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WO2001060353A1 - Preparation liquide a absorbabilite amelioree - Google Patents

Preparation liquide a absorbabilite amelioree Download PDF

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Publication number
WO2001060353A1
WO2001060353A1 PCT/JP2001/001187 JP0101187W WO0160353A1 WO 2001060353 A1 WO2001060353 A1 WO 2001060353A1 JP 0101187 W JP0101187 W JP 0101187W WO 0160353 A1 WO0160353 A1 WO 0160353A1
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Prior art keywords
group
substituted
hydroxy
alkyl
lower alkyl
Prior art date
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Ceased
Application number
PCT/JP2001/001187
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English (en)
Japanese (ja)
Inventor
Takeo Hirose
Yoshiko Kinoshita
Fumio Shimojo
Atsuo Oike
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
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Priority to AU2001232344A priority Critical patent/AU2001232344A1/en
Publication of WO2001060353A1 publication Critical patent/WO2001060353A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 solution having improved absorbency, comprising a compound represented by the following formula (I) or a salt thereof, a solvent capable of dissolving the compound or a salt thereof, and a water-soluble polymer. It is used in the medical field. Background art
  • compound (I) Compounds represented by the following formula (I) (hereinafter, referred to as “compound (I)”) are described in International Patent Application Publication No. WO99 / 54284 and tWO 01/057. No. 70, which can be produced by the method described in the publication, and is known to be useful as a cGMP-phosphodiesterase inhibitor.
  • compound (I) has low solubility in water, it is hardly absorbed when administered orally in a crystalline state or a fine powder state, and improvement of its absorbability has been desired.
  • Japanese Patent Application Laid-Open No. 9-501150 discloses a capsule containing a sparingly soluble compound or a salt thereof, a capsule content liquid, and a diamine or a surfactant and / or a cellulose derivative. According to this formulation, it is known that when the poorly soluble compound elutes from the capsule, the growth of crystals is suppressed to form fine crystals, and as a result, high bioavailability can be obtained by oral administration. Disclosure of the invention
  • the inventors of the present invention dissolve the compound (I) or a salt thereof (hereinafter, these are collectively referred to as “main drug”) in a solvent capable of dissolving the main drug, and add a water-soluble polymer thereto. Surprisingly, it was found that the solubility of the active substance in water was improved, and the absorption of the active substance was significantly improved as a result of maintaining the state in which crystals did not precipitate even if the active solubility of the active substance itself exceeded the saturation solubility in water. Heading, completed this invention. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing the change over time in the solubility of the liquid preparation (liquid preparation 1) obtained in Example 1 of the present invention and the liquid preparation (liquid preparation A) obtained in Comparative Example 1 in water.
  • R 1 is a hydrogen atom or a halogen atom
  • R 2 is an electron withdrawing group
  • R 3 has the formula: CONH—A—R 13 [where
  • A is a lower alkylene group
  • R 13 is a hydrogen atom; a hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl].
  • R 4 has the formula: one NH—R 14 [where,
  • R 14 is a lower alkoxy group; a substituted or unsubstituted heterocyclic group, saturated or unsaturated, lower alkyl or halo (lower) alkyl substitution which may be an amino group; the formula: A CH 2 - R 15 wherein R 15 is a cycloalkyl group or an unsaturated heterocyclic group; or a group represented by the formula: CR 16 R 17 R 18 wherein R 16 and R 17 are each Independently, a carpoxy group, a protected carboxy group, a labamoyl group optionally substituted with lower alkyl, or a halogen, hydroxy, cyano, azide, lower alkoxy, lower alkylthio, protected alkyl group Poxy, lower alkane sulfonyl, asiloxy, lower alkane sulfonyloxy, aryl, aryloxy (optionally substituted with cyano), unsaturated heterocyclic group (optionally substituted with lower alkyl) gu
  • R 16 and R 17 together with the carbon atom to which they are attached, are-a substituted or unsubstituted saturated carbocyclic group or an unsaturated carbocyclic group which may be substituted by hydroxy And R 18 is a hydrogen atom; a lower alkoxy group; or a hydroxy or lower alkoxy group! /, Which is a lower alkyl group).
  • R 18 is a hydrogen atom; a lower alkoxy group; or a hydroxy or lower alkoxy group! /, Which is a lower alkyl group).
  • R 1 is a hydrogen atom
  • R 2 is a halogen atom; a cyano group; a nitro group; a carpamoyl group; a lower alkyl group optionally substituted by a heterocyclic group; a rubamoyl group; a carboxy group; a protected carboxy group; a lower alkyl group; An alkyl group; a lower alkoxy group; an acyl group; or a lower alkanesulfonyl group;
  • R 2 3 is a lower alkyl group, a consequent opening alkyl or heterocyclic group, among these lower alkyl groups are hydroxy, protected human Dorokishi, Ashiru, lower alkoxy-substituted Ararukiruokishi, Amino, lower alkyl Ruamino, Ashiruamino , Lower alkoxycarbonylamino, lower alkane sulfonylamino, ureido, lower alkyl ureido, sulfamoylamino, protected carboxy, carboxy, lower alkane sulfonyl, lower alkylenedioxy, carbamoyl, lower alkyl carbamoyl and Cycloalkyl and heterocyclic groups may have from 1 to 3 substituents selected from the group consisting of sulfamoyl; hydroxy, protected hydroxy, acyl, lower alkoxy-substituted aralkyloxy, amino, Acylamin
  • R 2 4, R 2 5 and R 2 6 are the same or different, a hydrogen atom, a halogen atom, a lower Arukanoiru group, a carboxy group, a protected carboxy group, the force Rubamoiru group, a nitro group, Shiano group, a lower alkyl group A hydroxy-substituted lower alkyl group, a lower alkoxy group or a lower alkoxy-substituted aralkyl group; or any two of R 24, R 25 and R 26 together form a lower alkylenedioxy group.
  • Y may be an oxygen atom or a sulfur atom,
  • n is an integer of 1 or 2] means a group represented by
  • a liquid preparation having improved absorbability comprising: a compound represented by the formula: or a salt thereof; a nontoxic solvent capable of dissolving the compound or a salt thereof; and an ice polymer.
  • the compound (I) contained in the liquid preparation of the present invention has the following formula (la)
  • R 11 and R 12 have the same meanings as R 1 and R 2 in Definition 1 above, respectively.
  • R 13 and R 14 all have the same meaning as in definition 1 above.
  • X is CH or a nitrogen atom
  • R 21 and R 22 have the same meanings as R 1 and R 2 in Definition 2 above, respectively.
  • anthranilic acid derivatives (la) are those wherein in formula (Ia), R 11 is a hydrogen atom, R 12 is a nitro, cyano or halo (lower) alkyl group, and R 13 is Lower alkoxy is a phenyl group substituted with Z or halogen, wherein R 14 is a group represented by the formula: CR 16 R 17 R 18 wherein R 16 and R 17 are each independently substituted with hydroxy Or a lower alkyl group, R 16 and R 17 , together with the carbon atom to which they are attached, is a saturated carbocyclic group substituted with an acylamino group, and R 18 Is a hydrogen atom] and A is a lower alkylene group.
  • benzimidazole derivatives (I b-1) and imidapyridine derivatives (I b -2) preferred are those represented by the formula (I b), wherein X is a nitrogen atom, Y is an oxygen atom, and R 21 Is a hydrogen atom, R 22 is a cyano group, R 23 is a cyclohexyl group substituted with hydroxy or lower alkanoyloxy, R 24 is a hydrogen atom, R 25 is a halogen atom.
  • R 26 are compounds having a lower alkoxy group.
  • the anthranilic acid derivative ( Ia ;), the benzimidazole derivative (Ib-1) and the imidaviridine derivative (lb-2) may be in the form of a salt, wherein the salt is a pharmaceutically acceptable salt
  • the salt is a pharmaceutically acceptable salt
  • alkali metal salts sodium salt, potassium salt, etc.
  • alkaline earth metal salts calcium salt, magnesium salt, etc.
  • ammonium salts organic bases (trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine) , Dibenzylethylenediamine, etc.)
  • organic acids acetic acid, benzoic acid, succinic acid, fumaric acid, maleic acid, lactic acid, cunic acid, tartaric acid, dalconic acid, methanesulfonic acid, benzenesulfonic acid, formic acid, Salts with p-toluenesulfonic acid, trifluoroacetic acid,
  • Anthranilic acid derivatives ( Ia ), benzimidazole derivatives (Ib-1) and imidaviridine derivatives (Ib-2) and their salts are hydrated, It may be in the form of a solvate such as a nolate.
  • the solvent used in the present invention may be any as long as it dissolves the active ingredient and is pharmaceutically acceptable.
  • polyethylene glycol having an average molecular weight of less than 4,000 for example, polyethylene glycol 400
  • Polyhydric alcohols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and polyglycerin, fatty acid glycerin esters, fatty acid propylene glycol esters, sesame oil, soybean oil, corn oil, olive oil and the like.
  • polyhydric alcohols are more preferred, even more preferred are polyethylene glycol and propylene glycol having an average molecular weight of less than 4,000, most preferred are polyethylene glycol 400. . '
  • the above solvents can be used alone or in combination of two or more.
  • the water-soluble polymer used in the present invention may be any pharmaceutically acceptable one.
  • cellulose derivatives such as hydroxypropinoresenolylose, hydroxypropylmethinoresenolose, methylcellulose and carboxymethylcellulose;
  • Polybutylpyrrolidone polyethylene glycol having an average molecular weight of 4,000 or more (for example, polyethylenedaricol 600,000) and the like can be mentioned.
  • water-soluble polymers more preferred are hydroxypropylcellulose, hydroxypropylmethylcellulose, and polypyrrolidone.
  • Polyethylene glycol having an average molecular weight of 4,000 or more is more preferable.
  • the above water-soluble polymers can be used alone or in combination of two or more.
  • the liquid preparation of the present invention may appropriately contain a pharmaceutically acceptable natural or synthetic surfactant in addition to the water-soluble polymer.
  • natural surfactants include various substances derived from animals or plants, and synthetic surfactants. Examples include cationic, anionic or nonionic surfactants.
  • Examples of such synthetic surfactants include polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glyceryl mono fatty acid ester, polyoxyethylene propylene glycol mono fatty acid ester, polyoxyethylene sorbitol fatty acid ester, Natural fats and oils and polyoxyethylene derivatives of polyethylene, polyethylene daricol fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene-polyoxypropylene copolymer and block copolymer type surfactant surfactant, alkyl Examples include sulfates, phospholipids, bile salts, fatty acids, monohydric alcohol fatty acid esters, ethylene glycol fatty acid esters, and polyhydric alcohol fatty acid esters.
  • the above surfactants can be used alone or in combination of two or more.
  • liquid preparation of the present invention may appropriately contain commonly used general-purpose additives such as a brightener, a flavor, and the like.
  • the liquid preparation of the present invention can be usually produced by dissolving the active ingredient in a solvent, and mixing this solution with a water-soluble polymer and, if desired, a surfactant and other additives.
  • the water-soluble polymer may be suspended in a solvent.
  • the liquid preparation of the present invention can be made into a capsule preparation by filling the liquid preparation into a capsule.
  • the capsule may be either a soft capsule or a hard capsule.
  • the cap and the body are sealed by a conventional method so that the liquid content does not leak.
  • the size of the capsule is appropriately determined depending on the type of the active ingredient and its concentration.
  • the mixing ratio of the solvent and the water-soluble polymer can be appropriately selected according to the content of the active ingredient, or the elution pattern and duration of action of the intended active ingredient.
  • the solvent is 1 to 100 parts by weight
  • the water-soluble polymer is 0.05 to 20 parts by weight, more preferably 0.5 to 1 part by weight, based on 1 part by weight of the active ingredient. 0 parts by weight, More preferably, it is about 0.5 to 3.0 parts by weight.
  • the active ingredient of the present invention is useful as a cGMP-phosphodiesterase inhibitor.
  • a cGMP-phosphodiesterase inhibitor for example, angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, glomerular disease (eg, diabetic glomerulosclerosis) , Tubule-interstitial disease (for example, nephropathy induced by tacrolimus, cyclosporin, etc.), renal failure, atherosclerosis, vascular stenosis (such as after percutaneous transluminal coronary angioplasty) , Peripheral vascular disease, seizures, chronic reversible obstructive pulmonary disease (eg, bronchitis or asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, gut motility disorder ( Irritable bowel syndrome), erectile dysfunction (eg, organic or psychological erectile dysfunction), female sexual dysfunction, impotence Or diabetic complications (eg,
  • the dose of the active substance depends on the age and symptoms of the patient, but for systemic administration, it is usually 0.01 to 0.5 mg, lmg, 5 mg, 10 mg, 50 mg, 100 mg, 25 Omg and 50 Omg per dose. And an amount of about 0.01 to 1000 mg, preferably 0.2 to 500 mg, more preferably 0.5 to 10 Omg per day is administered. For long-term administration, the daily dose will range from about 0.3 mg to: L00 Omg.
  • Example 1 The present invention is not limited to these Examples.
  • Example 1 The present invention is not limited to these Examples.
  • drug 1 (3,4-dimethoxybenzyl) 1-2-[(trans-4-formamidocyclohexyl) amino] —5-nitrobenzamide 'dihydrate (hereinafter referred to as “drug 1”) (0 5 g) was dissolved in polyethylene glycol 400 (PEG-400) (about 30 mL). Was added and dissolved, and then PEG-400 was further added to adjust the total amount to 5 OmL.
  • PEG-400 polyethylene glycol 400
  • composition per 1 mL of the solution is as follows.
  • Active agent 11 Omg Low polymerization degree hydroxypropylcellulose 30 mg
  • the active substance 1 (0.5 g) was dissolved in PEG-400 (about 30 mL), and PEG-400 was further added to this solution to make a total volume of 5 OmL.
  • the composition per mL of solution is as follows.
  • liquid agent 1 The liquid agent obtained in Example 1 (hereinafter, referred to as “liquid agent 1”) and the liquid agent obtained in Comparative Example 1 (hereinafter, referred to as “liquid agent A”) were compared for the solubility of the main drug when added to water. did.
  • the test was conducted in accordance with the Dissolution Test Method 2 described in the 13th Revised Japanese Pharmacopoeia. That is, the solubility of the main drug was measured when 5 mL (5 Omg as the main drug 1) of each of Liquid Formulation 1 and Liquid Formulation A was added to a test solution consisting of 90 OmL of water at a paddle rotation speed of 50 rpm.
  • Figure 1 shows the results.
  • capsule 1 Capsules (hereinafter referred to as “capsule 1” and “capsule A”, respectively) in which the above liquid 1 and liquid A were filled into hard capsules, respectively, were used.
  • the capsenole was prepared so that the dose of the active drug 1 was 3.2 mg / kg.
  • bioavailability was calculated based on the area under the one-hour curve (AUC) when the PEG-400 solution of the active substance 1 was administered intravenously and when the forcepsel agent 1 or A was administered. ).
  • Capsule 1 containing Liquid 1 of the present invention reflects the excellent properties of maintaining supersaturated solubility, and shows Cma X and AUC when compared to Forcepsel A. Each of the 24 hours showed a value about 1.6 times higher. Also capsule The BA of drug 1 was about 90%, indicating that drug 1 was almost completely absorbed.
  • Example 2
  • (R) -N- (3,4-dimethoxybenzyl) 1-2- (2-hydroxy-11-methylethylamino) -1-5-nitrobenzamide (hereinafter referred to as the "drug 2") (15 g) was dissolved in PEG-400 (6585 g), and to this solution was added low-polymerization-hydroxypropylcellulose (150 g) and dissolved. This solution was filled into a soft capsule to obtain a force capsule agent.
  • composition per capsule is as follows.
  • drug 3 N- (4-Methoxy-1-benzyl) —2 -— [2-Hydroxy-1- (hydroxymethyl) ethylamino] —5-nitrobenzamide (hereinafter referred to as “drug 3”) (37. 5 g) of PEG-400 (6562.5 g) was added, and to this solution was added low-polymerized hydroxypropylcellulose (150 g) and dissolved. This solution was filled into soft capsules to obtain capsules.
  • composition per capsule is as follows.
  • the active substance 1 (15 g) was dissolved in PEG-400 (645 g), and to this solution was added low-density hydroxypropylcellulose (15 g) and dissolved. This solution The capsule was filled into a soft capsule to obtain a forcepsel agent.
  • composition per capsule is as follows c
  • Active agent 2 (0.5 g) was dissolved in PEG-400 (about 30 mL), hydroxypropylmethylcellulose (1.5 g) was added to this solution, and then PEG-400 was added to make a total volume of 5 OmL. .
  • composition per 1 mL of the solution is as follows.
  • Dissolve drug substance 3 (0.5 g) in PEG-400 (approximately 3 OmL), add polybutylpyrrolidone (1.5 g) to this solution, dissolve, and add PEG-400 to the total volume. To 5 OmL.
  • composition per 1 mL of the solution is as follows.
  • composition per 1 mL of the solution is as follows.
  • Active agent 4 1 Omg Polyethylene glycol 6000 3 Omg
  • N- (3-chloro-1-4-benzyl) 1-2- [2-hydroxy-1- (hydroxymethyl) ethylamino] -15- (trifluoromethyl) benzamide (hereafter referred to as the active drug 5j) (0.05 g) was dissolved in propylene glycol (approximately 3 OmL). To this solution was added low-polymerization hydroxypropylcellulose (0.5 g), and then propylene glycol was added to reduce the total amount. It was 5 OmL.
  • composition per 1 mL of the solution is as follows.
  • the active drug 3 (0.05 g) was dissolved in propylene glycol (about 3 OmL), hydroxypropylmethylcellulose (0.5 g) was added to this solution, and propylene glycol was further added to make a total amount of 5 g. OmL was used.
  • composition per 1 mL of the solution is as follows.
  • Active agent 3 1 mg Hydroxypropyl methylcellulose 1 Omg Propylene dalicol
  • Active substance 1 (0.05 g) is dissolved in propylene glycol (about 30 mL), and polyvinylpyrrolidone (0.5 g) is added to this solution, and then dissolved in propylene glycol. OmL was used.
  • composition per 1 mL of the solution is as follows.
  • Dissolve drug substance 2 (0.05 g) in propylene glycol (approximately 3 OmL), add polyethylene glycol 6000 (0.5 g) to this solution, dissolve, and then add propylene glycol to make a total volume of 5 OmL.
  • composition per 1 mL of the solution is as follows.
  • the main drug 2 (37.5 g) was dissolved in PEG-400 (6562.5 g), and low-polymerized hydroxypropylcellulose (150 g) was added to this solution and dissolved.
  • This solution is filled into a hard capsule, and a seal liquid containing gelatin as a main component is used to seal between the body and the cap of the hard capsule to prevent leakage of the content liquid. A capsule was obtained.
  • composition per capsule is as follows c
  • Dissolve 2-one (hereinafter referred to as “drug 6”) (0.5 g) in PE G-400 (approximately 30 mL), add low-polymerized hydroxypropylcellulose (1.5 g) to this solution and dissolve. After that, PEG-400 was further added to bring the total volume to 50 mL.
  • composition per 1 mL of the solution is as follows.
  • Active agent 61 Omg Low polymerization degree hydroxypropyl cellulose 30 mg
  • Dissolve 2-one (0.05 g) in propylene glycol (about 30 mL), add polyvinylpyrrolidone (1.5 g) to this solution, and dissolve. Further, propylene glycol was added to make a total volume of 50 mL.
  • composition per 1 mL of the solution is as follows.
  • composition per 1 mL of the solution is as follows.
  • Active agent 8 2mg Polyethylene glycol 6000 3 Omg
  • the liquid preparation of the present invention containing the anthranilic acid derivative (la) or the condensed imidazole derivative (Ib) or a salt thereof as the principal agent exists in a state where crystals do not precipitate up to a concentration approximately 100 times the solubility of the principal agent in water. It exhibits extremely good oral absorption.

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Abstract

L'invention porte sur une préparation liquide comportant un composé hydrosoluble (I) peu abondant ou l'un de ses sels, et dont l'absorbabilité par voie orale se trouve améliorée. Ladite préparation comporte outre ledit composé hydrosoluble ou l'un de ses sels, un solvant non toxique du composé ou de son sel, ainsi qu'un polymère hydrosoluble.
PCT/JP2001/001187 2000-02-21 2001-02-19 Preparation liquide a absorbabilite amelioree Ceased WO2001060353A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001232344A AU2001232344A1 (en) 2000-02-21 2001-02-19 Liquid preparation with improved absorbability

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JP2000043062 2000-02-21
JP2000-43062 2000-02-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014119985A3 (fr) * 2013-01-31 2014-11-27 Garcia Pérez Miguel Ángel Composition pharmaceutique présentant un inhibiteur sélectif de l'enzyme phosphodiestérase sous forme de gel oral

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193287A2 (fr) * 1985-02-19 1986-09-03 Nippon Kayaku Kabushiki Kaisha Préparations à base d'étoposide
EP0488181A1 (fr) * 1990-11-29 1992-06-03 Nippon Kayaku Kabushiki Kaisha Préparation de gélule contenant de la nifedipine
WO1995001166A1 (fr) * 1993-06-30 1995-01-12 Fujisawa Pharmaceutical Co., Ltd. Medicament encapsule
US5661169A (en) * 1994-07-05 1997-08-26 Sanofi 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives, their preparation and the pharmaceutical compositions containing them
WO1999054284A1 (fr) * 1998-04-20 1999-10-28 Fujisawa Pharmaceutical Co., Ltd. Derives d'acide anthrenilique utilises comme inhibiteurs de cgmp-phosphodiesterase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193287A2 (fr) * 1985-02-19 1986-09-03 Nippon Kayaku Kabushiki Kaisha Préparations à base d'étoposide
EP0488181A1 (fr) * 1990-11-29 1992-06-03 Nippon Kayaku Kabushiki Kaisha Préparation de gélule contenant de la nifedipine
WO1995001166A1 (fr) * 1993-06-30 1995-01-12 Fujisawa Pharmaceutical Co., Ltd. Medicament encapsule
US5661169A (en) * 1994-07-05 1997-08-26 Sanofi 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives, their preparation and the pharmaceutical compositions containing them
WO1999054284A1 (fr) * 1998-04-20 1999-10-28 Fujisawa Pharmaceutical Co., Ltd. Derives d'acide anthrenilique utilises comme inhibiteurs de cgmp-phosphodiesterase

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014119985A3 (fr) * 2013-01-31 2014-11-27 Garcia Pérez Miguel Ángel Composition pharmaceutique présentant un inhibiteur sélectif de l'enzyme phosphodiestérase sous forme de gel oral

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