WO1994011017A1 - Preparation buvable - Google Patents

Preparation buvable Download PDF

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Publication number
WO1994011017A1
WO1994011017A1 PCT/JP1993/001647 JP9301647W WO9411017A1 WO 1994011017 A1 WO1994011017 A1 WO 1994011017A1 JP 9301647 W JP9301647 W JP 9301647W WO 9411017 A1 WO9411017 A1 WO 9411017A1
Authority
WO
WIPO (PCT)
Prior art keywords
fatty acid
medium
chain fatty
preparation
oral administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1993/001647
Other languages
English (en)
Japanese (ja)
Inventor
Takehisa Hata
Fumio Shimojo
Akio Kawamura
Yasuo Shimazaki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to AU54336/94A priority Critical patent/AU5433694A/en
Publication of WO1994011017A1 publication Critical patent/WO1994011017A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid

Definitions

  • the present invention relates to a preparation for oral administration and is used in the medical field.
  • the compound represented by the following formula (I) has an immunopotentiating effect and is known to be useful as an immunopotentiator, a stake cancer drug, an anti-AIDS agent, an antiviral agent, etc. No. 45449, JP-A-60-104019 and JP-A-64-38030).
  • the compound represented by the following formula (I) and a salt thereof are generally administered in the form of an injection because of poor absorption when administered orally, but administration by injection not only causes pain to patients, There is a problem of local damage at the injection site.
  • studies on rectal preparations containing absorption enhancers have been actively pursued in recent years, but rectal administration is not only inconvenient for administration but also due to the added absorption.
  • rectal mucosal damage caused by the accelerator Therefore, it is desirable to improve the oral absorbability by subjecting poorly absorbable drugs to appropriate formulation treatment.
  • conventional formulation treatment for example, addition of an oral absorption enhancer
  • the inventors of the present invention have conducted intensive studies with the aim of improving the oral absorption of FK 565 and its salts, and found that sucrose fatty acid esters, bile acids or salts thereof, surfactants and fatty acid triglycerides were The inventors have found that FK 565, which is one of the poorly absorbable substances, and a salt thereof exert a remarkably excellent effect on improving the oral absorbability, and completed the present invention. Disclosure of the invention
  • This invention relates to compound (I) or a salt thereof, sucrose fatty acid ester, bile acid or
  • the present invention relates to a preparation for oral administration containing one or more absorption enhancers selected from salts, surfactants, olive oil and medium-chain fatty acid triglycerides.
  • Compound (I) which is the main drug of the present invention, has an immunopotentiating effect, is useful as a pile cancer agent, an anti-aze agent, an antiviral agent, and the like, and is represented by the following chemical formula.
  • compositions of compound (I) used in the present invention include, for example, sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and the like.
  • Organic or inorganic salts such as acetate, trifluoroacetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, hydrochloride, sulfate, nitrate, phosphate, etc. And acid addition salts with acids or inorganic acids.
  • FK565 Representative compounds (hereinafter referred to as FK565) among the compounds U) and salts thereof used as the active ingredient in the present invention are as follows.
  • FK565 or a salt thereof which is a representative compound of the compound (I) or a salt thereof.
  • the bile acids and salts thereof used in the present invention include cholic acid, glycolic acid, taurocholic acid, deoxycholic acid, ursodeoxycholic acid, dehydrocolic acid, glycodoxycholic acid, and taurodeoxychol. Acids, chenodeoxycholate, glycochenodeoxycholate, glycolidetocholate, taurodehydrocholate, and the like, and salts thereof (eg, metal salts such as sodium salts such as sodium salts). .
  • Monoesters, diesters, triesters of sucrose saturated or unsaturated fatty acids such as sucrose lauric acid, sucrose myristic acid, sucrose palmitic acid, sucrose stearic acid, sucrose oleic acid, etc. , Polyesters, and mixtures of two or more of these, or esters of sucrose and hardened tallow fatty acids (mono, di, tri, and polyester are mixed) [eg DK Ester F-160, DK Ester SS (trademark, Daiichi Kogyo Seiyaku Co., Ltd.]].
  • the surfactant include polyoxyethylene alkyl (preferably c; alkyl of c 20 ) ethers such as lauromacrogol (polyoxyethylene laurylene)
  • medium-chain triglycerides include saturated fats having 6 to 10 carbon atoms.
  • Triglycerides of fatty acids are mentioned, and specific examples include triglyceride of caproic acid, triglyceride of caprylic acid, and triglyceride of capric acid. Note that mixtures of these triglycerides with monoglycerides or diglycerides are also included in the medium-chain fatty acid triglycerides of the present invention.
  • a more preferred medium-chain fatty acid triglyceride is a mixture of triglyceride cabrylate and triglyceride caprylate, for example, Miglyol-812 (trademark: Dynamite Nobel).
  • the preparation for oral administration of the present invention contains an FK565 substance or a salt thereof, which is the active ingredient, and a sucrose fatty acid ester, a bile acid or a salt thereof, a surfactant, and a medium-chain fatty acid triglyceride.
  • One or more of the accelerators may include a disintegrant (eg, ECG505 (trademark, manufactured by Nichirin Chemical Co., Ltd.), etc.), a lubricant (eg, magnesium stearate, etc.) and / or Accordingly, organic bases (eg, sodium bicarbonate), excipients (eg, lactose), binders (eg, hydroxypropylcellulose), thickeners (eg, aluminum monostearate), etc. Or tableting according to a conventional method, or forming into a slug once, pulverizing, sieving and then tableting according to a conventional method, or filling into capsules, or the like.
  • a disintegrant eg, ECG505 (trademark, manufactured by Nichirin Chemical Co., Ltd.), etc.
  • a lubricant eg, magnesium stearate, etc.
  • organic bases eg, sodium bicarbonate
  • excipients eg, lactose
  • binders
  • a liquid preparation such as an aqueous solution, suspension, syrup or the like by a conventional method.
  • fine granules, granules, enteric preparations, etc. can also be produced by conventional methods. Further, it can be produced by a method such as filling an oily suspension or a hard capsule, a soft capsule and an enteric capsule with an oily suspension by adding medium chain fatty acid triglyceride.
  • a combination of one or more compounds selected from sucrose fatty acid esters, bile acids or salts thereof, and surfactants with medium-chain fatty acid triglycerides, or medium-chain fatty acids It is preferable to use triglyceride alone, and it is more preferable to use a combination of sucrose fatty acid ester and medium-chain fatty acid triglyceride. Further, a combination of a sucrose fatty acid ester and olive oil is also preferable as the absorption enhancer in the above-mentioned preparation.
  • the amount of the absorption enhancer in the above-mentioned preparation is usually 0.01 to 100 times the weight of the drug, preferably 0.25 to 50 times, but is not limited thereto. No, as appropriate Can be determined.
  • the dosage of the oral administration preparation according to the present invention depends on the age, weight, symptoms, etc. of the patient, but is generally 1 mg to 1 mg per day as compound (I) or a pharmaceutically acceptable salt thereof. g, preferably 10 mg to 500 mg, may be administered orally, by injection or inhalation once a day to 3 times a day. Examples of single doses include 5 mg, 10 mg, 20 mg, 5 Omg, lO Omg, and the like.
  • the rat was kept in a supine position, and laparotomy was performed under ether anesthesia to form a loop of 5 cm above the small intestine.
  • 0.5 ml of the following drug solution was injected into this loop.
  • the small intestinal loop was excised, and the drug solution remaining in the loop was washed and recovered with purified water to a total volume of 20 ml.
  • the concentration of the main drug in the recovered solution was measured by high performance liquid chromatography, and the remaining amount was determined. Furthermore, the absorption rate was calculated from the following equation.
  • the test results are shown in the following table.
  • the absorptivity was shown as the average soil standard error of the number of test examples.
  • Absorption promoter Number of cases Absorption rate after 30 minutes Sucrose fatty acid ester
  • mice Three S.D. male rats (body weight 200-270 g) fasted overnight were used per group. The rats were orally administered the following administration samples at a rate of lOmgZkg. After administration, blood samples were collected from the femoral artery over time, and the FK565 concentration was measured by high performance liquid mouth chromatography.
  • composition Prescription 1 Prescription 2 Prescription 3 Prescription 4 Control
  • an administration sample having the following composition was orally administered.
  • the prescription was 1 mgZkg, and the control was 1 OmgZkg.
  • a blood sample was collected from the forelimb vein, and the FK565 concentration in plasma was measured by high performance liquid chromatography.
  • FK 565 (0.5 mg) and sucrose fatty acid ester (DKS S, Daiichi Pharmaceutical) (2.5 mg) were added to pH 6.4 phosphate isotonic buffer (0.5 ml) and dissolved. To make an aqueous solution.
  • the above components are formulated in a conventional manner.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparation pharmaceutique à absorbabilité perorale excellente renfermant le FK565 ou une autre substance présentant une activité d'immunopotentialisation et étant utilisable comme agent anticancéreux, anti-SIDA ou antiviral, ou son sel, et un ou plusieurs agents favorisant l'absorption sélectionnés parmi les esters de sucrose et d'acides gras, l'acide biliaire et ses sels, les tensioactifs et les triglycérides d'acides gras à chaînes moyennes.
PCT/JP1993/001647 1992-11-16 1993-11-10 Preparation buvable Ceased WO1994011017A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54336/94A AU5433694A (en) 1992-11-16 1993-11-10 Orally administrable preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP30510792 1992-11-16
JP4/305107 1992-11-16

Publications (1)

Publication Number Publication Date
WO1994011017A1 true WO1994011017A1 (fr) 1994-05-26

Family

ID=17941188

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001647 Ceased WO1994011017A1 (fr) 1992-11-16 1993-11-10 Preparation buvable

Country Status (2)

Country Link
AU (1) AU5433694A (fr)
WO (1) WO1994011017A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004931A1 (fr) * 1994-08-09 1996-02-22 The Nisshin Oil Mills, Ltd. Composition perorale immunogene et son procede de preparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5976021A (ja) * 1982-10-22 1984-04-28 Fujisawa Pharmaceut Co Ltd Ｆｋ−５６５物質含有リポソ−ム製剤
JPS60104019A (ja) * 1983-11-10 1985-06-08 Fujisawa Pharmaceut Co Ltd ウイルス感染症用薬剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5976021A (ja) * 1982-10-22 1984-04-28 Fujisawa Pharmaceut Co Ltd Ｆｋ−５６５物質含有リポソ−ム製剤
JPS60104019A (ja) * 1983-11-10 1985-06-08 Fujisawa Pharmaceut Co Ltd ウイルス感染症用薬剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004931A1 (fr) * 1994-08-09 1996-02-22 The Nisshin Oil Mills, Ltd. Composition perorale immunogene et son procede de preparation

Also Published As

Publication number Publication date
AU5433694A (en) 1994-06-08

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