was amorphous. Further, when the obtained powder was dispersed in purified water and the particle diameter was measured, it was found to be fine particles of 2 to 602 m, and no fine particles of 1 m or less were observed.
  • the surfactant used in Comparative Example 4 is not nonionic but cationic. 22 g of YMO, 3.5 g of hydroxypropylmethylcellulose, and 0.5 g of sodium lauryl sulfate were added to a mixture of dichloromethane and methanol (8: 2), and this solution was spray-dried to obtain a powder.
  • Example 2 In the same manner as in Example 1, a powder of a solid composition having the following composition (weight ratio) was obtained.
  • YM022 is used as the very poorly water-soluble drug
  • hydroxypropylmethylcellulose CTC-5E is used as the polymer base
  • polyoxyethylene hydrogenated castor oil (HCO 60) is used as the surfactant.
  • YM022 1 g of YM022, 3.5 g of hydroxypropylmethylcellulose, 0.5 g of polyoxyethylene sorbitan monomer (Polysorbate 80; product name: Tween 80, manufactured by Kanto Chemical Co., Ltd.) : 2) and the solution was spray-dried to obtain a powder.
  • Polysorbate 80 product name: Tween 80, manufactured by Kanto Chemical Co., Ltd.
  • YM022 in the powder was amorphous.
  • the obtained powder was dispersed in purified water to obtain fine particles having a particle diameter of 0.1 to 1.
  • Example 7 the solid composition was a powder powder, and also contained lactose as a production aid.
  • 1 g of YM022, 3.5 g of hydroxypropylmethylcellulose, and 0.5 g of polyoxyethylene hydrogenated castor oil were dissolved in methanol, and the solution was spray-granulated into 45 g of lactose in a fluidized bed to obtain a powder powder.
  • YM022 in the powder was amorphous.
  • the obtained powder was dispersed in purified water to obtain fine particles having a particle size of 0.1 to 1 m.
  • Example 1 The powder of the solid composition obtained in Example 1 was filled in a capsule to obtain a capsule.
  • Example 2 To 200 g of the powder of the solid composition obtained in Example 1, 160 g of a disintegrant such as croscarmellose was mixed, and the mixture was tableted by a conventional method to obtain 36 Omg tablets containing 4 Omg of YM022.
  • a disintegrant such as croscarmellose
  • diphagepine having a solubility of 10 gZm 1 was used. 1 g of diphedibine, 3 g of hydroxypropylmethylcellulose, and 0.5 g of polyoxyethylene-hardened castor oil were added to a mixture of dichloromethane and methanol (8: 2), and this solution was spray-dried to obtain a powder.
  • the obtained powder was dispersed in purified water and the particle size was measured. O m distributed. The median particle size was 4 m.
  • Figure 7 shows the particle size distribution.
  • diphedipine in the powder was amorphous.
  • nifidipine had crystallized.
  • the solid composition of the present invention is obtained by converting an ultra-poorly water-soluble drug having a solubility of less than 10 g / m 1 into an amorphous form, and converting a solid composition containing a polymer base and a nonionic surfactant into a liquid. Improves absorption of very poorly water-soluble drugs from the gastrointestinal tract by forming stable fine particles with a particle size of 1 m or less when dispersed.
  • the very poorly water-soluble drug since the very poorly water-soluble drug remains amorphous even after the formation of the fine particles, its dissolution property is favorably maintained.
  • the very poorly water-soluble drug is eluted in the process until the fine particles are formed and in the process after the fine particles are formed, a long time after the very poorly water-soluble drug is dispersed in the liquid, for example, 3 to 7 days or Solubility can be maintained for more than that. That is, the solid composition of the present invention dispersed in a liquid can be stably maintained for a long time.

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Abstract

L'invention concerne une composition solide à solubilité et absorbabilité améliorées comprenant un médicament très difficilement soluble dans l'eau, dont la solubilité est inférieure ou égale à 10 νg/ml et qui se présente sous la forme suivante: substance amorphe, base polymère et tensioactif non ionique. Dispersée dans l'eau, cette composition forme des particules fines de taille inférieure ou égale à 1νm renfermant le médicament très difficilement soluble dans l'eau qui contient la substance amorphe. Dans ladite composition, le médicament très peu hydrosoluble est exsudé par les fines particules, ce qui améliore l'absorbtion du médicament à l'intérieur du tube digestif.
PCT/JP1995/002611 1994-12-21 1995-12-20 Composition solide a solubilite et absorbabilite ameliorees WO1996019239A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43141/96A AU4314196A (en) 1994-12-21 1995-12-20 Solid composition with improved solubility and absorbability

Applications Claiming Priority (2)

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JP6/318580 1994-12-21
JP31858094 1994-12-21

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WO1996019239A1 true WO1996019239A1 (fr) 1996-06-27

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Cited By (32)

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JP2000229846A (ja) * 1999-02-10 2000-08-22 Pfizer Prod Inc 放出制御型剤形
WO2002048142A1 (fr) * 2000-12-11 2002-06-20 Takeda Chemical Industries, Ltd. Compositions medicamenteuses presentant une meilleure absorbabilite
WO2002048141A1 (fr) * 2000-12-11 2002-06-20 Takeda Chemical Industries, Ltd. Composition medicinale dont la solubilite dans l'eau est amelioree
JP3413406B2 (ja) 1998-01-07 2003-06-03 明治製菓株式会社 結晶学的に安定な非晶質セファロスポリンの組成物とその製造方法
WO2003086405A1 (fr) * 2002-04-16 2003-10-23 Kowa Co., Ltd. Composition de dispersion solide
JP2004505911A (ja) * 2000-08-03 2004-02-26 ファイザー・プロダクツ・インク コレステリルエステル転移蛋白質阻害薬の医薬用組成物
WO2004030673A1 (fr) 2002-10-02 2004-04-15 Meiji Seika Kaisha, Ltd. Composition medicinale antibacterienne a absorptivite orale amelioree
WO2005034957A1 (fr) * 2003-10-08 2005-04-21 Meiji Seika Kaisha, Ltd. Composition antibacterienne non cristalline contenant du cefditoren pivoxil
JP2005162696A (ja) * 2003-12-04 2005-06-23 Nichiko Pharmaceutical Co Ltd 溶出性に優れたセフジトレンピボキシル製剤
JP2006028131A (ja) * 2004-07-21 2006-02-02 Toa Eiyo Ltd ピモベンダン経口投与製剤
JP2006056880A (ja) * 2004-07-21 2006-03-02 Toa Eiyo Ltd ピモベンダン経口投与製剤
JP2007191419A (ja) * 2006-01-19 2007-08-02 Toa Eiyo Ltd ピモベンダン経口投与製剤
WO2008114859A1 (fr) * 2007-03-22 2008-09-25 Astellas Pharma Inc. Composition pharmaceutique contenant un dérivé de pyrazole
JP2009506027A (ja) * 2005-08-26 2009-02-12 エスケー ケミカルズ カンパニー リミテッド 初期溶解率が改善されたプランルカスト固体分散体の薬剤学的組成物およびその製造方法
JP2009522278A (ja) * 2005-12-28 2009-06-11 バーテックス ファーマシューティカルズ インコーポレイテッド Ｎ−［２，４−ビス（１，１−ジメチルエチル）−５−ヒドロキシフェニル］−１，４−ジヒドロ−４−オキソキノリン−３−カルボキサミドの固体形態
US7550158B2 (en) 1999-02-10 2009-06-23 Bend Research, Inc. Controlled release by extrusion of solid amorphous dispersions of drugs
WO2011105070A1 (fr) 2010-02-25 2011-09-01 パナソニック株式会社 Appareil et procédé de régulation par l'offre et la demande, et programme associé
US8026286B2 (en) 1999-12-23 2011-09-27 Bend Research, Inc. Pharmaceutical compositions providing enhanced drug concentrations
JP4780522B2 (ja) * 2003-11-14 2011-09-28 味の素株式会社 フェニルアラニン誘導体の固体分散体または固体分散体医薬製剤
US8257741B2 (en) 1997-08-11 2012-09-04 Bend Research, Inc. Solid pharmaceutical dispersions with enhanced bioavailability
JP2014058584A (ja) * 2007-03-30 2014-04-03 Ajinomoto Co Inc 固体分散体製剤
US8697746B2 (en) 2010-07-14 2014-04-15 Senju Pharmaceutical Co., Ltd. Solid dispersion of alpha-ketoamide derivatives
US8828442B2 (en) 1999-02-10 2014-09-09 Bend Research, Inc. Pharmaceutical solid dispersions
JP2014177415A (ja) * 2013-03-13 2014-09-25 Daido Kasei Kogyo Kk ナノ粒子化製剤及びその製造方法
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