WO2003072085A1 - Preparations solides contenant un medicament a peine soluble dans l'eau d'une meilleure absorbabilite - Google Patents

Preparations solides contenant un medicament a peine soluble dans l'eau d'une meilleure absorbabilite Download PDF

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Publication number
WO2003072085A1
WO2003072085A1 PCT/JP2003/001965 JP0301965W WO03072085A1 WO 2003072085 A1 WO2003072085 A1 WO 2003072085A1 JP 0301965 W JP0301965 W JP 0301965W WO 03072085 A1 WO03072085 A1 WO 03072085A1
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Prior art keywords
drug
optionally substituted
surfactant
preparation
solid
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PCT/JP2003/001965
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English (en)
Japanese (ja)
Inventor
Takashi Hayashi
Asako Takakura
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Shionogi & Co., Ltd.
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Priority to JP2003570831A priority Critical patent/JP4632288B2/ja
Priority to AU2003211267A priority patent/AU2003211267A1/en
Publication of WO2003072085A1 publication Critical patent/WO2003072085A1/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
    • A61K31/40—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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a solid preparation, specifically, a solid preparation comprising a poorly water-soluble drug, a surfactant and a solid forming agent, and more specifically, a drug is rapidly dissolved from the preparation to maintain a supersaturated dissolved state for a long time.
  • the present invention relates to a solid preparation having improved absorption when orally administered.
  • the present inventors mixed a solution in which a sparingly water-soluble drug was dissolved in a surfactant and a solution in which a solid forming agent as an aqueous gel was dissolved, and dried the solution to make the water solubility of the drug equal to or higher than the solubility. It has been found that a solid preparation in which the so-called supersaturated dissolution state is maintained for a long time can be obtained, and the following invention has been completed.
  • the surfactant is one or more selected from the group consisting of polyethylene glycol, polyoxyethylene sorbin fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, and sucrose fatty acid ester
  • solid-forming agent according to any one of (1) to (6) above, wherein the solid forming agent is one or more selected from the group consisting of gelatin, polysaccharides, celluloses, and polyvinyls.
  • the listed formulation is one or more selected from the group consisting of gelatin, polysaccharides, celluloses, and polyvinyls.
  • the solid forming agent is gelatin, agar, sodium alginate, pectin, pullulan, hexane gum, gum arabic, carrageenan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium.
  • the preparation according to the above (7) which is one or more selected from the group consisting of lium, polyvinyl alcohol and polyvinyl pyrrolidone.
  • the solid forming agent is one or two or more selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose and cellulose acetate phthalate The preparation according to the above (7).
  • R 1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Heteroarylalkyl
  • R 2 is hydrogen, substituted Lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl
  • R 3 is a single bond, substituted Optionally substituted arylene or substituted arylene
  • the compounding ratio of the poorly water-soluble drug to the surfactant is 25 (W / W)% or less, and the poorly water-soluble drug, the surfactant and the solid forming agent are composed of water, alcohol, and acetone.
  • a solid preparation in which the solubility of a drug produced by dissolving in one or more solvents selected from the group and then drying the solution is improved.
  • Figure 1 Dissolution behavior of Compound A in Examples 1, 3 and Comparative Example 1.
  • the vertical axis represents the drug dissolution rate (%), and the horizontal axis represents the time (minutes) after the start of the dissolution test.
  • Figure 2 Dissolution concentration of Compound A in Examples 2 and 4 and Reference Examples 1 and 2.
  • the vertical axis represents the drug dissolution concentration (jug / ml), and the horizontal axis represents the time (minute) after the start of the dissolution test.
  • Figure 3 Dissolution concentration of Compound A in the formulation of Example 5.
  • the vertical axis represents the drug dissolution concentration (g / mL), and the horizontal axis represents the time (minutes) after the start of the dissolution test.
  • Figure 4 Dissolution concentration of compound B in the formulation of Example 6 and the formulation of Comparative Example 2.
  • the vertical axis represents the drug dissolution concentration (g / mL), and the horizontal axis represents the time (minutes) after the start of the dissolution test.
  • Figure 5 Dissolution concentration of phenytoin in the formulation of Example 7 and the formulation of Reference Example 3.
  • the vertical axis represents the drug dissolution concentration (/ g / mL), and the horizontal axis represents the time (minute) after the start of the dissolution test.
  • Figure 6 Dissolution concentration of difludipine in the formulation of Example 8 and the formulation of Reference Example 4.
  • the vertical axis represents the drug dissolution concentration (Ad g / mL), and the horizontal axis represents the time (minute) after the start of the dissolution test.
  • Figure 7 Shows a one-hour blood concentration curve after oral administration of the compound of Example 4 and a drug suspension equivalent to 50 mg of Compound A.
  • the vertical axis represents the drug concentration in blood (g / mL), and the horizontal axis represents the time (hour) after the start of the test.
  • FIG. 8 shows a one-hour blood concentration curve after oral administration of the preparation and the drug suspension of Example 4 in an amount equivalent to 200 mg of compound A.
  • the vertical axis represents the drug concentration in blood (gZmL), and the horizontal axis represents the time (hour) after the start of the test.
  • the poorly water-soluble drug in the present invention is not particularly limited, such as pharmaceuticals, quasi-drugs, veterinary drugs, etc., but preferably, the water solubility of the poorly water-soluble drug at 37 ° C is 100 jUL g / ⁇ L or less. . More preferably, the following formula (I)
  • R 1 is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Heteroarylalkyl
  • R 2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Good heteroarylalkyl
  • R 3 is a single bond, optionally substituted arylene or optionally substituted heteroarylene
  • R 1 ′ is benzyl, (indole-3-yl) methyl, (1-methylindole-3-yl) methyl, (5-methylindole-3-yl) methyl, (5— Fluoroindole-3-yl) methyl, (1-acetylethyl-3-yl) methyl, (1-methylsulfonylindole-3-yl) methyl, (1-alkoxycarbonyl-3-yl) methyl R) methyl (eg, ethoxycarbonylmethyl), or i-propyl; R 3 , R 4 and R 5 are as defined above], an optically active form thereof, or a pharmaceutically acceptable salt thereof, Or solvates thereof.
  • the following formula (III) is benzyl, (indole-3-yl) methyl, (1-methylindole-3-yl) methyl, (5-methylindole-3-yl) methyl, (5— Fluoroindole-3-yl)
  • R 6 is an optionally substituted arylene or an optionally substituted heteroaryl.
  • nitrophenylpyridine carboxylic acid drugs or hydantoin drugs include nitrophenylpyridine carboxylic acid drugs or hydantoin drugs.
  • nitrophenylpyridine carboxylic acid-based drug include diphdinapine and the like
  • specific examples of the hydantoin-based drug include phenytoin.
  • Difludipine is used as a calcium antagonist
  • phenytoin is used as an antiepileptic drug.
  • drugs that can be used in this formulation include antipyretic analgesics, such as phenacetin, indomethacin, and flurbiprofen; inotropics such as digitoxin; antiepileptic drugs such as diazepam and pheno Antibiotics such as barbital, for example, chloramphenicol, 7/5 — [(Z) —2- (2-amino-4-thiazolyl) -12-hydroxyhydroxyminoacetamide] 13— (1,2,3- Triazole-4-ylthiomethylthio) 1-l-carper 3-sefume 4 rubonic acid, (+)-(6R, 7R) -7-[(Z) —2- (2-amino-4-thiazolyl )-2-pentenamide]-3-Carpamoyloxymethyl-8-year old 5-thia 1-1-azabicyclo [4.
  • antipyretic analgesics such as phenacetin, indomethacin, and flurbiprof
  • Anti-fungal agents such as fluconazole, clotrimazole, isoconazole nitrate, econazole nitrate, miconazole nitrate, bifonazole, griseofulvin, etc.
  • Synthetic antibacterial agents such as ofloxacin, hydrochloric acid Cyproxasin, tosfloxacin tosylate, nofloxacin, lomefloxacin hydrochloride, pazufloxacin, etc.
  • Shiros Evening Zoe Al blockers such as prazosin hydrochloride, terazosin hydrochloride, and brazosin hydrochloride; carbonic anhydrase inhibitors; e.g., acetazolamide and methazolamide; adrenal cortical steroids; e.g., difluprednate, butesonide Diflucortron valerate, hydrocortisone butyrate propionate, clobezone butyrate, fluorometholone and the like, and pharmaceutically acceptable salts of these drugs.
  • carbonic anhydrase inhibitors e.g., acetazolamide and methazolamide
  • adrenal cortical steroids e.g., difluprednate, butesonide Diflucortron valerate, hydrocortisone butyrate propionate, clobezone butyrate, fluorometholone and the like, and pharmaceutically acceptable salts of these drugs.
  • the compounding ratio of the drug may be any compounding ratio in which the drug can be dissolved in the surfactant in order to increase the solubility of the drug, and preferably, the compounding ratio of the drug to the surfactant is 25 (W / W W)% or less, more preferably 1 to 25 (W / W)%, and still more preferably 3 to 25 (W / W)%. In this case, the drug can be completely dissolved in the surfactant, and the solubility of the drug can be increased.
  • the compounding ratio of the drug to the total amount of the preparation is 0.5 (W / W)% or more, preferably 0.5 (W / W)% to 30 (W / W)%, more preferably 0.75 (W / W)%. (W / W) -27.5 (W / W)%, more preferably 1 (W / W)% to 25 (W / W)%.
  • the surfactant used in the present invention may be any semi-solid or liquid surfactant that dissolves a poorly water-soluble drug and is physiologically acceptable.
  • Pharmaceutical Excipient Standard 1998 hereinafter referred to as “ Semi-solid or liquid surfactants listed in the Pharmaceutical Additive Regulations) and the 7th Edition of the Official Addendum of Food Additives (hereinafter sometimes abbreviated as “food additives”) can be used.
  • food additives can be used.
  • the HLB (hydrophilic hydrophobic ratio) of the surfactant is preferably 8 or more, more preferably 8 to 20, more preferably 12 to 20, and particularly preferably 14 to 20, for example, polyethylene.
  • polyethylene glycol Macrogol 200 (PE G200), Macrogol 300 (PEG300), Macrogol 400 (PEG400), McGoal 600 ( PEG 600) can be used.
  • Polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monoester. Palmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80) and the like can be used.
  • glycerin fatty acid esters examples include decaglycerin stearate monoester, decaglycerin stearate triester, hexaglycerin stearate monoester, hexaglycerin stearate sesquiester, tetraglycerin stearate monoester, and hexaglycerine stearic acid.
  • Triester Hexaglycerin monostearate, Decaglycerinoleic acid monoester, Hexaglycerinoleic acid monoester, Tetraglycerinoleic acid monoester, Decaglycerin caprylic acid monoester, Decaglycerin lauric acid monoester, Hexaglycerin Monolaurate, Monoester tetraglycerin Laurate, Condensed ricinoleate Tetraglycerin Kisaguriseri down condensed ricinoleic acid ester, polyglycerol condensed ricinoleic acid ester, etc. can be used to.
  • Polyoxyethylene hardened castor oil includes polyoxyethylene hardened castor oil 5, polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened Castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 100 E.0., Etc. can be used.
  • the mixing ratio thereof is preferably 1: 1 to 1:10, more preferably 1: 2 to 1: 8, and further preferably 1: 3 to 1: 7.
  • the mixing ratio of the surfactant of the present invention varies depending on the content of the main drug in the preparation, but is not less than 20 (W / W)% based on the total amount of the preparation, preferably 20 (W / W) based on the total preparation. W)% to 70 (W / W)%, more preferably 20 (W / W)% to 65 (W / W)%, still more preferably 30 (W / W)% to 62.5 (W / W)%. Above the upper limit of this range, the drug product cannot be prepared, and below the lower limit, the solubility of the drug does not improve.
  • the solid forming agent used in the present invention is physiologically acceptable and may be any compound that dissolves in water and forms a gel in water.
  • the solid forming agent include gelatin, polysaccharides, celluloses, and polyvinyls. preferable. Specifically, gelatin, agar, sodium alginate, pectin, pullulan, xanthan gum, gum arabic, carrageenan, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyvinyl alcohol And polyvinylpyrrolidone, more preferably gelatin, agar, pectin and gum arabic. One or more of these may be used in combination.
  • Examples thereof include gelatin and agar, agar and pectin, agar and acacia, but are not limited to combinations thereof.
  • agar and gelatin are used, and the mixing ratio thereof is preferably 1: ;! To 1:20, more preferably 1: 5 to 1:15, even more preferably 1: 7.5 to 1: 12.5.
  • an enteric formulation that does not dissolve in the stomach but dissolves in the intestine can be prepared.
  • the solid forming agent in this case include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate, and more preferably hydroxypropylmethylcellulose.
  • Methyl cell mouth is acetate succinate.
  • the mixing ratio of the solid forming agent of the present invention varies depending on the content of the active ingredient in the preparation and the like, but is at least 20 (W / W)%, preferably 20 (W / W)% to 7 to the total amount of the preparation. 0 (W / W)%, more preferably 22.5 (W / W)% to 62.5 (W / W)%, still more preferably 25 (W / W)-60 (W / W )%.
  • the preparation of the present invention may contain a physiologically acceptable excipient depending on the poorly water-soluble drug, surfactant and solid forming agent.
  • a physiologically acceptable excipient depending on the poorly water-soluble drug, surfactant and solid forming agent.
  • sucrose, lactose, silica (silicon dioxide), synthetic aluminum silicate and crystalline cellulose can be used. And preferably sucrose.
  • the mixing ratio of the above-mentioned excipient of the present invention varies depending on the content of the active ingredient in the preparation and the like, but is preferably 0.5 (W / W)% to 5 (W / W)% based on the total amount of the preparation. It is preferably 0.75 (W / W) to 4.5 (W / W)%, more preferably 1 (W / W)% to 4 (W / W)%.
  • the compounding ratio of the drug to the surfactant is preferably 25 (W / W)% or less, and the compounding ratio of each component to the total amount of the preparation is 0.5 (W / W) for the poorly water-soluble drug.
  • surfactant is 20 (W / W)% to 70 (W / W)%
  • solid forming agent is 20 (W / W)% to 70 (W / W) W)%
  • the compounding ratio of the drug to the surfactant is 1 to 25 (W / W)%, and the compounding ratio of each component to the total amount of the preparation is 0.75 (W / W) for the poorly water-soluble drug. ⁇ 27.5 (W / W)%, surfactant 20 (W / W)% ⁇ 65 (W / W)%, solid forming agent 22.5 (W / W)% -62.5 (W / W)%, and 0.75 (W / W)% to 4.5 (W / W)% if an excipient is added.
  • the compounding ratio of the drug to the surfactant is 3 (W / W)% to 25 (W / W)%, and the compounding ratio of each component to the total amount of the preparation is 1 (W / W) of the poorly water-soluble drug.
  • surfactant is 30 (W / W)% -62.5 (W / W)%
  • solid forming agent is 25 (W / W)% to 6 0 (W / W)%
  • a poorly water-soluble drug, a surfactant, and a solid-forming agent are one or more solvents selected from the group consisting of water, alcohol, and acetone. Then, the aqueous solution, alcohol solution or acetone solution may be dried to produce the compound. For example, first, 1) dissolve a poorly water-soluble drug in a surfactant (after melting in the case of a semi-solid or solid surfactant). On the other hand, 2) the solid former is dissolved in one or more solvents selected from the group consisting of water, alcohol or acetone. The solutions of 1) and 2) may be mixed and dried to prepare a solid preparation.
  • the drying method may be a method known to those skilled in the art. For example, there is a method of drying all over the desiccator, drying in a tray dryer, or drying by a spray dryer.
  • the form of the preparation is not particularly limited, but is preferably granules, powders and fine granules, and more preferably granules.
  • the preparation of the present invention is solidified, it can be easily taken as it is, and it is convenient to carry. It is also possible to prepare granules, powders and fine granules, then blend them into tablets, granules, capsules and the like and form them. At this time, the tablets and granules may contain pharmaceutically acceptable additives such as excipients, binders and lubricants. In the case of a capsule, it can be filled into a hard capsule and a soft capsule. After forming these tablets, granules or capsules, gastric-soluble film base, hydrophobic film base, and enteric film base are coated on these preparations to produce gastric-, sustained-release, and enteric-coated preparations. You can also.
  • the drug in the preparation dissolves promptly and maintains a so-called supersaturated dissolution state in which the drug dissolves over a long period of time in excess of the solubility of the drug.
  • the paddle method according to the 14th revised Japanese Pharmacopoeia should be less than the solubility of the drug by 10 minutes after the start of the dissolution test.
  • the drug dissolves highly, and after 60 minutes, dissolves the drug 1.5 times or more, more preferably 3 times or more, more preferably 4 times or more the solubility of the drug.
  • the supersaturated dissolution state is maintained for preferably 60 minutes or more, more preferably 90 minutes or more, and even more preferably 120 minutes or more.
  • the drug does not dissolve in a dissolution test solution at a pH of less than 37 ° C and a supersaturated dissolution for a long time in a dissolution test solution at a pH of 37 or more. Maintain state.
  • the paddle method described above after the preparation is poured into a dissolution test solution having a pH of 5 or more, the drug dissolves higher than the solubility of the drug by 10 minutes, and the solubility of the drug is 60 minutes after 60 minutes.
  • the maximum blood concentration (C max) of the present formulation when orally administered to an animal differs depending on the dose and the drug, but it is preferably that when the drug suspension is administered. It is at least 1.2 times, more preferably at least 2 times, even more preferably at least 2.5 times.
  • the area under the blood concentration curve (AUC) also varies depending on the dose and the drug, but is preferably at least 1.2 times, more preferably at least 2.5 times, more preferably at the time of administration of the drug suspension. Is more than 3.5 times.
  • This formulation is basically composed of a drug, a surfactant and a solid forming agent, but a drug and a surfactant or a drug and a solid forming agent may form a complex.
  • the cause of the increase in water solubility of the drug included in this drug product is estimated as follows. That is, when the drug substance is dissolved in a surfactant and dried with a solid former, the drug substance is present in the drug substance in the surfactant dispersed in molecular units. When this is added to water, it is thought that micelles containing the drug substance in high concentration are rapidly formed in the water and dissolved in the water.
  • Example 1 The production method of the preparation is shown below. Other Examples, Comparative Examples and Reference Examples were manufactured in the same manner.
  • the preparation of the reference example was a solution in which the drug was dissolved in the indicated surfactant.
  • the raw materials used for the preparation are listed.
  • the drug is compound A (N ⁇ - [2- [5-[[4-Methylphenyl] ethynyl] ceryl]] sulfonyl] -D-triptophan) was used after pulverization.
  • Polyethylene glycol is Macrogol 400 (PEG 400)
  • polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80)
  • sucrose, gelatin, and agar are pharmaceutical products.
  • the compound A10Omg is dissolved in a solution obtained by mixing PGE4001400mg and Tween8506mg heated to about 60 ° C. This solution is referred to as “surfactant solution”. On the other hand, 80 mg of gelatin and 80 mg of agar are added to 12 mL of distilled water and kept at around 100 ° C. This solution is referred to as “solid forming agent solution”.
  • the dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition.
  • the amount of the drug in the formulation injected into the test solution was 90 mg.
  • Test method Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm
  • Test solution 90 OmL of distilled water, water temperature 37 ⁇ 0.5 ° C, Sample volume of test solution: 2 mL
  • Test liquid sampling time 10, 20, 30, 60, 90, 120, 180 minutes after the start of test
  • Drug concentration measurement method The collected liquid was filtered through a 0.45 / zm filter, and the filtrate was diluted with acetonitrile.
  • the elution rate was calculated by substituting each value into the following equation.
  • a Ti , A Ti-1 Peak area of the sample sampled at the i-th and i-th first 1/100: dilution factor, S: drug amount in drug (mg)
  • FIG. 1 shows the measurement results of the dissolution rates of Examples 1, 3 and Comparative Example 1.
  • Examples 1 and 3 the drug eluted more rapidly than after the start of the test, and reached a dissolution rate of 100% 90 minutes after the start of the test.
  • Comparative Example 1 only about 60% of the drug was eluted even after 180 minutes.
  • the ratio of the drug to the surfactant was 14 and 20 (W / W)%, respectively, and the drug was completely dissolved in the surfactant at the time of preparation. Had dissolved.
  • the compounding ratio of the drug to the surfactant was 33 (W / W)%, and the drug was not completely dissolved in the surfactant at the time of preparation.
  • FIG. 2 shows the measurement results of the drug dissolution concentration in Examples 2 and 4 and Reference Examples 1 and 2.
  • the drug dissolution concentration became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and thereafter, the concentration was significantly higher than the solubility for more than 120 minutes, that is, the so-called supersaturated solution was maintained.
  • the dissolution behavior was almost the same as the preparations of Reference Examples 1 and 2. Stability test methods and results
  • Example 4 A sample compound stored in a sealed container at 40 ° C for 1 month A 10 mg equivalent of Example 4 was placed in acetonitrile to extract the drug, and the drug concentration in the extract was determined by HPLC. It was measured. As a result, the drug residual ratio was 99.8%, and the drug in the preparation was stable.
  • Solid formulations were prepared according to the formulation shown in Table 2. The production method is shown below.
  • the raw materials used for the preparation are listed.
  • the drug is obtained by pulverizing compound A (N "-[2- [5-[[4-methylphenyl] ethynyl] chenyl]] sulfonyl] -D-tritophan) described in WO 97/27 174.
  • Polyethylene glycol was Macrogol 400 (PEG 400)
  • polyoxyethylene sorbitan fatty acid ester was polyoxyethylene sorbitan monooleate (Tween 80)
  • HPMCAS—LF hydroxypropyl methyl cellulose acetate succinate
  • Compound A10 Omg is dissolved in a solution obtained by mixing PEG4001100 mg and Tween8000400 mg heated to about 60 ° C. This solution is referred to as “surfactant solution”. On the other hand, add 200 mg of HPMCAS-LF120 to 4.5 mL of acetone and dissolve. This solution is referred to as “solid forming agent solution”.
  • the surfactant solution and the solid forming agent solution are mixed, placed in a desiccator, and stored under reduced pressure under vacuum.
  • the obtained solid was pulverized with a tablet pulverizer and sieved, and a 24 mesh live product was used as a sample.
  • HPMCAS-LF Hydroxypropyl methylcellulose acetate succinate
  • the dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. First, the preparation was put into the first liquid, and after 120 minutes, the preparation in the test liquid was taken out. The formulation was put into the second liquid, and the dissolution test was performed. In the test solution, a preparation equivalent to 125 mg of the drug was added.
  • Test method Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm
  • Test solution 1st solution (pH 1.2) 900 mL, water temperature 37 ⁇ 0.5 ° C
  • Second solution (pH 6.7) 900 mL, water temperature 37 ⁇ 0.5 ° C
  • Test liquid sampling time 120 minutes after the start of the test 120, 125, 130, 135, 150, 165, 180, 240 minutes
  • Test liquid collection volume 2 mL
  • Drug concentration measurement method The collected liquid was filtered with a 0.45 m pore size filter, and the filtrate was diluted with acetonitrile.
  • Figure 3 shows the measurement results of drug dissolution concentration.
  • the drug did not elute in the first solution until 120 minutes after the start of the dissolution test, and when it was subsequently poured into the second solution, the drug dissolution concentration was increased by 5 minutes after the start of the dissolution test. And maintained concentrations above solubility for over 90 minutes thereafter.
  • the raw materials used for the preparation are listed.
  • the drug is the compound B ((2R) -2-[[4- [3- (4-fluorophenyl) -1,2,4-oxaziazol-5-yl] benzenesulfonyl] described in WO 01/83464] Amino] -3-phenylpropionic acid) was used after pulverization.
  • Polyethylene glycol was Macrogol 400 (PEG 400)
  • polyoxetylene sorbitan fatty acid ester was polyoxyethylene sorbitan monooleate (Tween 80)
  • sucrose, gelatin and agar were compliant with the pharmaceutical specifications. .
  • This solution is referred to as “surfactant solution”.
  • 800 mg of gelatin and 80 mg of agar are added to 12 mL of distilled water and kept at around 100 ° C.
  • This solution is referred to as “solid forming agent solution”.
  • Mix the surfactant solution and the solid former solution leave the solution at room temperature, put it in a desiccator overnight, and store it under vacuum and vacuum overnight.
  • the obtained solid was pulverized with a tablet pulverizer and sieved to obtain a sample of 24 mesh.
  • the dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. The test Into the solution was added a preparation equivalent to 60 mg of the drug / product.
  • Test method Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm
  • Test solution 900 mL of distilled water, water temperature 37 ⁇ 0.5 ° C
  • Test liquid collection time 10, 20, 30, 60, 90, 120, 180 minutes after the start of test
  • Test liquid collection volume 1 mL
  • Drug concentration measurement method The collected liquid was filtered with a 0.45 pore size filter, and the filtrate was diluted with acetonitrile.
  • FIG. 4 shows the measurement results of the drug dissolution concentration.
  • the drug dissolution concentration of Comparative Example 2 became lower than the solubility 60 minutes after the start of the test.
  • the drug dissolution concentration in Example 6 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter.
  • Example 7 According to the formulation shown in Table 4, the solid preparation of Example 7 and the solution of Reference Example 3 were produced. The method for producing the solid preparation is shown below.
  • Polyethylene glycol is Macrogol 400 (PEG 400)
  • polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80)
  • phenytoin and hydroxypropyl methylcellulose TC-15EW (HPMC) are the Japanese Pharmacopoeia.
  • One of the conforming products was used.
  • the dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. A preparation equivalent to 60 mg of drug was injected into the test solution.
  • Test method Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm
  • Test solution 900 mL of distilled water, water temperature 37 ⁇ 0.5 ° C
  • Test liquid collection time 10, 20, 30, 60, 90, 120, 180 minutes after the start of test
  • Test liquid collection volume 1 mL
  • Dissolution test results Fig. 5 shows the measurement results of the drug dissolution concentration.
  • the drug dissolution concentration in Example 7 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter.
  • the elution behavior of Example 7 was almost the same as that of Reference Example 3.
  • Example 8 According to the formulation shown in Table 5, the solid preparation of Example 8 and the solution of Reference Example 4 were produced. The method for preparing the solid preparation is shown below.
  • Polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80), diphedipine and hydroxypropyl methylcellulose TC-15EW (HPMC) are Japanese Pharmacopoeia compliant products. Using.
  • the surfactant solution and the solid former solution are mixed, and the solution is allowed to stand at room temperature, put in a desiccator overnight, and store under reduced pressure under vacuum overnight.
  • the obtained solid was pulverized with a tablet pulverizer and sieved to obtain a sample of 24 meshes.
  • HPMC Hydroxypropyl methylcellulose T C—5 EW
  • the dissolution test was performed according to the method specified in the 14th revised Japanese Pharmacopoeia.
  • the test In the solution, a preparation equivalent to 100 mg of the drug was introduced.
  • Test method Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm
  • Test solution 900 mL of distilled water, water temperature 37 ⁇ 0.5 ° C
  • Test liquid sampling time 10, 20, 30, 60, 90, 120, 180 minutes after the start of test
  • Test liquid collection volume 1 mL
  • Drug concentration measurement method The collected liquid was filtered through a 0.45 / m pore size filter, and the filtrate was diluted with methanol. The drug concentration in the diluted solution was determined by the HPLC method [wavelength: 2
  • FIG. 6 shows the measurement results of the drug dissolution concentration.
  • the drug dissolution concentration in Example 8 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter.
  • the elution behavior of Example 8 was almost the same as that of Reference Example 4.
  • Example 4 The obtained solid preparation of Example 4 was subjected to an absorption test.
  • the absorption test was performed as follows.
  • Example 4 The solid preparation of Example 4 was coarsely pulverized with a tablet pulverizer, and an empty gelatin capsule was filled with the preparation having a main drug amount of 5 O mg and an amount equivalent to 200 mg.
  • the capsule was orally administered to three male Beagle dogs fasted for 24 hours before administration, and then loaded with 50 mL of distilled water via a catheter.
  • As a control the same 0.1% HPC-SL suspension prepared so that the active drug content in 1 OmL was 5 Omg and 200 mg was administered to the same three beagle dogs as described above before administration. After a 4-hour fast, 10 mL of the suspension sample was injected into the stomach of the dog using a gastric catheter, and then the syringe and the catheter were washed.
  • HPLC conditions were as follows: Pre-column: Cosmosil 5 ph (150 mm x 4.
  • Figures 7 and 8 show the one-hour blood concentration curves when 50 mg and 200 mg of the drug were administered to the Example 4 preparation and the drug suspension, respectively.
  • Table 6 shows Cmax and AUC Indicates a value.
  • the blood concentration of the preparation of Example 4 was significantly increased as compared to the drug suspension, and the C max was about 2.8 times higher than that of the suspension at the time of administration of 200 mg, and the AU C was about 3.7 times.

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Abstract

L'objectif de cette invention est d'améliorer les propriétés de dissolution d'un médicament à peine soluble dans l'eau et de produire, ainsi, des préparations solides présentant une meilleure absorbabilité lorsqu'elles sont administrées par voie orale. Ces préparations solides, qui contiennent un médicament à peine soluble dans l'eau, un tensioactif et un excipient solide, sont caractérisées en ce que le rapport de composition médicament à peine soluble dans l'eau/tensioactif est inférieur ou égal à 25 % (poids/poids).
PCT/JP2003/001965 2002-02-27 2003-02-24 Preparations solides contenant un medicament a peine soluble dans l'eau d'une meilleure absorbabilite WO2003072085A1 (fr)

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JP2003570831A JP4632288B2 (ja) 2002-02-27 2003-02-24 難水溶性薬物の吸収性を改善した固形状製剤
AU2003211267A AU2003211267A1 (en) 2002-02-27 2003-02-24 Solid preparations with improved absorbability of hardly water-soluble drug

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012150675A1 (fr) * 2011-05-02 2012-11-08 ライオン株式会社 Composition contenant du panaxadiol

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JPH0543461A (ja) * 1991-12-27 1993-02-23 Wakamoto Pharmaceut Co Ltd ５−（３−ｎ−ブチルオキサリルアミノフエニル）テトラゾール含有医薬品組成物の製造法
WO1994023700A1 (fr) * 1993-04-22 1994-10-27 Rijksuniversiteit Gent Laboratorium Voor Farmaceutische Technologie Preparation solide a liberation rapide, sa production et son utilisation
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
WO1999000112A1 (fr) * 1997-06-30 1999-01-07 Chugai Seiyaku Kabushiki Kaisha Composition contenant du sucralfate et procede de production
WO2001083464A1 (fr) * 2000-04-21 2001-11-08 Shionogi & Co., Ltd. Derives d'oxadiazole efficaces en matiere de traitement ou de prevention d'etats pathologiques glomerulaire
JP2003073261A (ja) * 2001-09-05 2003-03-12 Shin Etsu Chem Co Ltd 難溶性薬物を含む医薬用固形製剤の製造方法

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JPS4914618A (fr) * 1972-06-02 1974-02-08
JPS649932A (en) * 1987-07-01 1989-01-13 Toyo Capsel Kk Soft capsule preparation using newly combined component as the base
KR100355130B1 (ko) * 1992-09-18 2003-01-30 야마노우치세이야쿠 가부시키가이샤 하이드로겔서방성정제
JPH07291854A (ja) * 1994-04-26 1995-11-07 Tanabe Seiyaku Co Ltd 溶解性の改善された医薬品製剤
JPH08291063A (ja) * 1995-04-21 1996-11-05 Maruho Kk 易吸収性製剤及びその製造法
CZ20021083A3 (cs) * 1999-09-27 2002-06-12 American Cyanamid Company Farmaceutický prostředek
KR20010107754A (ko) * 2000-05-26 2001-12-07 민경윤 경구투여용 속용정의 제조 방법

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Publication number Priority date Publication date Assignee Title
JPH0543461A (ja) * 1991-12-27 1993-02-23 Wakamoto Pharmaceut Co Ltd ５−（３−ｎ−ブチルオキサリルアミノフエニル）テトラゾール含有医薬品組成物の製造法
WO1994023700A1 (fr) * 1993-04-22 1994-10-27 Rijksuniversiteit Gent Laboratorium Voor Farmaceutische Technologie Preparation solide a liberation rapide, sa production et son utilisation
WO1997027174A1 (fr) * 1996-01-23 1997-07-31 Shionogi & Co., Ltd. Derives d'acides amines sulfones et inhibiteurs de metalloproteinases contenant ces derives
WO1999000112A1 (fr) * 1997-06-30 1999-01-07 Chugai Seiyaku Kabushiki Kaisha Composition contenant du sucralfate et procede de production
WO2001083464A1 (fr) * 2000-04-21 2001-11-08 Shionogi & Co., Ltd. Derives d'oxadiazole efficaces en matiere de traitement ou de prevention d'etats pathologiques glomerulaire
JP2003073261A (ja) * 2001-09-05 2003-03-12 Shin Etsu Chem Co Ltd 難溶性薬物を含む医薬用固形製剤の製造方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012150675A1 (fr) * 2011-05-02 2012-11-08 ライオン株式会社 Composition contenant du panaxadiol
US9510613B2 (en) 2011-05-02 2016-12-06 Lion Corporation Panaxadiol-containing composition

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