WO2003097102A1 - Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree - Google Patents

Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree Download PDF

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WO2003097102A1
WO2003097102A1 PCT/JP2003/006346 JP0306346W WO03097102A1 WO 2003097102 A1 WO2003097102 A1 WO 2003097102A1 JP 0306346 W JP0306346 W JP 0306346W WO 03097102 A1 WO03097102 A1 WO 03097102A1
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Prior art keywords
disintegrant
sugar alcohol
preparation according
mixing ratio
weight
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PCT/JP2003/006346
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English (en)
Japanese (ja)
Inventor
Shuichi Matsuda
Hidekazu Syodai
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Shionogi & Co., Ltd.
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Priority to JP2004505098A priority Critical patent/JP4743684B2/ja
Priority to AU2003235395A priority patent/AU2003235395A1/en
Publication of WO2003097102A1 publication Critical patent/WO2003097102A1/fr

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    • 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
    • A61K31/542—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 heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a preparation having improved solubility of a poorly water-soluble drug, and more particularly to an oral administration preparation containing at least a poorly water-soluble drug, a disintegrant and a sugar alcohol.
  • JP-A-62-89 describes compounds containing cefcapene pivoboxyl hydrochloride.
  • Japanese Patent Application Laid-Open No. Hei 4-300821 discloses a sustained-release preparation containing cefcapene pivoxil hydrochloride.
  • the present inventors improve the dissolution of poorly water-soluble drugs by blending a disintegrant and a sugar alcohol in the parent drug product and optimizing the mixing ratio of the disintegrant to the sugar alcohol.
  • the inventors have found that the present invention described below has been completed.
  • disintegrant is one or more disintegrants selected from celluloses, starches and polyvinyls.
  • the disintegrant is a low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, partially pregelatinized starch, carboxymethylsutyl sodium, pregelatinized starch and
  • the disintegrant is a low-substituted hydroxypropylcellulose, and the mixing ratio of the disintegrant to the sugar alcohol is 0.3 to 1.2 times by weight. 6) The preparation according to any one of the above.
  • the sugar alcohol is xylitol, D-mannitol, maltitol, erythritol, trehalose,! )
  • the preparation according to the above (8) which is one or more selected from the group consisting of sorbitol mono-lactitol.
  • the disintegrant is low-substituted hydroxypropylcellulose, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to sugar alcohol is 0.8 to 1.2 times by weight.
  • the preparation according to the above (1) which is characterized in that:
  • the disintegrant is croscarmé sodium D-sodium
  • the sugar alcohol is xylitol
  • the mixing ratio of the disintegrant to the sugar alcohol is 2.5 to 3.5 times by weight.
  • the disintegrant is carboxymethylcellulose calcium and the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 times or more by weight.
  • the poorly water-soluble drug is (+)-(6R, 7R) -17-[(Z) -12- (2-amino-4-thiazolyl) -12-pentenamide] -3 Moyloxime methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-1-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride or hydrate thereof.
  • the poorly water-soluble drug is (+)-(6,7) -7-E (Z) -2- (2-Amino-1-4-thiazolyl) —2-pentenamide] -3-carbamoylo Ximetyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid piperyloxy methyl ester hydrochloride or hydrate thereof, disintegrant Is carboxymethylcellulose calcium, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 4 times by weight.
  • a sustained-release preparation obtained by coating the preparation of the above-mentioned (21) with a sustained-release base or an enteric base.
  • the poorly water-soluble drug is characterized by containing a disintegrant and a sugar alcohol in a ratio of 0.2 to 5 times the weight ratio of the disintegrant to the sugar alcohol.
  • Figure 1 Relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and xylitol, a sugar alcohol, to the dissolution rate 60 and 120 minutes after the start of the dissolution test for cefcapene pivoxil hydrochloride. Show. The vertical axis represents the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis represents the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.
  • Figure 2 The relationship between the weight ratio of croscarmellose sodium, a disintegrant, and xylitol, a sugar alcohol, and the dissolution rate 60 and 120 minutes after the start of the dissolution test of cefcapene pivoxil hydrochloride. .
  • the vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.
  • Figure 3 The weight ratio of low-substituted hydroxypropylcellulose as a disintegrant and D-mannitol as a sugar alcohol and the dissolution rate of cefcapene pivoxil hydrochloride at 60 and 120 minutes after the start of the dissolution test. Show the relationship.
  • the vertical axis shows the dissolution rate of cefcapene pivoxil hydrochloride (%), and the horizontal axis shows the amount of disintegrant, sugar alcohol (mg) and its weight. Indicates a quantitative ratio. '
  • Figure 4 Relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and maltitol, a sugar alcohol, and the dissolution rate of cefcapene pivoxil hydrochloride 60 and 120 minutes after the start of the dissolution test. Show. The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.
  • Figure 5 Weight ratio of low-substituted hydroxypropyl cell mouth, a disintegrant, and erythritol, a sugar alcohol, and cefcapene pipoxyl hydrochloride at 60 and 120 minutes after the start of the dissolution test. 1 shows the relationship between the elution ratios of the compounds. The vertical axis represents the dissolution rate (%) of penifivoxil hydrochloride, and the horizontal axis represents the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.
  • Figure 6 The relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and trehalose, a sugar alcohol, and the dissolution rate of cefcapene pivoxil hydrochloride 60 and 120 minutes after the start of the dissolution test. Show. The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.
  • Figure 7 shows the relationship between the weight ratio of carboxymethylcellulose calcium, a disintegrant, and xylitol, a sugar alcohol, and the dissolution rate of cefpeniboxil hydrochloride at 60 and 120 minutes after the start of the dissolution test.
  • the vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending ratio (%) of disintegrant and bran alcohol and their weight ratio.
  • the poorly water-soluble drug in the present invention is not particularly limited, such as pharmaceuticals, quasi-drugs, veterinary drugs, etc., but has a water solubility at 37 ° C., preferably 100 ⁇ g / ml or less, more preferably It is preferably at most 100 g / mL, particularly preferably at most 100 g / mL. Specifically, preferably 7?
  • the content of the poorly water-soluble drug may be such that the desired pharmacological effect can be obtained and the formulation can be formed, but it is preferably 20 to 80 (W / W) based on the total amount of the formulation. %, More preferably 30 to 60 (W / W)%, and particularly preferably 30 to 55 (W / W)%. If the content of the poorly water-soluble drug is too high, the drug is susceptible to temporal change, and the dissolution may be reduced. Conversely, if it is too low, the desired pharmacological effect cannot be obtained.
  • the disintegrant to be used in the present invention may be any one that can disintegrate a solid preparation in water, and preferably a solid disintegrant listed in a drug rule or a food additive can be used.
  • L-HPC low-substituted hydroxypropylcellulose
  • carboxymethylcellulose carboxymethylcellular monocalcium
  • carboxymethylcellulose sodium carboxymethylcellulose sodium
  • croscarmellose sodium partially pregelatinized starch
  • Carboxymethyl starch sodium pregelatinized starch
  • polyvinylpyrrolidone more preferably low-substituted hydroxypropylcellulose, croscarmellose sodium, or calcium carboxymethylcellulose (CM C-Ca).
  • CM C-Ca calcium carboxymethylcellulose
  • the content of the disintegrant varies depending on the content of the poorly water-soluble drug in the preparation, etc., but is preferably 5 (W / W)% or more, and more preferably 5 to 50 (W) / W)%, more preferably 7.5-45 (W / W)%, particularly preferably 10-40 or 20-30 (W / W)%. If the blending ratio of the disintegrant is too high, the formulation disintegrates immediately, and sufficient dissolution cannot be ensured. Conversely, if it is too low, the drug product does not disintegrate and almost no drug is eluted.
  • the sugar alcohol used in the present invention may be any sugar alcohol that is usually soluble in water, and preferably a solid sugar alcohol described in a pharmaceutical rule or food additive can be used. More preferably, the saccharide having a solubility in water of at least 15 (W / V)% at 25 ° C., more preferably at least 30 (W / V)%, particularly preferably at least 50 (W / V)%.
  • Alcohols for example, sugar alcohols of monosaccharides and disaccharides. Specifically, xylitol, D-mannitol, maltitol, erythritol, trehalose, D-sorbitol, lactitol and the like can be used.
  • xylitol particularly preferred are xylitol, D-mannitol, maltitol, erythritol, and trehalose.
  • the content of the sugar alcohol varies depending on the content of the active ingredient in the preparation, but is preferably 5% (W / W)% or more, more preferably 5 to 50 (WZW), based on the total amount of the preparation. %, More preferably 7.5-45 (W / W)%, particularly preferably 10-40 (W / W)%. If the mixing ratio of the sugar alcohol is too high, the composition is susceptible to temporal changes, and preparations cannot be prepared. Conversely, if it is too low, sufficient drug dissolution cannot be obtained. Further, the sugar alcohol may be added as an excipient.
  • the compounding ratio of the disintegrant to the sugar alcohol may be any ratio at which the dissolution property of the poorly water-soluble drug from the preparation increases, but the compounding ratio of the disintegrant to the sugar alcohol is preferably 0.2 to 0.2 by weight. It is 5 times, more preferably 0.25 to 4.5 times, particularly preferably 0.3 to 4 times. If the disintegrant is low-substituted hydroxypropylcellulose, the mixing ratio of the disintegrant to the bran alcohol is preferably 0.2 to by weight; L ⁇ 5 times, more preferably 0.25 to: 1. 25 times, particularly preferably 0. 3 to 1.2 times.
  • the mixing ratio of the disintegrant (preferably CMC-Ca) to the sugar alcohol is preferably 0.5 to 5 times by weight, more preferably 0.6 to 0.4. It is 5 times, particularly preferably 0.8 to 4 times, and further preferably 2.5 to 3.5 times.
  • the mixing ratio of the disintegrant to the sugar alcohol is preferably 0.6 to 1.4 times by weight, more preferably 0 to 1.4. The ratio is 7 to 1.3 times, particularly preferably 0.8 to 1.2 times.
  • One of the preferred combinations of disintegrant and sugar alcohol is croscarmellose sodium and sugar alcohol is xylitol in consideration of dissolution properties and processability of the preparation.
  • sugar is preferable.
  • the mixing ratio of the disintegrant to alcohol is 2 to 4 times by weight, more preferably 2.25 to 3.75 times, particularly preferably 2.5 to 3.5 times, and most preferably about 3 to 3 times. It is twice.
  • the disintegrant is CM C—Ca and the sugar alcohol is xylitol.
  • the mixing ratio of the disintegrant to the sugar alcohol is preferably 2 to 4 times by weight, more preferably 2 to 4 times. 25-3.75 times, particularly preferably 2.5-3.5 times, most preferably about 3 times. If the content of the disintegrant is too high, the granulation property is deteriorated, and the raw material becomes porous. As a result, strength that can withstand the coating cannot be obtained.
  • the preparation of the present invention may further optionally contain pharmaceutically acceptable additives such as a binder, a granulation aid, an excipient, and a stabilizer.
  • pharmaceutically acceptable additives such as a binder, a granulation aid, an excipient, and a stabilizer.
  • binder those well-known in the art can be widely used, and examples thereof include methylcellulose, hydroxypropylcellulose (HPC), polyvinyl alcohol, gelatin, dextrin and the like. Cypropyl cellulose.
  • the content of the binder is preferably usually 0.5 to 15 (W / W)%, preferably 1.0 to 10 (W / W)%, more preferably 1.5 based on the total amount of the preparation. ⁇ 5 (W / W)%.
  • the granulation aid those well-known in the art can be widely used.
  • hydrogenated castor oil, waxes such as stearyl alcohol, macrogol 40 Polyethylene glycols such as 000, Macrogol 600, and the like are exemplified, but hardened castor oil is preferred.
  • the content of the granulation auxiliary is preferably usually 5 to 25 (W / W)%, preferably 3 to 20 (W / W)%, more preferably 2 to 1 based on the total amount of the preparation. 0 (W / W)%.
  • excipient those well known in the art can be widely used, and examples thereof include lactose, sucrose, sugar alcohol, corn starch, potato starch, hydroxypropyl starch, and synthetic aluminum silicate. But preferably lactose, sucrose, sugar alcohols, corn starch and potato starch.
  • the content of the excipient may be appropriately set in consideration of the content of the active substance, the size of the target preparation, etc., but is usually 40 to 90 (W / W)%, preferably It is from 45 to 85 (W / W)%, more preferably from 50 to 80 (W / W)%.
  • the content of the stabilizer may be appropriately determined in consideration of the content of the active ingredient, the size of the target drug product, and the like, but is usually 0.1 to 2 ⁇ .0 (W / W )%, Preferably 0.5-10.0 (W / W)%.
  • the form of the preparation of the present invention is not particularly limited, but is preferably a solid preparation such as granules, powders, fine granules and tablets, and particularly preferably granules.
  • the granule of the present invention is not particularly limited, but is preferably produced by the following method. That is, a poorly water-soluble drug, a sugar alcohol, a disintegrant and, if desired, an excipient, a stabilizer and the like are mixed, and an aqueous solution containing a binder is added to the mixed powder, followed by kneading. Then, granulate with an extrusion granulator and dry the granules. After drying, the granules may be sized and classified to produce granules. Further, in order to adjust the shape of the granules after classification, the granules may be spheroidized with a marmalizer or the like. Ma Granules can also be prepared by a tumbling granulation method, a fluidized bed granulation method, a stirring granulation method or a stirring fluidized bed granulation method.
  • the tablet may contain pharmaceutically acceptable additives such as excipients, binders, and lubricants.
  • a capsule it can be filled into a hard capsule or a soft capsule.
  • the drug is rapidly eluted from the preparation.
  • the paddle method of the 14th revised Japanese Pharmacopoeia (paddle stirring speed 50 rpm, test temperature 37 ° C, 14th revised Japanese Pharmacopoeia second liquid [pH 6.8])
  • the dissolution rate at 120 minutes after the start of the dissolution test at 37 ° C is preferably 60% or more, more preferably 70% or more, and particularly preferably 80% or more.
  • the dissolution rate after 60 minutes is preferably 80% or more, more preferably 85% or more, and particularly preferably 9% or more. 0% or more.
  • the elution rate after 120 minutes is preferably 90% or more.
  • the drug product is basically composed of a drug, a sugar alcohol and a disintegrant, but a drug and a sugar alcohol or a drug and a disintegrant may form a complex.
  • the granules, tablets, capsules and the like of the present invention can be formed into a sustained-release or enteric-coated preparation by coating with a sustained-release base or an enteric base after molding.
  • the sustained-release base include ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, stearic acid, hydrogenated soybean oil, hydrogenated naptone oil, and hydrogenated oil.
  • enteric film bases include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, hydroxypropylmethylcellulose acetate maleate, carboxymethyl ester Chilsel D-S, Metacry There are lactic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, cellulose acetate phthalate, and purified ceramic.
  • the coating of the sustained-release base or the enteric base described above may be carried out, if desired, after forming an underlayer on the elementary granules.
  • the component of the underlayer include HPMC and talc.
  • the device for coating the sustained-release base and the enteric base may be any industrially used one. Examples thereof include a pan coating device, a fluidized-bed coating device, Examples include a Wurster type coating apparatus, a centrifugal fluidized bed type coating apparatus, and a stirring and tumbling fluidized bed type coating apparatus.
  • the number of doses of the sustained-release or enteric-coated preparation is not particularly limited, but is preferably 1 to 3 times, more preferably 1 to 2 times, particularly preferably 1 time.
  • the present invention preferably comprises at least a poorly water-soluble drug, a disintegrant and a sugar alcohol in the preparation, and optimizes the mixing ratio of the disintegrant and the sugar alcohol, for example, at 37 ° C. It is intended to provide a drug product whose drug dissolution rate is 120% or more 120 minutes after the start of the test.
  • the mixing ratio of the disintegrant to the sugar alcohol is 0.2 to 5 times, preferably 0.25 to 4.5 times, more preferably 0.3 to 4 times by weight. It also provides a method for improving the dissolution of sexual drugs.
  • the present invention also provides a method for producing a preparation having improved dissolution of the poorly water-soluble drug, which comprises the method for improving dissolution. '
  • the drug was used by pulverizing the above-mentioned cefcapene pipoxyl hydrochloride described in JP-A-62-89.
  • the disintegrant is low-density hydroxypropylcellulose (hereinafter referred to as L-HPC)
  • the sugar alcohol is xylitol
  • the granulation aid is hydrogenated castor oil
  • the binder is hydroxypropylcellulose (hereinafter HPC-L). )
  • Cefcapene pivoxil hydrochloride, L-HPC, xylitol and hydrogenated castor oil were mixed in a mortar, and a 3 (W / V)% aqueous solution of HPC-L was added and kneaded.
  • the kneaded mixture was extruded using an extrusion granulator [mesh ⁇ 0.6 mm, machine name Dome Gran (manufactured by Nonipadal)], and dried at 50 ° C for 30 minutes. Thereafter, the granules were sized using a 14-mesh sieve, and classified using a 20-42 mesh sieve to prepare granules.
  • a dissolution test was performed on the above drug product according to the method prescribed in the Japanese Pharmacopoeia, 14th Edition. The details of the conditions of the dissolution test are as follows.
  • the dosage of the preparation in the test solution was about 270 mg (titer amount of cefcapene pivoxil hydrochloride 10 Omg).
  • Test method JP method 2 (paddle method) Stirring speed 50 rpm
  • Test solution 2nd solution (pH about 6.8) 900mL, water temperature 37 ⁇ 0.5 ° C
  • Test liquid sampling time 5, 15, 30, 45, 60, 90, 120 (min)
  • Test liquid collection volume 2 mL
  • Dissolution test Dissolve the granules corresponding to the indicated amount of this product precisely, and use 90 OmL of the Disintegration Dissolution Test Solution 2 (90 OmL) maintained at 37 ° C as a test solution. No. 2 Perform the test at 50 revolutions per minute according to the method. After the start of the dissolution test, aspirate 2 mL of the eluate with a hole pipe with a cartridge-type cotton stopper over time, and add 8 mL of the test solution to this solution to make a sample solution. After collecting the eluate, replenish the same volume of the test solution into the test vial.
  • Figure 1 shows the relationship between the dissolution rate 60 minutes and 120 minutes after the start of the dissolution test and the amounts and proportions of disintegrants and sugar alcohols.
  • Cefcapene pivoxoxy hydrochloride having different contents of croscarmellose sodium as disintegrant and xylitol as sugar alcohol by the same method as in the above example. A granule containing the same was produced. Table 2 shows the composition.
  • HPC-L Hydroxypropyl cellulose
  • Figure 2 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the mixing ratio of disintegrant and sugar alcohol.
  • HPC-L Hydroxypropylcellulose Dissolution test 60 minutes and 120 minutes after the start of the dissolution test and the dissolution rate of disintegrant and sugar alcohol Figure 3 shows the relationship.
  • the mixing ratio of the disintegrant to the sugar alcohol in Example 7 was 0.33 times, the dissolution increased most, and the dissolution rate at 120 minutes after the start of the dissolution test was 60% or more. there were.
  • Cefcapene pivoxil hydrochloride-containing granules having different contents of low-substituted hydroxypropylcellulose as a disintegrant and maltitol as a sugar alcohol were produced in the same manner as in the above Examples.
  • the composition is shown in Table 4.
  • Cefampipoxyl hydrochloride-containing granules having different contents of low-substituted hydroxypropyl cellulose as a disintegrant and erythritol as a sugar alcohol were produced in the same manner as in the above Examples.
  • Table 5 shows the composition. (Table 5)
  • HPC-L Hydroxypropylcellulose
  • Figure 5 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the blending ratio of disintegrant and sugar alcohol.
  • Cefcapene pipoxyl hydrochloride-containing granules having different contents of low-substituted hydroxypropylcellulose as a disintegrant and trehalose as a sugar alcohol were produced in the same manner as in the above Examples. Table 6 shows the composition.
  • HPC-L Hydroxypropyl cellulose
  • Figure 6 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the mixing ratio of disintegrant and sugar alcohol.
  • Example 19 A sustained release granule comprising the following components was produced. First, elementary granules were prepared according to the method of Example 1, an underlayer was formed, and then an enteric layer was coated.
  • Talc 70.1 Figure 7 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test (pH 6.8) and the mixing ratio of disintegrant (CMC Ca) and sugar alcohol (xylitol). .
  • the mixing ratio of the disintegrant to the sugar alcohol was 0.33 or more
  • the dissolution rate was 80% or more
  • the dissolution rate was 1 to 3 times
  • the dissolution rate was almost 90% or more.
  • pH 1.2 almost no drug dissolution was observed even after 2 days from the start of the test.
  • the present invention provides a formulation having improved solubility of a poorly water-soluble drug. Sustained-release preparations containing this preparation maintain the efficacy of the drug, reduce the number of doses of the drug, and improve patient compliance. Furthermore, the stability over time of the drug incorporated in the preparation of the present invention is high, and long-term storage is possible.

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Abstract

La présente invention concerne une préparation pharmaceutique qui présente une propriété de dissolution améliorée d'un médicament lui-même faiblement soluble dans l'eau, ladite préparation comprenant les constituants suivants: 1) un médicament faiblement soluble dans l'eau, 2) un délitant, et 3) un itol; selon un rapport de combinaison du délitant et de l'itol compris entre 0,2 et 5.
PCT/JP2003/006346 2002-05-22 2003-05-21 Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree WO2003097102A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2004505098A JP4743684B2 (ja) 2002-05-22 2003-05-21 難水溶性薬物の溶出性を改善する方法
AU2003235395A AU2003235395A1 (en) 2002-05-22 2003-05-21 Pharmaceutical preparation improved in dissolving property of drug slightly soluble in water

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JP2002-147113 2002-05-22
JP2002147113 2002-05-22

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WO2006115285A1 (fr) * 2005-04-21 2006-11-02 Takeda Pharmaceutical Company Limited Composition pharmaceutique
WO2006137466A1 (fr) * 2005-06-23 2006-12-28 Kowa Company, Ltd. Composition pharmaceutique
JP2007508351A (ja) * 2003-10-17 2007-04-05 サンド・アクチエンゲゼルシヤフト 抗生物質組成物
WO2007060802A1 (fr) * 2005-11-24 2007-05-31 Ono Pharmaceutical Co., Ltd. Preparation pharmaceutique solide et composition de preparation pharmaceutique
JP2010090168A (ja) * 2007-03-29 2010-04-22 Daiichi Sankyo Co Ltd 医薬組成物
JP2012525323A (ja) * 2009-04-30 2012-10-22 武田薬品工業株式会社 固形製剤
US9402907B2 (en) 2011-08-10 2016-08-02 Daiichi Sankyo Company, Limited Pharmaceutical composition containing diamine derivative
JP2016188188A (ja) * 2015-03-30 2016-11-04 共和薬品工業株式会社 エンタカポン含有医薬組成物
US9918975B2 (en) 2010-03-19 2018-03-20 Daiichi Sankyo Company, Limited Method for improving dissolution of anticoagulant agent

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JP4743684B2 (ja) * 2002-05-22 2011-08-10 塩野義製薬株式会社 難水溶性薬物の溶出性を改善する方法

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EP0629404A1 (fr) * 1993-06-16 1994-12-21 Meiji Seika Kaisha Ltd. Composition pharmaceutique contenant du cefditoren pivoxil
EP0862915A1 (fr) * 1995-10-13 1998-09-09 Meiji Seika Kaisha Ltd. Composition antibacterienne administree par voie orale
JPH09309829A (ja) * 1996-05-22 1997-12-02 Taiyo Yakuhin Kogyo Kk ニトレンジピン含有経口投与製剤およびその製造法
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JP2000273039A (ja) * 1999-01-20 2000-10-03 Taisho Pharmaceut Co Ltd 口腔内崩壊性組成物
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JP2002087965A (ja) * 2000-09-14 2002-03-27 Lion Corp 口中崩壊性アスピリン含有錠剤

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JP2007508351A (ja) * 2003-10-17 2007-04-05 サンド・アクチエンゲゼルシヤフト 抗生物質組成物
WO2006115285A1 (fr) * 2005-04-21 2006-11-02 Takeda Pharmaceutical Company Limited Composition pharmaceutique
WO2006137466A1 (fr) * 2005-06-23 2006-12-28 Kowa Company, Ltd. Composition pharmaceutique
WO2007060802A1 (fr) * 2005-11-24 2007-05-31 Ono Pharmaceutical Co., Ltd. Preparation pharmaceutique solide et composition de preparation pharmaceutique
JPWO2008129846A1 (ja) * 2007-03-29 2010-07-22 第一三共株式会社 医薬組成物
JP4463875B2 (ja) * 2007-03-29 2010-05-19 第一三共株式会社 医薬組成物
JP2010090168A (ja) * 2007-03-29 2010-04-22 Daiichi Sankyo Co Ltd 医薬組成物
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US9707296B2 (en) 2007-03-29 2017-07-18 Daiichi Sankyo Company, Limited Pharmaceutical composition
JP2012525323A (ja) * 2009-04-30 2012-10-22 武田薬品工業株式会社 固形製剤
US9918975B2 (en) 2010-03-19 2018-03-20 Daiichi Sankyo Company, Limited Method for improving dissolution of anticoagulant agent
US9402907B2 (en) 2011-08-10 2016-08-02 Daiichi Sankyo Company, Limited Pharmaceutical composition containing diamine derivative
JP2016188188A (ja) * 2015-03-30 2016-11-04 共和薬品工業株式会社 エンタカポン含有医薬組成物

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JP2010090175A (ja) 2010-04-22
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JPWO2003097102A1 (ja) 2005-09-15
AU2003235395A1 (en) 2003-12-02

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