CN110121348A - The pharmaceutical composition of solid dispersions and oil dispersion comprising ED-71 - Google Patents

The pharmaceutical composition of solid dispersions and oil dispersion comprising ED-71 Download PDF

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Publication number
CN110121348A
CN110121348A CN201780081610.0A CN201780081610A CN110121348A CN 110121348 A CN110121348 A CN 110121348A CN 201780081610 A CN201780081610 A CN 201780081610A CN 110121348 A CN110121348 A CN 110121348A
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Prior art keywords
soluble polymer
water soluble
cellulose
oil
solution
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仓崎和贵
高野隆介
松冈庆宏
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
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    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

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Abstract

According to the present invention, the method for inhibiting the oxidation of ED-71 is provided, it includes following processes: preparation includes (5Z, 7E)-(1R, 2R in a solvent, 3R) -2- (3- hydroxy propyloxy group) -9,10- open loop cholesteric -5,7,10 (19)-triolefin -1,3,25- triols (ED-71) and include water soluble polymer or alkali compounds mixed solution process；And, the process of solvent is removed from obtained mixed solution, and, a kind of method of decomposition inhibiting ED-71 is provided, it includes: the process of the oil-in-water emulsion of the aqueous solution of fat solution of the preparation comprising ED-71 and water soluble polymer, wherein, above-mentioned water soluble polymer is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.

Description

The pharmaceutical composition of solid dispersions and oil dispersion comprising ED-71
Technical field
The present invention relates to include (5Z, 7E)-(1R, 2R, 3R) -2- (3- hydroxy propyloxy group) -9,10- open loop gallbladder Steroid -5,7,10 (19)-triolefin -1,3,25- triol (hereinafter also referred to ED-71) pharmaceutical composition and its manufacturing method, Inhibit the method etc. of oxidation or the decomposition of ED-71.
Background technique
ED-71 (common first names: Chinese mugwort ground ostelin) is the active form vitamin D with osteogenic action3Synthesis of derivatives, It manufactures, sell as the osteoporosis treatment agent of oral administration.
ED-71 can be come formulation in the same manner as other vitamin D derivatives in the form of soft capsule.Patent document 1 is public It has opened seamless soft made of enclosing MCT Oil (hereinafter also referred to MCT) solution of ED-71 in gelatina shell Capsule.In addition, patent document 1 can inhibit it is disclosed that by adding the antioxidants such as dl- alpha-tocopherol into the solution The generation of the tachysterol body and trans- body of decomposition product as ED-71.
Currently, the ED-71 preparation on sale other than soft capsule is still unknown.Patent document 2, which discloses, can be adapted for sclerotin The strontium salt of osteoporosis and the complexing agent of vitamin D derivative list Chinese mugwort ground ostelin as an example of vitamin D derivative. In addition, tablet can be made by describing the mixture in patent document 2.But the record is only general as tablet It records, and is not disclosed in effect when cooperating the special additive other than strontium salt in ED-71 preparation.
Patent document 3 describes one kind 1 α-(OH)-D3Composition, the composition is for example by 1 α-(OH)-D3And poly- second Vinyl pyrrolidone adds Lactis Anhydrous after being dissolved in ethyl alcohol, and vacuum distillation removes ethyl alcohol after stirring, then obtained reaction is produced Object crushes, to obtain.
Existing technical literature
Patent document
Patent document 1:WO2005/074943A1
Patent document 2:CN102688249A
Patent document 3:WO90/09796A
Summary of the invention
Subject to be solved by the invention
0.75 μ g glue of 0.5 μ g capsule of EDIROL (registered trademark) and EDIROL as osteoporosis treatment agent sale Capsule is only spherical soft capsule, needs the ED-71 preparation excellent come development function by new preparation.Additionally, there are make ball The soft capsule of shape becomes aspherical and is easier the demand about usability for grabbing and being not easy rolling etc.For side Just the patient for needing to be administered ED-71 needs to develop the aspherical ED-71 preparation of the dosage form other than soft capsule.
The present inventors has carried out utilizing with regard to this preparation and has mixed the additive of the ED-71 of solid and solid Solid dispersions (solid dispersion) manufacture preparation exploitation and using make ED-71 fat solution particle The exploitation of the preparation of oil dispersion made of being scattered in excipient (oil dispersion) manufacture, as a result, it has been found that with after class Topic.
Firstly, having found following projects in the exploitation of the preparation manufactured using solid dispersions: the ED-71's of solid Stability is low, need exist to improving its stability.
In addition, finding following projects in the exploitation of the preparation manufactured using oil dispersion: directly using ED-71 when using Fat solution preparation oil dispersion when, the satisfactory preparation of quality cannot be manufactured.In addition, in order to solve the project repeatedly It is studied, has as a result obtained the design for coating the particle of the fat solution of ED-71 with specific additive, but by This has found that new technical task, i.e., used additive will lead to the stability decline of ED-71 mostly.
The present invention is in view of the above situation to complete, it is intended that providing the various dosage forms other than soft capsule The means for inhibiting ED-71 to decompose in ED-71 preparation.
Solution for solving the problem
The present inventors has made intensive studies in order to achieve the above object, as a result, it has been found that, for solid dispersions Speech, the decomposition of the ED-71 of solid is as caused by aoxidizing, it was found that by using being generally acknowledged that without antioxidation The alkali compounds conduct such as the water soluble polymers such as hydroxypropyl methyl cellulose or meglumine, L-arginine and tetrapotassium pyrophosphate Additive is so as to significantly inhibiting the oxidation.
In addition, it is found that for oil dispersion, by using the hydroxypropyl methyl cellulose for belonging to water soluble polymer Or hydroxypropyl cellulose is as additive, and the satisfactory preparation of quality (especially tablet) can be manufactured, and will not draw Play the stability decline of ED-71.
The present inventors is based on these discoveries and further research has been repeated, so as to complete the present invention.
That is, more specifically the present invention provides [1] below~[12].
[1] a kind of method for the oxidation for inhibiting ED-71, it includes following processes:
Preparation includes (5Z, 7E)-(1R, 2R, 3R) -2- (3- hydroxy propyloxy group) -9,10- open loop gallbladder in a solvent Steroid -5,7,10 (19)-triolefin -1,3,25- triol, that is, ED-71 and include the mixed of water soluble polymer or alkali compounds The process for closing solution；And
The process of solvent is removed from obtained mixed solution.
[2] method according to [1], wherein the weight ratio of ED-71 and additive is 1:50~1:5000.
[3] method according to [1] or [2], wherein water soluble polymer is from hydroxypropyl methyl cellulose, polyoxy second Alkene polyoxypropylene diols, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-beta-cyclodextrin, polyvinyl are in oneself Amide-polyvinyl acetate-polyethyleneglycol-graft copolymer amino alkyl methacrylate copolymer, methacrylic acid ammonia Base alkyl ester copolymer, amino alkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose-fatty Ester, polyvinylpyrrolidone, polyvinylpyrrolidone, copolyvidone, Crodaret, 2- hydroxypropyl- Beta-cyclodextrin, D- alpha-tocopherol polyethanediol succinate, Crodaret dextrin, Arabic gum, hydroxypropyl Methylcellulose-acetate succinate, alkali treated gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate- It is selected in acrylic acid-methacrylic acid copolymer, pre-gelatinized starch, hydroxyethyl cellulose and lecithin powder, alkali compounds It is selected from meglumine, L-arginine and tetrapotassium pyrophosphate.
[4] a kind of pharmaceutical composition comprising ED-71,
Its by preparation in a solvent comprising ED-71 and include water soluble polymer or alkali compounds mixing it is molten Liquid, and remove solvent from the mixed solution and manufacture,
Water soluble polymer is from hydroxypropyl methyl cellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene Polyoxypropylene diols, sulfobutyl ether-beta-cyclodextrin, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethylene glycol grafting Copolymer amino alkyl methacrylate copolymer, amino alkyl methacrylate copolymer, methacrylic acid amino alkane Base ester copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty ester, polyvinylpyrrolidone, polyvinylpyrrolidine Alkanone, copolyvidone, Crodaret, 2-HP-BETA-CD, D- alpha-tocopherol polyethylene glycol amber Amber acid esters, Crodaret dextrin, Arabic gum, hydroxypropyl methyl cellulose-acetate succinate, at alkali Manage gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate-acrylic acid-methacrylic acid copolymer, pre-gelatinized It is selected in starch, hydroxyethyl cellulose and lecithin powder, alkali compounds is from meglumine, L-arginine and tetrapotassium pyrophosphate Middle selection.
[5] pharmaceutical composition according to [4], wherein the weight ratio of ED-71 and additive is 1:50~1:5000.
[6] a kind of manufacturing method of the pharmaceutical composition comprising ED-71, it includes following processes:
The process of the oil-in-water emulsion of the aqueous solution of fat solution of the preparation comprising ED-71 and water soluble polymer；
The process for making oil-in-water emulsion adhere to or be adsorbed in excipient；And
The process for keeping oil-in-water emulsion dry,
Wherein, above-mentioned water soluble polymer is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
[7] method according to [6], wherein the weight ratio of oil-in-water emulsion and excipient is 1:4~1:20.
[8] method according to [6] or [7], wherein excipient is selected from sugar or glycitols.
[9] a kind of pharmaceutical composition comprising ED-71,
Described pharmaceutical composition is in excipient or the surface of excipient includes the particle for being wrapped by agent cladding, the cladding Agent includes the water soluble polymer selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose,
The particle includes the fat solution of ED-71.
[10] pharmaceutical composition according to [9], for by the coating tablet of HPMC film coating.
[11] a kind of method for the decomposition for inhibiting ED-71, it includes following processes:
The process of the oil-in-water emulsion of the aqueous solution of fat solution of the preparation comprising ED-71 and water soluble polymer,
Wherein, above-mentioned water soluble polymer is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
[12] method according to [11], also includes following processes:
Obtained oil-in-water emulsion is dry.
Invention effect.
According to the present invention it is possible to inhibit the decomposition of ED-71 in solid dispersions and oil dispersion.Further, it is possible to use solid The ED-71 preparation of various dosage forms other than body dispersion and oil dispersion manufacture soft capsule.
Detailed description of the invention
Fig. 1 is the skeleton diagram of the manufacturing process of the tablet of oil dispersion of the manufacture comprising ED-71.
Fig. 2 is the emulsifying shown when mixing 2% aqueous solution of water soluble polymer with MCT Oil The photo of state.HPMC, HPC, PVP and POVA-COAT are followed successively by from the left side.
Specific embodiment
In the present invention, ED-71 is following formula (I) compounds represented.
[changing 1]
ED-71 can for example be obtained according to the method recorded in Japanese Unexamined Patent Publication 10-72432, that is, with (1R, 2R, 3R) -2- (3- hydroxy propyloxy group) cholesteric -5,7- diene -1,3,25- triol be initial substance, ultraviolet light irradiation and After thermal isomerization reaction, is purified with reversed-phase HPLC, obtain its crystallization with ethyl acetate after concentration.
The solid dispersions of I.ED-71
I-1. inhibit the method for the oxidation of ED-71
The 1st aspect of the present invention is related to the solid dispersions of ED-71.In this specification, the solid dispersions of ED-71 Refer to composition made of mixing the additive of the ED-71 of solid and solid.Shown in embodiment as be described hereinafter, it is known that ED-71 can be decomposed in preservation due to oxidation.The present invention provides the side decomposed ED-71 caused by inhibiting such oxidation Method.The method include that as the process for mixing ED-71 with the additive in water soluble polymer and alkali compounds , the mixed solution that preparation is in a solvent comprising ED-71 and water soluble polymer or alkali compounds and from the mixed solution The process for removing solvent.By mixing ED-71 and additive, so that the oxidation of ED-71 is inhibited.
The inhibition of the oxidation of ED-71 can be confirmed as follows: to the ED-71's as obtained from implementing method of the invention Solid dispersions carry out shading, the survival rate of ED-71 are investigated after saving 7 days or 14 days at 60 DEG C, to be confirmed.Such as For fruit compared with the standard items of the ED-71 without additive, the survival rate of the ED-71 of the solid dispersions is high, then judges ED- 71 oxidation is inhibited.About the survival rate of ED-71, with high performance liquid chromatography (measurement wavelength 265nm) to preservation sample ED-71 is measured with initial samples and as the precursor (chemical name: 6Z- (1R, 2R, 3R) -2- (3- hydroxyl third of its isomers Oxygroup) -9,10- open loop cholesteric -5 (10), 6,8 (9)-triolefin -1,3,25- triol；Pre is also referred to as in this specification ED-71 peak area) calculates the survival rate of ED-71 by calculating formula below.
ED-71 peak area in the survival rate (%) of ED-71=preservation sample is total/initial samples in the peak ED-71 Area total × 100
The peak area of ED-71+1.98 × pre of peak area ED-71 (ED-71 peak area is total=)
Water soluble polymer used in the present invention can be the previous and substance with antioxidation that is unaware of it, can Enumerate for example hydroxypropyl methyl cellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, Sulfobutyl ether-beta-cyclodextrin, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethyleneglycol-graft copolymer methyl-prop Olefin(e) acid aminoalkyl ester copolymer, amino alkyl methacrylate copolymer, amino alkyl methacrylate copolymer, hydroxyl Propyl cellulose, ethyl cellulose, sucrose fatty ester, polyvinylpyrrolidone, polyvinylpyrrolidone, copolymerization dimension Ketone, Crodaret, 2-HP-BETA-CD, D- alpha-tocopherol polyethanediol succinate, polyoxy Ethylene hydrogenation castor oil dextrin, Arabic gum, hydroxypropyl methyl cellulose-acetate succinate, alkali treated gelatin, methyl Cellulose, polyvinyl acetate, polyvinyl acetate-acrylic acid-methacrylic acid copolymer, pre-gelatinized starch, ethoxy Acceptable water soluble polymer on the preparations such as cellulose and lecithin powder.In preferred embodiment, water soluble polymer is selected from: sulphur Butyl ether-beta-cyclodextrin, polyethylene glycol, sucrose fatty ester (F-160), Vinylcaprolactam homopolymer-polyvinyl acetate Ester-polyethyleneglycol-graft copolymer, D- alpha-tocopherol polyethanediol succinate, hydroxypropyl methyl cellulose-acetic acid esters Succinate, polyvinyl acetate, Crodaret, dextrin, Kollidon 90, hydroxypropyl methyl Cellulose, 2-HP-BETA-CD, hydroxypropyl cellulose, polyoxyethylene polyoxypropylene glycol, is total to hydroxyethyl cellulose Povidone, ethyl cellulose, amino alkyl methacrylate copolymer, methylcellulose and polyvinylpyrrolidone K30. In preferred mode, water soluble polymer is selected from: hydroxypropyl methyl cellulose-acetate succinate, polyvinyl acetate Ester, Crodaret 40, dextrin, Kollidon 90, hydroxypropyl methyl cellulose, hydroxy ethyl fiber Element, 2-HP-BETA-CD, polyoxyethylene polyoxypropylene glycol 101, hydroxypropyl cellulose, polyoxyethylene polyoxypropylene Glycol F68, copolyvidone, ethyl cellulose, amino alkyl methacrylate copolymer E100, methylcellulose and polyethylene Base pyrrolidones K30.These can be used singly or in combination of two or more.
Alkali compounds used in the present invention can be the previous and substance with antioxidation that is unaware of it, can arrange Acceptable alkali compounds on citing such as meglumine, L-arginine and tetrapotassium pyrophosphate preparation.In preferred embodiment, alkalinity Compound is meglumine or L-arginine.These can be used singly or in combination of two or more.
As additive used in aforesaid way, preferably water soluble polymer.
The mixing of ED-71 and additive can be carried out by commonly used approach in formulation art.As such side Method, it can be mentioned, for example: the method for solvent is removed after so that ED-71 and additive is dissolved or be suspended in water or organic solvent equal solvent； Melting mixing method；Deng.By above-mentioned mixing, it will form that additive uniformly exists in ED-71 or ED-71 is in additive mostly In uniform existing solid dispersions.The uniformly existing solid dispersion in additive that it is preferable to use ED-71 in the present invention Body.
In the method using solvent, can be in ED-71 and additive it is at least one kind of be not dissolved in the solvent but It is suspended in the state of the solvent, it is preferred that both ED-71 and additive are dissolved in the solvent.That is, being mixed in preferred embodiment It is to be dissolved with the mixed solution of ED-71 and water soluble polymer or alkali compounds in a solvent by preparing, and from the mixing The mode of solvent is removed in solution to carry out.
As long as solvent used in the present invention be preparation on acceptable solvent, such as are as follows: acetic acid, acetone, acetonitrile, Methyl phenyl ethers anisole, benzene, n-butyl alcohol, 2- butanol, butyl acetate, t-butyl methyl ether, carbon tetrachloride, chlorobenzene, chloroform, isopropylbenzene, ring Hexane, 1,2- dichloroethanes, 1,2- dichloroethylene, methylene chloride, 1,2- dimethoxy-ethane, N, N- dimethylacetamide Amine, N,N-dimethylformamide, dimethyl sulfoxide, 1,4- dioxanes, ethyl alcohol, cellosolvo, ethyl acetate, second two Alcohol, ether, Ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2- methoxyl group second Alcohol, methyl acetate, isoamyl alcohol, methyl butyl ketone, hexahydrotoluene, hex- 2- ketone, isoamyl acetate, methyl ethyl ketone, methyl tert-butyl Base ketone, 2- methyl-1-propyl alcohol, N-Methyl pyrrolidone, nitromethane, pentane, amylalcohol, propyl alcohol, isopropanol, acetic acid third Ester, pyridine, sulfolane, tetrahydrofuran, naphthane, toluene, 1,1,1- trichloroethanes, 1,1,2- trichloro ethylene and dimethylbenzene. In preferred embodiment, solvent is n-butyl alcohol, 2- butanol, ethyl alcohol, cellosolvo, ethylene glycol, methanol, 2- methoxyl group second The alcohol such as alcohol, isoamyl alcohol, 2- methyl-1-propyl alcohol, amylalcohol, propyl alcohol and isopropanol, more preferable ethyl alcohol.These can individually be made With or be used in combination of two or more.In addition, alcohol can be the aqueous alcohol (such as hydrous ethanol) for being mixed with water.
The removing of solvent can be carried out by commonly used approach in formulation art.As such method, can enumerate Such as vacuum distillation removing, freeze-drying, spray drying, fluidized bed drying, heat drying, the precipitation method in lean solvent, air-supply Dry, natural drying etc., preferably vacuum distillation remove.
The obtained mixture is scattered in the addition of state or solid in the additive of solid as ED-71 mostly Agent is scattered in the state in ED-71.Wherein, " state being scattered in ... " refers to: in the ingredient as parent, Qi Tacheng Divide substantially evenly existing state.In one mode, the weight ratio of ED-71 and additive in mixture are 1:0.01~1: 100000, preferably 1:0.1~1:10000, more preferably 1:1~1:8000 are even more preferably 1:50~1:5000.Separately In one mode, the weight ratio of ED-71 and additive in mixture are 1:1~1:10000, such as 1:10~1:10000,1: 100~1:10000 or 1:1000~1:10000.The specific example of weight ratio as ED-71 and additive in mixture, It can be mentioned, for example 1:1,1:10,1:100,1:1000,1:4000 and 1:10000, preferably 1:1000 and 1:4000.As in addition Preferred specific example, 1:10000 can be enumerated.ED-71 weight less than additive weight mode in, mostly at The state being scattered in for ED-71 in the additive of solid.
It I-2. include the pharmaceutical composition of ED-71
ED-71 and additive are mixed into the mixture being inhibited to the oxidation of ED-71 using by the above method (that is, solid dispersions) can manufacture the pharmaceutical composition comprising ED-71.Therefore, the present invention provides a kind of comprising ED-71 Pharmaceutical composition, mixed solution by preparation in a solvent comprising ED-71 and water soluble polymer or alkali compounds, And solvent is removed from the mixed solution and is manufactured.In a mode of the invention, ED-71 is scattered in selected from water soluble polymer And in the additive of alkali compounds.In pharmaceutical composition of the invention, by the way that ED-71 and additive are mixed, thus The oxidation of ED-71 is inhibited.
The content of ED-71 in pharmaceutical composition of the invention is not particularly limited, in a mode, with per unit system ED-71 amount in agent is calculated as 0.05~5 μ g, preferably 0.5~0.75 μ g.
The mixture (solid dispersions of ED-71) of ED-71 and additive can method by recording in above-mentioned I-1 To prepare.It is recorded in water soluble polymer and alkali compounds such as I-1 in the present invention.In addition, pharmaceutical composition of the invention The weight ratio of ED-71 and additive in object are 1:0.01~1:100000, preferably 1:0.1~1 in a mode: 10000, more preferably 1:1~1:8000 are even more preferably 1:50~1:5000.In another way, in mixture The weight ratio of ED-71 and additive is 1:1~1:10000, such as 1:10~1:10000,1:100~1:10000 or 1:1000 ~1:10000.The specific example of weight ratio as ED-71 and additive in mixture, it can be mentioned, for example 1:1,1:10, 1:100,1:1000,1:4000 and 1:10000, preferably 1:1000 and 1:4000.As other preferred specific example, can arrange Lift 1:10000.
The oral preparations such as tablet, capsule, granule, powder can be made in pharmaceutical composition of the invention.These are oral Preparation can be manufactured by method used in formulation art.For example, the manufacturing method as tablet, can enumerate below I), ii) and method iii).
I) it will be mixed together with the additional additives such as ED-71 and the mixture of additive and excipient, disintegrating agent, lubricant After conjunction, compression forming is carried out, to manufacture tablet.
Ii after) ED-71 is mixed with the mixture of additive with additional additives such as excipient, bonding agents, Bian Tianjia Or spraying solvent (such as purified water, ethyl alcohol or its mixed liquor) side is granulated.Suitable lubrication is added into obtained granules After agent, disintegrating agent as needed etc. and mixing, compression forming is carried out, to manufacture tablet.
Iii after) ED-71 is mixed with the mixture of additive with excipient, Bian Tianjia or spraying by bonding agent and according to The other additives needed are dispersed or dissolved in liquid obtained from solvent (such as purified water, ethyl alcohol or its mixed liquor), Bian Jin Row is granulated.After suitable lubricant, disintegrating agent as needed etc. are added into obtained granules and mixes, it is compressed into Type, to manufacture tablet.
As the additive of the addition other than water soluble polymer and alkali compounds, in addition to excipient, disintegrating agent, combination It, can be respectively using for example for improving the surfactant of the release property of drug, pH adjusting agent, being used for other than agent and lubricant The fluidizing reagent, the stabilizer for improving stability, the flavoring for increasing taste or smell for improveing the mobility in process are rectified Odorant agent (Japanese: flavoring rectifys smelly drug), the colorant for increasing color.These dosage is logical relative to 100 parts by weight of preparation It is often 0~99.999 parts by weight, preferably 50~99.5 parts by weight, more preferably 90~99 parts by weight.
As excipient, it can be mentioned, for example: cornstarch, potato starch, wheaten starch, rice starch, the pre- paste in part Change the starch such as starch, pre-gelatinized starch, porous-starch；The sugar such as lactose hydrous, fructose, glucose, mannitol, D-sorbite Or glycitols；Calcium phosphate dibasic anhydrous；Avicel cellulose；Precipitated calcium carbonate；Calcium silicates etc..In preferred embodiment, excipient is starch Class, lactose hydrous, avicel cellulose or calcium phosphate dibasic anhydrous.
As disintegrating agent, it can be mentioned, for example: Explotab, carboxymethyl cellulose, calcium carboxymethylcellulose, carboxymethyl Sodium starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropul starch etc..Disintegrating agent Dosage is preferably 0.5~25 parts by weight relative to 100 parts by weight of preparation, further preferably 1~15 parts by weight.
As bonding agent, it can be mentioned, for example: hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, povidone (polyvinylpyrrolidone), Arabic gum powder etc..The usage amount of bonding agent is preferably 0.1 relative to 100 parts by weight of preparation ~50 parts by weight, further preferably 0.5~40 parts by weight.
As lubricant, it can be mentioned, for example: stearic acid, magnesium stearate, calcium stearate, talcum, sucrose fatty ester, rich horse Sour sodium stearyl ester, light silicon dioxide etc..
As surfactant, it can be mentioned, for example: polysorbate80, polyethylene glycol stearate 40, Lauromacrogol etc..
As pH adjusting agent, it can be mentioned, for example: acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, Phosphoric acid and the salt of either of which person.
As fluidizing reagent, it can be mentioned, for example: the silica such as light silicon dioxide, aqueous silicon dioxide；Talcum etc..? This, is as the specific example of light silicon dioxide, it can be mentioned, for example: Sylysia320 (trade name, Fuji Silysia chemistry (strain)), Aerosil 200 (trade name, Japan Aerosil (strain)) etc..
As stabilizer, it can be mentioned, for example: the P-hydroxybenzoic acid such as methyl p-hydroxybenzoate, propylparaben Ester；The alcohol such as methaform, benzyl alcohol, benzyl carbinol；Benzalkonium chloride；The phenols such as phenol, cresols；Thimerosal；Dehydroactic acid；And sorb Acid.
Odorant agent is rectified as flavoring, it can be mentioned, for example: usually used sweetening material, acid flavoring, fragrance etc. in formulation art.
It can be any colorant for allowing to add in drug as colorant, it can be mentioned, for example: food is No. 5 yellow The edible pigments such as (Sunset Yellow, the food in the U.S. are No. 6 yellow), Food Red 2, food indigo plant 2；Edible color lake pigment, three Aoxidize two iron etc..
In addition, tablet can be also comprising antioxidant as additional additive.Antioxidant can i), ii) and Iii it is added in any process in manufacturing method).For example, in the case where manufacturing method i), can by antioxidant and Other additives carry out compression forming after mixing together with mixture, to manufacture tablet.
As antioxidant, it can be mentioned, for example: nitrite (such as sodium nitrite), sulphite (such as sodium sulfite, Exsiccated sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite), thiosulfate (such as sodium thiosulfate), α-thioglycerol, 1, 3- butanediol, thioacetic acid and its salt (such as sodium thioglycolate), Thiomalate (such as thiomalic acid sodium), thiocarbamide, Thiolactic acid, edetate (such as edetate sodium), dichloroisocyanuric acid salt (such as dichloroisocyanurate), citric acid, half Cystine and its salt (such as cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, arabo-ascorbic acid and its salt (example Such as sodium isoascorbate), ascorbic acid and its ester compounds (such as L-ascorbyl stearate, vitamin-c palmitate Ester), phosphatide (such as soybean lecithin), metal-chelator and its salt (such as ethylenediamine tetra-acetic acid, Ca-EDTA two Sodium, disodium ethylene diamine tetraacetate), tartaric acid and its salt (such as rochelle salt), Polyphenols (such as catechin), glutathione, Dibutyl hydroxy toluene, butylated hydroxyanisole (BHA), propylgallate, natural VE, tocopherol acetate, concentration mixing Tocopherol, tocopherol homologues (such as d- alpha-tocopherol, dl- alpha-tocopherol, 5,8 dimethy tocol, 7,8- bis- Methyltocol, δ-methyltocol, 5,7,8- trimethyl tocotrienols, 5,8- dimethyl tocotrienols, 7,8- Dimethyl tocotrienols, 8-methyl tocotrienol) etc..Wherein, preferably tocopherol acetate, dibutyl hydroxy toluene, day Right vitamin E, dl- alpha-tocopherol, d- alpha-tocopherol, concentration mixed tocopherol, ascorbyl palmitate, L- are anti-bad Hematic acid stearate, butylated hydroxyanisole (BHA), propylgallate, more preferable dl- alpha-tocopherol, dibutyl hydroxy toluene, Butylated hydroxyanisole (BHA), gallic acid, even more preferably dl- alpha-tocopherol.
The usage amount of antioxidant is preferably 0.001~10 parts by weight relative to 100 parts by weight of preparation, further preferably 0.01~1 parts by weight.
The additive of above-mentioned addition of more than two kinds can be used in mixed way with suitable ratio.
Coating additive appropriate is further used and available dragee coatings piece or film coating piece by tablet.As Coating additive can enumerate sugar-coat base, coating agent, enteric film coating base, slow release film coating base etc..
As sugar-coat base, it can be mentioned, for example the sugar such as white sugar, erythrite or sugar alcohols, furthermore, it is possible to be applied in combination selected from cunning It is one kind or two or more in stone, precipitated calcium carbonate, gelatin, Arabic gum, pulullan polysaccharide, Brazil wax etc..
As coating agent, it can be mentioned, for example: ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, Talcum, Brazil wax, paraffin etc..
It is coated base as enteric film, it can be mentioned, for example: hydroxypropyl methylcellulose phthalate, hydroxypropyl first The cellulose-based high scores such as base cellulose-acetate succinate, carboxymethylethylcellulose, Cellacefate Son；Eudragit L100 (EUDRAGIT L (trade name), Evonik Degussa company), methacrylic acid copolymer LD (EUDRAGIT L-30D55 (trade name), Evonik Degussa company), Eudragit S100 (EUDRAGIT S (trade name), Evonik Degussa company) etc. acrylic acid series macromolecule；Natural goods such as shellac etc..
As slow release film coating base, it can be mentioned, for example: the cellulose polymers such as ethyl cellulose；Methacrylic acid Aminoalkyl ester copolymer RS (EUDRAGIT RS (trade name), Evonik Degussa company), ethyl acrylate-methyl-prop The acrylic acid series macromolecules such as e pioic acid methyl ester copolymer soliquoid (EUDRAGIT NE (trade name), Evonik Degussa company)； Cellulose acetate etc..
Above-mentioned coating of more than two kinds can be used in mixed way with additive with suitable ratio.
In order to adjust dissolution rate, it can according to need and water-soluble substances, plasticizer etc. are added in coating additive. As water-soluble substances, can be used selected from glycitols such as the water soluble polymers such as hydroxypropyl methyl cellulose class, mannitol, white The carbohydrates such as sugar, anhydrous maltose, sucrose fatty ester, polyoxyethylene polyoxypropylene glycol, polysorbate, NaLS One or more of equal surfactants etc..As plasticizer, can be used selected from acetylated monoglyceride, triethyl citrate, Glycerol triacetate, dibutyl sebacate, dimethyl sebacate, MCT Oil, CitroflexA-2, In tributyl citrate, tributyl 2-acetylcitrate, dibutyl adipate, oleic acid, olein alcohol (Japanese: オ レ イ ノ ー Le) etc. 1 kind or more.
In addition, can be used as the method for being coated with additive to tablet with above-mentioned coating and forming coatings Conventional method in formulation art, it can be mentioned, for example: pan coating method, fluidized coating method, turnadle pan coating, fluidisation rolling coating Method.Coating solution used in these methods can by by above-mentioned coating additive, talcum and solvent (preferably ethyl alcohol or The mixture of ethyl alcohol and water) it mixes to obtain.The solid component concentration of such coating solution is excellent relative to the weight of coating solution entirety It is selected in the range of 5~15 weight %.
Pharmaceutical composition of the invention it is formulation in, be granulated in addition to can be by the principle recorded in embodiment, device Other than progress, extruding pelletization, broken whole grain, rotating granulation, dry type granulation, wet type high shear granulator and fluidisation can also be passed through Each principle that bed is granulated carries out.
As using extruding pelletization as the prilling granulator of principle, it can be mentioned, for example: Twin Dome Gran, Basket Ryuzer, half dry type/low moisture pelletizer pan-type pelletizer, half dry type/small particle pelletizer fine grained pan-type pelletizer, Pelleter Double (Japanese: ペ レ ッ タ ー ダ Block Le), Basket Ryuzer and Multi Gran (Japanese: マ Le チ グ ラ Application) (the above are Dalton systems)；And KEX extruder and KRC kneader (the above are chestnut, this ironworker is made).
As using broken whole grain as the prilling granulator of principle, it can be mentioned, for example: Power Mill (Dalton system), whole grain Machine Fiore F and Roundel Mill (the above are the DS longevity work it is made)；Without sieve pelletizing machine Nebulasizer (nara machinery system Make made)；QUICK MILL QMY (SEISHIN enterprise system)；Rolling granulators (MATSUBO system)；(the ridge NEW SPEED MILL Field Seiko system)；And (the above are FREWITT companies, Switzerland by MF type pelletizing machine Oscillator and broken pelletizing machine Coni Witt System is sold by EARTHTECHNICA).
As using rotating granulation as the prilling granulator of principle, it can be mentioned, for example: MARUMERIZER (Dalton system)；And Centrifugal fluidization coating granulator CF and GRANUREX GX (the above are FREUND industry systems).
As using dry type granulation as the prilling granulator of principle, it can be mentioned, for example: ROLLER COMPACTOR (FREUND industry System), PHARMAPAKTOR (HOSOKAWA MICRON system), RCP ROLLER COMPACTOR (this ironworker of chestnut is made) and PHARMA COMPACTOR (MATSUBO system).
As using wet type high shear granulator as the prilling granulator of principle, it can be mentioned, for example: SP GRANULATOR and SPARTAN RYUZER (the above are Dalton systems)；VERTICAL GRANULATOR (POWREX system)；GEA AEROMATIC PHARMA Connect (EUROTECHNO system) is used in FIELDER MULTIPROCESSOR research and development；MIXER&GRANULATOR (NMG) (nara machinery production is made)；It is crushed rotary NEW GRA MACHINE SEG (SEISHIN enterprise system)；NEW SPEED KNEADER (ridge field Seiko system)；HIGH SPEED MIXER (ADVANCE series), DYNAMIC DRYER, HIGH FLEX GRAL and MICROWAVE GRANULATOR DRYER (is sold the above are deep river POWTECH system, by EARTHTECHNICA It sells)；And TM type is granulated MIXER (Japanese COKE industry system).
As using fluidized bed prilling as the prilling granulator of principle, it can be mentioned, for example: NEW MARUMERIZER, rotary fluid Bed, micro fluidized bed and SWING PROCESSOR (the above are Dalton systems)；FLOW COATER CONTAINMENT,FLOW COATER Universal, FLOW COATER FLO and SPIR A FLOW SFC (the above are FREUND industry systems)； AGGLOMASTER (HOSOKAWA MICRON system)；GEA AEROMATIC FIELDER FLEX STREAM(EUROTECHNO System)；And SPRUDE (great river original makes institute).
About mixing, other than the principle device recorded in using embodiment carries out, also using convection type, (machinery is stirred Mix formula), diffusion type (container is rotary) and kneading mediate each principle of (Japanese: kneading ニ ー ダ ー) to carry out.
As the mixing arrangement for taking convection type (mechanical agitation type) as principle, it can be mentioned, for example: mixing and blending machine NDM type, Mixing and blending machine XDM type, mixing and blending machine DM type, trial-production research mixing and blending machine AMXDMDM type, use for laboratory are mixed Conjunction blender TWIN MIX, PUG MIXER, ribbon-type blender, (the above are Dalton by SPARTAN MIXER and PASTE MIXER System)；CYCLOMIX and NAUTA MIXER (the above are HOSOKAWA MICRON systems)；Vertical installation MAG-NEO seals mixer (development of MAGNEO skill)；(the above are assistant bamboo chemical machinery industry by bottom surface type SUPERMAG MIXER and S MIXER SUPERMIX System)；JULIA MIXER and ribbon blender (the above are the DS longevity work it is made)；PX MIXER (SEISHIN enterprise system)； LOEDIGE MIXER (MATSUBO system), FM MIXER RC type and MP MIXER (the above are Japanese COKE industry systems)；And RIBOCONE (original production in great river is made).
As the mixing arrangement for taking diffusion type (container is rotary) as principle, it can be mentioned, for example GEA BUCK SYSTEM IBC blender and IBC blender with GEA BUCK SYSTEM NIR measurement device (the above are EUROTECHNO systems)；V-type Mixing machine and Wtypeofblender (the above are the DS longevity work it is made)；V-type blender (nara machinery production is made)；Wtypeofblender SCM and V-Mixer SVM (the above are SEISHIN enterprise systems)；CAPSULE ROCKING MIXER (love knows motor system)；And BOHLE CONTAINER MIXER PM (longevity industry system).
As using kneading kneading as the mixing arrangement of principle, it can be mentioned, for example: continuous kneader and batch type kneader (the above are Dalton systems)；T.K.HIVIS MIX and T.K.HIVIS DISPER MIX (the above are PRIMIX systems)； LEISTRITZ EXTRUDER (nara machinery production is made)；And planetary-type mixer (shallow field ironworker system).
As other mixing arrangements, it can be mentioned, for example: Conti-TDS (Dalton system) and MIXING TORQUE (the above are assistant bamboo chemical machineries by METER ST-3000II PROCESS REACTOR DDL3000 and stirring simulation MixSim Industry system).
Other than above-mentioned each principle, can also using the principles such as flowing stirring-type, formula without mixing and high-shear come Mixing.
Tabletting is carried out based on each principle of the tabletting of one-shot formula and rotary tabletting, from the viewpoint of efficiency, is preferably revolved Rotatable tabletting.
As using rotary tabletting as the preforming device name of principle, other than the preforming device recorded in embodiment, go back It can be mentioned, for example: removable high speed tablet press FITTE (BOSCH PACKAGING TECHNOLOGY system)；High speed tablet press COMPRIMA and high speed tablet press SYNTHESIS (the above are MUTUAL systems)；ROTARY PRESS MZ400(MORI MACHINERY system)；GEA COURTOY MODULE type tablet press machine p-type, S type, D type and GEA PHARMA SYSTEM PERFORMA P (the above are EUROTECHNO systems)；Research and development small rotary formula tablet press machine, the rotary tabletting of miniature high-speed The removable washing rotary tablet machine of machine, medium-sized Highspeedrotarytabletpress, compound Highspeedrotarytabletpress, turntable and CONTAINMENT tablet press machine (the above are the production of chrysanthemum water is made)；And to suppress tablet press machine, CVX type turntable removable for BX type HX type Tablet press machine, the small-sized tablet press machine of X-type AP type, the medium-sized tablet press machine of X-type AP type, AP type large size tablet press machine and the large-scale compound pressure of X-type AP type Piece machine (made as field ironworker Shang).
Single-layer sheet can be obtained by above-mentioned preforming device, such as: GEA COURTOY MODULE type double-layer tablets can be used Tablet press machine D type (EUROTECHNO system) and multilayer tablet press machine (production of chrysanthemum water is made) etc. can manufacture multilayer tablet；Also it can be used Cored tablet press machine (chrysanthemum water production made) and APMS type c-type cored tablet press machine (field ironworker are made) etc. manufacture clad sheet.
Be coated in addition to recorded in embodiment principle, device carry out other than, also using pan coating (horizontal pot), pan coating (inclination pot) and each principle of air suspension formula (fluidized bed) carry out.
As the coating device for taking pan coating (horizontal pot) as principle, it can be mentioned, for example HICOATER FZ, AQUA COATER AQC CONTAINMENT and AQUA COATER AQC (the above are FREUND industry systems).
As the coating device for taking pan coating (inclination pot) as principle, it can be mentioned, for example: POWREX COATER PRC and DRIA COATER DRC (the above are POWREX systems)
As the coating device for taking air suspension formula (fluidized bed) as principle, it can be mentioned, for example GLATT POWDER COATER GPCG SPC, Multiplex and compound fluidized bed SFP (the above are POWREX systems).
As other coating devices, it can be mentioned, for example: Hybridization System (nara machinery production is made) and MECHANO HYBRID (Japanese COKE industry system).
Bone metabolism updates (Japanese: being metabolized back to translocation) Lai Gaishan bone density to pharmaceutical composition of the invention and bone is strong by inhibiting Degree, for that can treat or the treatment or prevention of preventible disease or symptom (such as osteoporosis).
In the present invention, the treatment or prevention of disease or symptom include: the morbidity prevention of the disease；The inhibition for deteriorating or being in progress Or it prevents；It has been inflicted with the mitigation for more than one symptoms that the individual of the disease occurs or inhibits to deteriorate or progress；It is secondary The treatment or prevention etc. of disease.
The administration object of pharmaceutical composition of the invention is mammal.Mammal is preferably people.
Pharmaceutical composition of the invention is delivered medicine into object with the effective quantity on treating or preventing." in treatment or prevention Effective quantity " refers to: the amount for treating or preventing effect is played for specific disease, administration mode and administration route, it can basis Object kind, the type of disease, symptom, gender, age, place disease, other elements suitably determine.Administration route be usually take orally to Medicine.
The dosage of pharmaceutical composition of the invention can according to the type of object, the type of disease, symptom, gender, the age, Place disease, other elements suitably determine, for adult, can be administered daily usually in terms of ED-71 0.01~10 μ g, preferably 0.5~ 0.75μg。
Moreover, it relates to a kind of method of the treatment or prevention for disease or symptom, it includes following step: will A effective amount of pharmaceutical composition of the invention in treatment or prevention delivers medicine to the object for needing to be administered.
" effective quantity in treatment or prevention " in the present invention refers to: for specific disease or symptom, administration mode and Administration route and play treat or prevent effect amount, can according to the type of the type of object, disease or symptom, symptom, gender, Age, place disease, other elements suitably determine.
" object " in the present invention is, for example, mammal, is preferably people.
" administration " in the present invention typically refers to be administered orally.
It as " disease or the symptom " in the present invention, can enumerate: can be by inhibiting bone metabolism to update, improving bone density and bone Intensity is come the disease or symptom (such as osteoporosis) that treat or prevent.
The oil dispersion of II.ED-71
It II-1. include the pharmaceutical composition and its manufacturing method of ED-71
The 2nd aspect of the present invention is related to the oil dispersion of ED-71.In this specification, the oil dispersion of ED-71 refers to Composition made of being scattered in the particle of the fat solution of ED-71 in excipient.
The present invention provides the pharmaceutical composition of the oil dispersion comprising such ED-71.Specifically, providing one kind and including The pharmaceutical composition of ED-71, in excipient or the surface of excipient includes the particle for being wrapped by agent cladding, the cladding Agent includes the water soluble polymer selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose, which includes ED-71's Fat solution.
In addition, the present invention provides the manufacturing method of such pharmaceutical composition.Specifically, a kind of drug comprising ED-71 The manufacturing method of composition, it includes following processes: the water of (i) preparation fat solution comprising ED-71 and water soluble polymer The process of the oil-in-water emulsion of solution；(ii) process for making oil-in-water emulsion adhere to or be adsorbed in excipient；And (iii) make the process that oil-in-water emulsion is dry, wherein above-mentioned water soluble polymer is from hydroxypropyl methyl cellulose and hydroxypropyl It is selected in base cellulose.In this way, forming the particle of the fat solution of ED-71 by water soluble polymer in excipient The state of cladding can manufacture the preparation (especially tablet) for having used the oil dispersion of ED-71.In formulation art, make to wrap The method that fat solution containing effective component is infiltrated in excipient be it is known, still, without using fat solution and use water packet Oil type emulsion and adheres to oil-in-water emulsion or making after being adsorbed in excipient oil-in-water emulsion dry to use The method of the fat-coated solution of ingredient in water layer is previous and is unaware of.
About process (i), grease used in the present invention, can enumerate: MCT Oil (is also remembered below Make " MCT "), tricaprylin, caproic acid, octanoic acid, capric acid, oleic acid, linoleic acid, linolenic acid, vegetable oil etc..Here, as plant Object oil, can enumerate: coconut oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape seed oil, safflower oil Deng.In these, MCT, tricaprylin, caproic acid, octanoic acid or the capric acid of unsaturated fatty acid, particularly preferred MCT are preferably free of.
The concentration of the ED-71 in fat solution in process (i) can be according to the disease or symptom, administration as object The suitably decision such as mode, administration route, for example, 0.001~0.3 weight %, preferably 0.005~0.1 weight %, more preferably For 0.01~0.05 weight %.
Antioxidant can be further added into the fat solution in process (i).As the antioxidant in the present invention, It can be mentioned, for example: nitrite (such as sodium nitrite), sulphite (such as sodium sulfite, exsiccated sodium sulfite, bisulfite Sodium, sodium pyrosulfite), thiosulfate (such as sodium thiosulfate), α-thioglycerol, 1,3 butylene glycol, thioacetic acid and Its salt (such as sodium thioglycolate), Thiomalate (such as thiomalic acid sodium), thiocarbamide, thiolactic acid, edetate (example Such as edetate sodium), dichloroisocyanuric acid salt (such as dichloroisocyanurate), citric acid, cysteine and its salt (such as half Guang Propylhomoserin hydrochloride), it is benzotriazole, 2-mercaptobenzimidazole, arabo-ascorbic acid and its salt (such as sodium isoascorbate), anti-bad Hematic acid and its ester compounds (such as L-ascorbyl stearate, ascorbyl palmitate), phosphatide (such as soybean lecithin Rouge), metal-chelator and its salt (such as ethylenediamine tetra-acetic acid, calcium disodium edathamil, disodium ethylene diamine tetraacetate), wine Stone acid and its salt (such as rochelle salt), Polyphenols (such as catechin), glutathione, dibutyl hydroxy toluene, butylhydroxy Methyl phenyl ethers anisole, propylgallate, natural VE, tocopherol acetate, concentration mixed tocopherol, tocopherol homologues (such as D- alpha-tocopherol, dl- alpha-tocopherol, 5,8 dimethy tocol, 7,8- dimethyl tocol, δ-methyltocol, 5,7,8- trimethyl tocotrienols, 5,8- dimethyl tocotrienols, 7,8- dimethyl tocotrienols, 8- methyl are raw Educate trienol) etc..Wherein, preferably tocopherol acetate, dibutyl hydroxy toluene, natural VE, dl- alpha-tocopherol, D- alpha-tocopherol, concentration mixed tocopherol, ascorbyl palmitate, L-ascorbyl stearate, butylhydroxy benzene first Ether, propylgallate, more preferable dl- alpha-tocopherol, dibutyl hydroxy toluene, butylated hydroxyanisole (BHA) or gallic acid, Even more preferably dl- alpha-tocopherol or dibutyl hydroxy toluene.
The additive amount of antioxidant in fat solution is not particularly limited, and antioxidant, which usually can be used, to be used Research on maximum utilized quantity amount below (such as drug additive topical reference book (Yao Shi newspaper office, 2000) in record preparatory approval example most Below big dosage, below the middle use limit amount recorded of food additives statutory document (japanese food additive association, 1999) Amount etc.).
In preferred embodiment, dl- alpha-tocopherol with 0.01 weight % or more (such as 1 weight % or more) and 10 weight % with Under the concentration of (such as 5 weight % or less) make an addition in fat solution.About dibutyl hydroxy toluene, butylated hydroxyanisole (BHA), The additive amount of propylgallate etc. is also identical as above-mentioned dl- alpha-tocopherol.
Covering used in the present invention includes water soluble polymer.Water soluble polymer from hydroxypropyl methyl cellulose and It is selected in hydroxypropyl cellulose.When being added with more additive in the fat solution of ED-71, the stability of ED-71 can be made Decline, but hydroxypropyl methyl cellulose and hydroxypropyl cellulose will not be such that the stability of ED-71 declines.In addition, using hydroxypropyl In the case where ylmethyl cellulose and hydroxypropyl cellulose, the emulsified state of oil-in-water emulsion can be maintained for a long time.
Wherein, the stability of ED-71 does not decline this point and can be confirmed as follows in pharmaceutical composition of the invention: You Benfa Bright pharmaceutical composition manufactures tablet, carries out investigating the remaining of ED-71 after shading saves 1,3 or 6 months at 40 DEG C to it Rate, to be confirmed.About the survival rate of ED-71, with high performance liquid chromatography (measurement wavelength 265nm) to preservation sample ED-71 is measured with initial samples and as the precursor (chemical name: 6Z- (1R, 2R, 3R) -2- (3- hydroxyl third of its isomers Oxygroup) -9,10- open loop cholesteric -5 (10), 6,8 (9)-triolefin -1,3,25- triol；Pre is also referred to as in this specification ED-71 peak area) calculates the survival rate of ED-71 by calculating formula below.
The content of ED-71 is relative to the ratio between mark amount (%)=(amount of weighing of ED-71 standard items/ED-71 standard items In ED-71 peak area it is total) × initial samples or save ED-71 peak area in sample it is total × (initial samples or guarantor Deposit the weight of sample used in sample total weight/measurement)/mark amount × 100
The peak area of ED-71+1.98 × pre of peak area ED-71 (ED-71 peak area is total=)
The content of ED-71 in the survival rate (%) of ED-71=preservation sample is relative to the ratio between mark amount (%)/initial The content of ED-71 in sample is relative to the ratio between mark amount (%) × 100
It should be noted that the meaning of each term in above-mentioned formula is as follows.
" mark amount ": every 1 theoretical content
" ED-71 standard items ": the raw medicine of ED-71
" the ED-71 peak area in the amount of weighing of ED-71 standard items/ED-71 standard items is total ": per unit peak face The weight (value for the content by the ED-71 in calculated by peak area measurement sample) of long-pending ED-71 standard items
Hydroxypropyl methyl cellulose and hydroxypropyl cellulose are acceptable grade on preparation.
Hydroxypropyl methyl cellulose in the present invention can for example be bought with trade name TC-5 from SHIN-ETSU HANTOTAI's chemical industry.
In addition, in the present invention, hydroxypropyl cellulose (HPC) refers to: drug additive topical reference book 2016 (is compiled: Japanese medicine Product additive association；Distribution: (strain) Yao Shi newspaper office；ISBN978-4-8408-1329-7 in), with constitution number 002303 hydroxypropyl cellulose recorded is and the low-substituted hydroxypropyl cellulose that is recorded in the topical reference book with constitution number 002440 Different substances.For the hydroxypropyl cellulose used in the present invention, molar substitution (MS) (indicates the repetitive unit of HPC The ratio that the hydroxyl of (glucose ring) is replaced by hydroxy propyloxy group) it is usually 2~3, preferably 2.5~3, more preferably 3.It is another Aspect, the molar substitution of low-substituted hydroxypropyl cellulose are 0.2~0.4.Hydroxypropyl cellulose in the present invention for example can be with It is bought with trade name Klucel from ISP JAPAN and purchase is reached from Japanese Cao with trade name HYDROXYPROPYL CELLULOSE It buys.
Covering in the present invention may include the additive other than water soluble polymer, such as may include stabilizer, anti- Oxidant.
The concentration of the water soluble polymer in aqueous solution in process (i) suitably determines according to the amount of ED-71, for example, 1 ~15 weight %, preferably 2~10 weight %, more preferably 3~6 weight %, more preferably 4~6 weight %, it is further more excellent It is selected as 5~6 weight %.Aqueous solution in process (i) may include the additive other than water soluble polymer, such as may include steady Determine agent, antioxidant.
Oil-in-water emulsion can be prepared by commonly used approach in formulation art, preferably pass through machinery emulsification Method preparation.For machinery emulsification method it can be mentioned, for example the method for using following device, described device has chemi-stirrer, vortex mixing Device, homogenizer, HYDROSHEAR, colloid mill, fluid injection-type mixer, supersonic generator, uses glass at homogeneous mixer The wet crushing mill of pearl, the film mulser using perforated membrane, electronic emulsifier unit using electric energy etc..It, can be with as homogenizer It uses such as T-50Ultra Turrax (IKA system).
The ratio (weight ratio, o/w ratio) of the aqueous solution of the fat solution and water soluble polymer of ED-71 is as long as can be with In the range of preparing oil-in-water emulsion, usually 1:1.5~1:20, preferably 1:2~1:20 or 1:2~1:4.It is excellent It selects in mode, when the concentration of the water soluble polymer in the aqueous solution of water soluble polymer is 3~6 weight %, 4~6 weight % Or when 5~6 weight %, the ratio of the aqueous solution of the fat solution and water soluble polymer of ED-71 is 1:1.5~1:20,1:2 ~1:20 or 1:2~1:4.
In addition, the fat solution of ED-71 and the ratio (weight ratio) of water soluble polymer as long as ED-71 can be formed Fat solution the range of state that is coated by water soluble polymer of particle, usually 1:0.05~1:10, preferably 1:0.1~1:1 or 1:0.1~1:0.3.In preferred embodiment, when the water soluble polymer in the aqueous solution of water soluble polymer When concentration is 3~6 weight %, 4~6 weight % or 5~6 weight %, the fat solution of ED-71 and the ratio of water soluble polymer Rate (weight ratio) is 1:0.05~1:10,1:0.1~1:1 or 1:0.1~1:0.3.
The particle is preferably spherical.Its partial size is usually 0.01~100 μm, and preferably 0.1~10 μm.
About process (ii), excipient used in the present invention, it can be mentioned, for example cornstarch, potato starch, The starch such as wheaten starch, rice starch, part pre-gelatinized starch, pre-gelatinized starch, porous-starch；Lactis Anhydrous, lactose water Close the sugar such as object, fructose, glucose, mannitol, D-sorbite, erythrite or glycitols；Calcium phosphate dibasic anhydrous；Avicel cellulose； Precipitated calcium carbonate；Calcium silicates etc., preferably sugar or glycitols, further preferably mannitol, Lactis Anhydrous, lactose hydrous, Further preferably mannitol.
The ratio (weight ratio) of oil-in-water emulsion used in process (ii) and excipient can be according to the kind of excipient Class etc. and change, usually 1:1~1:100, the preferably range of 1:4~1:20.Especially when excipient is mannitol, such as Fruit weight ratio then available preferred pelletizing that can be used for manufacturing the preparations such as tablet in the range of common 1:4~1:20 End.
Attachment from oil-in-water emulsion to excipient or absorption can by commonly used approach in formulation art into Row, it can be mentioned, for example: while be sprayed method that emulsified liquid side is granulated to excipient, addition emulsion and being mixed into excipient The method etc. of stirring.Such method can be used such as high-speed stirred pelletizer (POWREX VG-600CT), be mixed Machine (product river industry made DM type) etc. carries out.It should be noted that attachment or absorption also include infiltration (in porous figuration In the case where agent, infiltrate oil-in-water emulsion to hole).
It is the oil-in-water emulsion for adhering to or be adsorbed in excipient is dry, it is believed that thus from water solubility in process (iii) High molecular aqueous solution removes water, forms the particle that fat solution is directly coated by water soluble polymer.The obtained oil Granular media includes the particle of the fat solution containing ED-71, for showing good manufacturing when manufacturing the preparations such as tablet (such as mobility, compact property).
The drying of oil-in-water emulsion can be carried out by commonly used approach in formulation art, can enumerate example Such as: fluidized drying, ventilation drying, spray drying, standing and drying, stirs drying, is pneumatic conveying drying, vacuum drying, micro- at freeze-drying Wave drying, infrared ray/far infrared drying etc..In addition, drying can carry out together with being heated or cooled.It can be used and for example flow Change bed granulating and drying machine (POWREX WSG-200pro), vacuum drier (Japan dry mechanism Conical Dryer) etc. into Row drying.
The oral preparations such as tablet, capsule, granule, powder can be made in pharmaceutical composition of the invention.These are oral Preparation can be manufactured by method used in formulation art.For example, the manufacturing method as tablet, can enumerate below I), ii) and method iii).
I) after the oil dispersion of ED-71 and additional additive (excipient, disintegrating agent, lubricant etc.) being mixed together, Compression forming is carried out, to manufacture tablet.
Ii after) oil dispersion of ED-71 is mixed with additional additive (excipient, bonding agent etc.), Bian Tianjia or spray Mist solvent (such as purified water, ethyl alcohol or its mixed liquor) side is granulated.Suitable lubricant, root are added into obtained granules After disintegrating agent according to needs etc. and mixing, compression forming is carried out, to manufacture tablet.
Iii after) mixing the oil dispersion of ED-71 with additional additive (excipient etc.), Bian Tianjia or spraying will knot Mixture and other additives as needed are dispersed or dissolved in obtained from solvent (such as purified water, ethyl alcohol or its mixed liquor) Liquid, while being granulated.After suitable lubricant, disintegrating agent as needed etc. are added into obtained granules and mixes, Compression forming is carried out, to manufacture tablet.
It, can be respectively using for example for improving surfactant, the pH of the release property of drug as additional additive Regulator, the fluidizing reagent for improveing the mobility in process, the stabilizer for improving stability, for increasing taste or gas The flavoring of taste rectifys odorant agent, the colorant for increasing color.
In addition, tablet can be also comprising antioxidant as additional additive.Antioxidant can i), ii) and Iii it is added in any process in manufacturing method).For example, in the case where manufacturing method i), can by antioxidant and Other additives carry out compression forming after mixing together with oil dispersion, to manufacture tablet.Furthermore it is also possible to manufacture piece as follows Agent: oil dispersion is prepared using the fat solution of the ED-71 in advance dissolved with antioxidant, it is mixed with other additives Afterwards, compression forming is carried out, to manufacture tablet.
Excipient, disintegrating agent, bonding agent, lubricant, surfactant, pH adjusting agent, fluidizing reagent, stabilizer, flavoring are rectified Each substance recorded in above-mentioned I-2 can be used in odorant agent and colorant.In addition, above-mentioned antioxygen can be used in antioxidant Agent.
The additive of two or more above-mentioned additions can be used in mixed way with suitable ratio.
Coating additive appropriate is further used and available dragee coatings piece or film coating piece by tablet.Coating The substance recorded in above-mentioned I-2 can be used with additive.In preferred embodiment, pharmaceutical composition of the invention is by HPMC The coating tablet of film coating.
Granulation, mixing, tabletting in the manufacture of pharmaceutical composition of the invention and coating in above-mentioned I-2 by recording Principle device carries out.
Pharmaceutical composition of the invention improves bone density and bone strength by inhibiting bone metabolism more to newly arrive, for that can control Treatment or the treatment or prevention of preventible disease or symptom (such as osteoporosis).
In the present invention, the treatment or prevention of disease or symptom include: the morbidity prevention of the disease；The inhibition for deteriorating or being in progress Or it prevents；It has been inflicted with the mitigation for more than one symptoms that the individual of the disease occurs or inhibits to deteriorate or progress；It is secondary The treatment or prevention etc. of disease.
The administration object of pharmaceutical composition of the invention is mammal.Mammal is preferably people.
Pharmaceutical composition of the invention is delivered medicine into object with the effective quantity on treating or preventing." in treatment or prevention Effective quantity " refers to: the amount for treating or preventing effect is played for specific disease, administration mode and administration route, it can basis Object kind, the type of disease, symptom, gender, age, place disease, other elements suitably determine.Administration route be usually take orally to Medicine.
The dosage of pharmaceutical composition of the invention can according to the type of object, the type of disease, symptom, gender, the age, Place disease, other elements suitably determine, for adult, can be administered daily usually in terms of ED-71 0.01~10 μ g, preferably 0.5~ 0.75μg。
Moreover, it relates to a kind of method of the treatment or prevention for disease or symptom, it includes following step: will A effective amount of pharmaceutical composition of the invention in treatment or prevention delivers medicine to the object for needing to be administered.
" effective quantity in treatment or prevention " in the present invention refers to: for specific disease or symptom, administration mode and Administration route and play treat or prevent effect amount, can according to the type of the type of object, disease or symptom, symptom, gender, Age, place disease, other elements suitably determine.
" object " in the present invention is, for example, mammal, is preferably people.
" administration " in the present invention typically refers to be administered orally.
It as " disease or the symptom " in the present invention, can enumerate: can be by inhibiting bone metabolism to update, improving bone density and bone Intensity is come the disease or symptom (such as osteoporosis) that treat or prevent.
II-2. inhibit the method for the decomposition of ED-71
The present invention also provides a kind of methods of decomposition for inhibiting ED-71, and it includes following processes: preparation includes ED-71 Fat solution and water soluble polymer aqueous solution oil-in-water emulsion process, wherein above-mentioned water soluble polymer It is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
The oil-in-water type cream of the aqueous solution of in the present invention, fat solution of the preparation comprising ED-71 and water soluble polymer The process (i) changed in the manufacturing method for the pharmaceutical composition comprising ED-71 recorded in the process and above-mentioned II-1 of liquid is identical. Think that the fat solution of ED-71 becomes the state covered by water soluble polymer in oil-in-water emulsion.It can not drop The oil dispersion of manufacture ED-71, the pharmaceutical composition object space using it in the state of the stability of ED-71 in Low grease solution Face, this method are useful.
It should be noted that all existing technical literatures quoted in this specification are integrated into this theory by referring to mode In bright book.
Illustrate the present invention in further detail by embodiment.
Embodiment
Following abbreviation is used in the present embodiment.
EtOH: ethyl alcohol
HPMC: hydroxypropyl methyl cellulose
THF: tetrahydrofuran
BHT: dibutyl hydroxy toluene
MCT: MCT Oil
HPC: hydroxypropyl cellulose
PVP: polyvinylpyrrolidone
PVA copolymer (PVA copolymer): polyvinyl alcohol-acryl acid-methyl methacrylate copolymer
A. solid dispersions
Reference example A1~A3
ED-71 is dissolved in EtOH (ethyl alcohol (99.5) special grade chemical, modern saliva pharmaceutical industries) and prepares EtOH solution (0.1mg/mL).Its 100 μ L is dispensed into glass tube, solvent is distilled off under decompression, obtains dry ED-71.By its list Solely (reference examples A1) is put into aluminium bag and shading in the presence of atmosphere, or in deoxidier (PHARMAKEEP KD-20, Mitsubishi Aerochemistry) in the presence of (reference example A1) or (silica gel (middle graininess (blue) and Wako Pure Chemical Industries system) exists in hygroscopic agent Under (reference example A2) or the condition of (reference example A3) is put into aluminium bag in the presence of atmosphere in the presence of deoxidier and hygroscopic agent Simultaneously shading, saves in the thermostat for being adjusted to 60 DEG C, investigates ED-71 after 7 days and after 14 days in (Lamizip, AS ONE) Survival rate (%).
The survival rate of ED-71 measures by the following method.
To equipped with ED-71 above-mentioned glass tube in dispense 100 μ L of EtOH and 400 μ L of acetonitrile, will by pipetting into The liquid stirred gone as sample solution.Separately, used ED-71EtOH solution (0.1mg/mL) when sample will be prepared 100 μ L are dispensed into sky glass tube, and 400 μ L of acetonitrile is added, and the liquid stirred by pipetting is molten as standard Liquid.Sample solution and standard solution are surveyed with high performance liquid chromatography (Waters Alliance, measurement wavelength 265nm) It is fixed, find out the ED-71 peak area of sample solution and the peak area of pre ED-71.
The survival rate of ED-71 is found out by calculating formula below.
The survival rate (%)=accelerating the ED-71 peak area in sample solution total/of ED-71 does not accelerate in sample solution ED-71 peak area it is total
The peak area of ED-71+1.98 × pre of peak area ED-71 (ED-71 peak area is total=)
Show the result in A1 table.A1 table shows: the reason of ED-71 is decomposed is oxygen, in the presence of deoxidier, ED-71 Being stabilized.
[table 1]
A1 table
Embodiment A1
The ED-71 of 15mg is dissolved in the EtOH (HPLC grades and Wako Pure Chemical Industries) of 100mL.It is weighed into sample container As water soluble polymer HPMC (TC-5R, SHIN-ETSU HANTOTAI's chemical industry) 375mg and make it dissolve 70v/v%EtOH in 10mL (water and EtOH are mixed with volume ratio 30:70), to prepare additive solution.By 20 μ L of ED-71 ethanol solution and add Add 80 μ L of agent solution to mix in 1mL glass tube, then, solvent is distilled off under decompression, it is dry, to obtain embodiment A1's Composition.The composition is arranged on 96 hole pipe supports together with pipe, aluminium bag and shading are put into the presence of atmosphere, is being adjusted To save in 60 DEG C of thermostats, the survival rate of ED-71 is investigated after 7 days and after 14 days.
Additive solution is replaced using 70v/v%EtOH, is prepared as reference examples A2 with embodiment A1 in addition to this, with Embodiment A1 similarly investigates the survival rate of ED-71.
Show the result in A2 table.By A2 table it is found that under the high temperature conditions, compared with when ED-71 is independent, HPMC is deposited It is more stable in lower ED-71.
[table 2]
A2 table
Embodiment A2~A6
The HPMC that embodiment A1 is replaced using the water soluble polymer recorded in A3 table, by same as embodiment A1 Method manufactures ED-71 composition, and the stability at 60 DEG C is investigated in the same manner as embodiment A1, is compared with reference examples A2.It will As a result it is shown in A3 table.Show that the composition of embodiment A2~A6 is stablized than reference examples A2 under the high temperature conditions.
[table 3]
A3 table
Embodiment A7~A19
The 70v/v%EtOH of embodiment A1 is replaced using EtOH, in addition using water soluble polymer generation shown in A4 table For HPMC, the ED-71 composition of embodiment A7~A19 is obtained by method same as embodiment A1.In addition, and reference examples A2 is prepared as the reference examples A3 without water soluble polymer.The ED-71 in these samples is investigated in the same manner as embodiment A1 60 DEG C at stability.Show the result in A4 table.Show that the composition of embodiment A7~A19 compares under the high temperature conditions According to stabilization.
[table 4-1]
A4 table
[table 4-2]
Embodiment A20~A28
The 70v/v% of embodiment A1 is replaced using 50v/v%EtOH (mixing water and EtOH with volume ratio 50:50) In addition EtOH replaces HPMC using water soluble polymer shown in A5 table, obtains reality by method same as embodiment A1 Apply the ED-71 composition of an A20~A28.In addition, being prepared as the reference examples without water soluble polymer with reference examples A2 A4.The stability at 60 DEG C of the ED-71 in these samples is investigated in the same manner as embodiment A1.Show the result in A5 table.Table The composition of bright embodiment A7~A19 is stablized than control under the high temperature conditions.
[table 5]
A5 table
Embodiment A29
The 70v/v%EtOH of embodiment A1 is replaced using THF (HPLC grades and Wako Pure Chemical Industries), in addition uses lecithin Powder (chemistry with, NACALAI TESQUE) replaces HPMC, obtains embodiment A29's by method same as embodiment A1 ED-71 composition.In addition, being prepared as the reference examples A5 without water soluble polymer with reference examples A2.It is same with embodiment A1 Stability at 60 DEG C of ED-71 in these samples of sample-plot survey.Show the result in A6 table.Show the group of embodiment A29 Object is closed to stablize than control under the high temperature conditions.
[table 6]
A6 table
Embodiment A30 and A31
The HPMC that embodiment A1 is replaced using alkali compounds shown in A7 table, passes through method same as embodiment A1 Obtain the ED-71 composition of embodiment A30 and A31.The 60 of prepared ED-71 composition are investigated in the same manner as embodiment A1 Stability at DEG C is compared with reference examples A2.Show the result in A7 table.Show that the composition of embodiment A30 and A31 exist Stablize than control under hot conditions.
[table 7]
A7 table
Embodiment A32
The 70v/v%EtOH that embodiment A1 is replaced using 50v/v%EtOH, in addition used as the burnt phosphorus of alkali compounds Sour four potassium (food additive grade, peaceful Chemical Industries) replace HPMC, obtain embodiment by method same as embodiment A1 The ED-71 composition of A32.The stability at 60 DEG C of prepared ED-71 composition is investigated in the same manner as embodiment A1, with Reference examples A4 is compared.Show the result in A8 table.Show that the composition of embodiment A32 is more steady than compareing under the high temperature conditions It is fixed.
[table 8]
A8 table
Embodiment A33~A38
The ED-71 of 15mg is dissolved in the EtOH (HPLC grades and Wako Pure Chemical Industries) of 100mL, so that preparation is dissolved with The EtOH solution of ED-71.Weigh the hydroxypropyl methyl cellulose (TC- as water soluble polymer respectively into sample container 5R, SHIN-ETSU HANTOTAI's chemical industry), as meglumine (Merck) each 750mg of alkali compounds, make it dissolve the 70v/v% in 20mL EtOH (is mixed water and EtOH with volume ratio 30:70), according to the concentration for reaching 37.5mg/mL~0.0375mg/mL Mode dilutes respectively, to prepare additive solution.Reach the side of A9 table according to the ratio between ED-71 raw medicine amount and additive capacity The EtOH solution for being dissolved with ED-71 and additive solution are dispensed into centrifuge tube by formula, so that preparation is dissolved with ED-71's Additive solution.By the prepared additive solution dissolved with ED-71 according in such a way that ED-71 raw medicine amount is calculated as 3 μ g Be dispensed into 1mL glass tube respectively, then, solvent be distilled off under decompression, be dried in vacuo, obtain composition (embodiment A33~ A38).The composition is arranged on 96 hole pipe supports together with pipe, simultaneously shading is put into aluminium bag in the presence of atmosphere, is being adjusted To save in 60 DEG C of thermostats, the survival rate of ED-71 is investigated after 7 days.It should be noted that being asked by calculating formula below The survival rate of ED-71 out.
The survival rate (%)=accelerating the ED-71 peak area in sample total/of ED-71 does not accelerate the ED-71 in sample Peak area is total the peak area of ED-71+1.98 × pre of peak area ED-71 (ED-71 peak area is total=)
In addition, the EtOH solution dissolved with ED-71 prepared by unused additive solution is according to ED-71 raw medicine The mode that amount is calculated as 3 μ g is dispensed into respectively in 1mL glass tube, then, solvent is distilled off under decompression, is dried in vacuo, to make Standby composition (reference examples A6), investigates the survival rate of ED-71 in the same manner as embodiment A33~A38.
Show the result in A10 table.By A10 table it is found that under the high temperature conditions, even if being arbitrary adding proportion, ED-71 and hydroxypropyl methyl cellulose or meglumine coexist it is lower than it is independent when stablize.In addition, it is seen that the addition ratio of additive Example more high, ED-71 survival rate more the tendency improved.
Embodiment A39~A41
The 70v/v%EtOH of embodiment A33~A38 is replaced using EtOH, in addition used as the poly- of water soluble polymer Vinyl pyrrolidone (K-30, BASF) as additive with replace hydroxypropyl methyl cellulose or meglumine, by with implementation The identical method of example A33~A38 obtains ED-71 composition (embodiment A39~A41).It is adjusted in the same manner as embodiment A33~A38 Look into the stability at 60 DEG C of the ED-71 in these samples.Show the result in A11 table.Under the high temperature conditions, even appoint Anticipate adding proportion, when ED-71 and polyvinylpyrrolidone coexist than it is independent when stablize.In addition, it is seen that the addition of additive The ratio the high, ED-71 survival rate more the tendency improved.
[table 9]
A9 table
[table 10]
A10 table
[table 11]
A11 table
B. oil dispersion
Embodiment B1: formula variation 1
The ED-71 of 50mg is dissolved in the EtOH of 2.5mL, to prepare the ethyl alcohol lysate of ED-71.By BHT (Merck) 1g and dl- alpha-tocopherol (special with and Wako Pure Chemical Industries) 2g is dissolved in the MCT of 97g (O.D.O.C, day is clear Oillio in), to prepare MCT liquid.The ethyl alcohol lysate 0.5mL of ED-71 is added into the MCT liquid of preparation, uses vortex mixing Device stirring.It is further distilled off under reduced pressure, to prepare ED-71 fat solution.To prepared ED-71 grease Hydroxypropyl methyl cellulose 300mg is added in solution 150mg, to prepare ED-71 composition (embodiment B1).By preparation ED-71 composition saves in the presence of atmosphere in the thermostat for being adjusted to 60 DEG C, investigates ED-71 after 14 days and after 28 days Survival rate (%).
As reference material, use above-mentioned ED-71 fat solution itself (reference examples B1).
In addition, replacing the hydroxypropyl methyl cellulose of embodiment B1 using the additive (300mg) recorded in B1 table, lead to Method manufacture ED-71 composition identical with embodiment B1 is crossed, the stability at 60 DEG C is investigated in the same manner as embodiment B1.
Show the result in B1 table.By B1 table it is found that the grease liquid itself of the composition of embodiment B1 and reference examples B1 Equi-stable is more stable, in addition, compared with the composition of reference examples B2~B34, it is stable under the high temperature conditions.
[table 12-1]
B1 table
[table 12-2]
[table 12-3]
Embodiment B2: formula variation 2
Using the additive recorded in B2 table replace embodiment B1 hydroxypropyl methyl cellulose, by with embodiment B1 The ED-71 composition of identical method manufacture embodiment B2 and reference examples B35, is investigated in the same manner as embodiment B1 at 60 DEG C Stability is compared with reference examples B1.Show the result in B2 table.Show: the composition of embodiment B2 and reference examples B1 are same Deng stable or more stable, in addition, compared with the composition of reference examples B2~B34 shown in the B1 table, it is more steady under the high temperature conditions It is fixed.It should be noted that the composition of reference examples B35 has no the stability decline of ED-71, but distinguish: due to using Portugal's first The reasons such as required emulsified state in the manufacturing process of aftermentioned oil dispersion tablet cannot be maintained when amine is as additive, Therefore meglumine is not suitable as the additive for manufacturing oil dispersion tablet.
[table 13]
B2 table
The test of [test example] emulsion stabilization
As described later, need to maintain the MCT solution and high water solubility of ED-71 during manufacturing oil dispersion tablet The emulsified state of the aqueous solution of molecule.Therefore, the emulsion of MCT and water soluble polymer is prepared, and investigates emulsified state.
By HPMC (TC-5R, SHIN-ETSU HANTOTAI chemistry), HPC (SSL, SHIN-ETSU HANTOTAI's chemistry), PVP (K90, BASF), POVA-COAT (F, Datong District's chemical conversion industry system) it is dissolved in purified water, 2% and 5% aqueous solution is prepared respectively.Each liquid 20mL is added separately to plastics The 50mL centrifuge tube of system.It is added thereto with 0.1g/L dissolution oil red (oil red O, NACALAI TESQUE) and is colored as red Each 10mL of MCT Oil.
With homogenizer with about 10,000rpm stirring 1 minute and make its emulsify after, determine 2 hours after and after 24 hours whether there is or not Oil reservoir is separated to the top of emulsion.
Show the result in B3 table.In addition, the centrifugation behind 24 hours when by 2% aqueous solution for using water soluble polymer Emulsified state (photo) in pipe is shown in Fig. 2.Water layer and oil reservoir do not separate in the case where HPMC, HPC and PVA copolymer, In contrast, being separated in the case where PVP.
[table 14]
B3 table
: do not occur separation ,+: separated
Stability of the embodiment B3~B11:ED-71 when preparing lotion
The ED-71 of 100mg is dissolved in the EtOH of 5.0mL, to prepare the ethyl alcohol lysate of ED-71.By BHT (Merck) 1g and dl- alpha-tocopherol (special with and Wako Pure Chemical Industries) 2g is dissolved in the MCT of 97g (O.D.O.C, day is clear Oillio in), to prepare MCT liquid.The ethyl alcohol lysate 0.5mL of ED-71 is added into the MCT liquid of preparation, uses vortex mixing Device stirring, is made the MCT liquid dissolved with ED-71.Water-soluble polymer solution shown in B4 table is prepared respectively.According to B5 The ratio recorded in table mixes the MCT liquid for being dissolved with ED-71 and water-soluble polymer solution, is stirred with homogenizer with 5400rpm It mixes 1 minute and makes its emulsification, thus lotion of the preparation containing ED-71.According to the amount amount for being calculated as about 1 μ g with ED-71 raw medicine amount The prepared lotion containing ED-71 is taken, carries out vacuum distillation removing with vacuum drier, obtained sample is used for residual Deposit rate measurement (embodiment B3~B11).Sample is saved in the presence of atmosphere in the thermostat for being adjusted to 60 DEG C, investigates just system The content value and survival rate (%) of ED-71 content value after standby, the ED-71 after 14 days and after 25 days.It should be noted that pressing The MCT liquid for being dissolved with ED-71 is measured according to the amount for being calculated as about 1 μ g with ED-71 raw medicine amount, is evaporated under reduced pressure with vacuum drier It removes, using resulting sample as standard items, calculates each content value.The content value and survival rate of ED-71 passes through calculating below Formula is found out.
ED-71 peak area in content value (%)=sample of ED-71 is total/standard items in ED-71 peak area close The meter peak area of ED-71+1.98 × pre of peak area ED-71 (ED-71 peak area is total=)
The survival rate (%) of ED-71=acceleration sample content value is average/and the content value of sample immediately after preparation is average
Show the result in B5 table.By B5 table it is found that the low formula of the concentration of water soluble polymer (1%) the case where Under, the deviation of the content value of ED-71 is big.It is considered that the reason is that with regard to the low formula of the concentration of water soluble polymer and It says, the separation of visible lotion after preparation, the visible deviation of the amount of weighing of the ED-71 in the lotion of sampling.With regard to water soluble polymer Concentration be 5% or 6% sample for, the deviation of result is small, and the ED-71 survival rate after 25 days be illustrated as 95% with On.For the highly concentrated formula (10% or 15%) of water soluble polymer, though the ED- of the sample after deviation small 25 days 71 survival rates drop to 90% or so.
The concentration of water-soluble polymer solution as HPMC or HPC containing 1%~15%, in order to make ED-71 in cream Stabilized in liquid and preferably 5~6%.
[table 15]
B4 table
[table 16]
B5 table
* water soluble polymer adding proportion=water-soluble polymer solution (g)/MCT liquid (g) dissolved with ED-71
[Production Example] oil dispersion tablet
Dl- alpha-tocopherol (and Wako Pure Chemical Industries) 0.142kg and BHT (Merck) 0.284kg is dissolved in MCT, and (day is clear Oillio ethyl alcohol (99.5%) (the modern saliva drug work of Chinese mugwort ground ostelin (ED-71) 1.1813g is added in) 9.025kg thereto Industry) (0.078kg) solution, ethyl alcohol (solution 1) is then distilled off under reduced pressure.
Hydroxypropyl methylcellulose (HPMC) (TC-5R, SHIN-ETSU HANTOTAI's chemical industry) 1.134kg is dissolved in purified water 17.766kg (solution 2).
The solution 2 of 6kg is added into the solution 1 of 3kg, with homogenizer (IKA T-50Ultra Turrax；Revolving speed 9, 600rpm) stir 10 minutes.The operation is repeated 3 times, emulsion is obtained.
It will be granulated on one side for mannitol (Merck) 165.6kg after 850 μm of vibrating screen sieving in high-speed stirred with mesh It is stirred under conditions of blade 56rpm, intersection screw rod 1500rpm in machine (POWREX VG-600CT), on one side spraying addition cream Change liquid, stirs 15 minutes, obtain prilling powder.
Wet type pelletizing machine (POWREX U-20) operating one for being equipped with 9.5mm (square hole) sieve is made with 300rpm on one side While obtained prilling powder is sieved, and prilling powder is transferred to fluidized-bed granulation dryer (POWREX WSG- 200pro), it is dried.
For the prilling powder after drying, the dry type pelletizing machine (POWREX for the sieve for being equipped with diameter 2mm is made with 800rpm U-20 processed) operating, carry out whole grain.
By whole grain product and respectively with the mannitol 3.0kg and cross-linked carboxymethyl cellulose after 850 μm of mesh of sieved sieve The mixture of sodium (DFE pharma) 3.6kg mixes 15 minutes, then with use the mannitol after 850 μm of mesh of sieved sieve respectively 6.6kg is mixed 3 minutes with the mixture of calcium stearate (Merck) 0.72kg, then with tablet press machine (IMA COMPRIMA) with about The pressure tabletting of 7.5kN and tablet is made.When tabletting, alcohol content of ossify by every 1 Chinese mugwort is adjusted in the way of being 0.75 μ g Whole tablet weight.
Obtained tablet is all put into seed-coating machine (POWREX PRC-450), the spraying HPMC at 60 DEG C Water (74.520kg) solution of 6.480kg, dry, further hydroxypropyl methylcellulose 4.950kg, talcum (Merck) by spraying The water (65.167kg) of 1.350kg, titanium oxide (stone originates in industry) 2.664kg and di-iron trioxide (chemical conversion of the sixth of the twelve Earthly Branches in the last of the ten Heavenly stems) 0.036kg are outstanding Supernatant liquid, it is dry, obtain tablet made of being coated with 2 tunics (alcohol content of ossify to every 1 Chinese mugwort is 0.75 μ g).
It should be noted that the 2nd layer is spraying hydroxyl when ossify tablet that alcohol content is 0.5 μ g with preparing every 1 Chinese mugwort Third methylcellulose 4.950kg, talcum (Merck) 1.350kg, titanium oxide (stone originates in industry) 2.502kg, di-iron trioxide (the sixth of the twelve Earthly Branches in the last of the ten Heavenly stems Chemical conversion) 0.018kg and Yellow ferric oxide (chemical conversion of the sixth of the twelve Earthly Branches in the last of the ten Heavenly stems) 0.180kg water (65.167kg) suspension and be coated to be formed 's.
By manufacturing process schematic diagram in Fig. 1.
[test example] accelerated stability test
By tablet obtained in each 500 " [Production Example] oil dispersion tablets " (every 1 Chinese mugwort alcohol content of ossify be Two kinds of 0.5 μ g and 0.75 μ g) it puts into high-density polyethylene bottle container (NC-130, stretching rolling chemistry).Use polypropylene cap (SK-200B, stretching rolling chemistry) is closed by bottle, saves in the thermostat for being adjusted to 40 DEG C/75%RH, after 1 month, 3 months The survival rate of ED-71 is investigated afterwards and after 6 months.
The survival rate of ED-71 is measured by the following method.
5 tablets are put into 30mL centrifuge tube.Water: acetonitrile (20:80) 7mL is added, irradiates ultrasonic wave 30 minutes.In ultrasound In wave irradiation, stir 1 time within every 10 minutes.Polytetrafluoroethylene (PTFE) (PTFE) filter in 0.20 μm of aperture of supernatant is filtered, it will Initial about 1mL is discarded, using remaining filtrate as sample solution.Separately use ED-71 standard items water: acetonitrile (20:80) The concentration for being dissolved and being become about 0.6 μ g/mL, by preparing standard solution with method identical when preparing sample solution.With High performance liquid chromatography (Waters Alliance, measurement wavelength 265nm) measurement sample solution and standard solution, in sample ED-71 content quantified.
The survival rate of ED-71 is found out by calculating formula below.
The survival rate (%) of ED-71=relative to mark amount the ratio (%) for accelerating the ED-71 content in sample/it is opposite In the ratio (%) × 100 for the ED-71 content of mark amount not accelerated in sample
It should be noted that mark amount refers to: being intended to make weight (0.5 μ g or 0.75 μ of the ED-71 contained in often a piece of g)。
[table 17]
The accelerated stability test result of oil dispersion tablet
The results show that acceleration of the tablet obtained in " [Production Example] oil dispersion tablet " in ICH guide (Q1A) defined Under the conditions of stablize.
Industrial availability
In accordance with the invention it is possible to the ED-71 system of dosage form that the decomposition for providing ED-71 is inhibited, other than soft capsule Agent.

Claims (12)

1. a kind of method for the oxidation for inhibiting ED-71, it includes following processes:
Preparation includes (5Z, 7E)-(1R, 2R, 3R) -2- (3- hydroxy propyloxy group) -9,10- open loop cholesteric-in a solvent 5,7,10 (19)-triolefin -1,3,25- triol, that is, ED-71 and include water soluble polymer or alkali compounds mixing it is molten The process of liquid；And
The process of solvent is removed from obtained mixed solution.
2. according to the method described in claim 1, wherein, the weight ratio of ED-71 and additive is 1:50~1:5000.
3. method according to claim 1 or 2, wherein water soluble polymer is from hydroxypropyl methyl cellulose, polyoxyethylene Polyoxypropylene diols, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, sulfobutyl ether-beta-cyclodextrin, polyvinyl acyl in oneself Amine-polyvinyl acetate-polyethyleneglycol-graft copolymer amino alkyl methacrylate copolymer, methacrylic acid amino Alkyl ester copolymer, amino alkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty ester, Polyvinylpyrrolidone, polyvinylpyrrolidone, copolyvidone, Crodaret, 2- hydroxy propyl-Beta- Cyclodextrin, D- alpha-tocopherol polyethanediol succinate, Crodaret dextrin, Arabic gum, hydroxypropyl first Base cellulose-acetate succinate, alkali treated gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate-the third Selected in olefin(e) acid-methacrylic acid copolymer, pre-gelatinized starch, hydroxyethyl cellulose and lecithin powder, alkali compounds from It is selected in meglumine, L-arginine and tetrapotassium pyrophosphate.
4. a kind of pharmaceutical composition comprising ED-71,
Its by preparation in a solvent comprising ED-71 and include water soluble polymer or alkali compounds mixed solution, and Solvent is removed from the mixed solution and is manufactured,
Water soluble polymer is from hydroxypropyl methyl cellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyoxyethylene polyoxy Propylene glycol, sulfobutyl ether-beta-cyclodextrin, Vinylcaprolactam homopolymer-polyvinyl acetate-polyethylene glycol graft copolymerization Object amino alkyl methacrylate copolymer, amino alkyl methacrylate copolymer, amino alkyl methacrylate Copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty ester, polyvinylpyrrolidone, polyvinylpyrrolidone Ketone, copolyvidone, Crodaret, 2-HP-BETA-CD, D- alpha-tocopherol polyethylene glycol amber Acid esters, Crodaret dextrin, Arabic gum, hydroxypropyl methyl cellulose-acetate succinate, alkali process Gelatin, methylcellulose, polyvinyl acetate, polyvinyl acetate-acrylic acid-methacrylic acid copolymer, pre-gelatinized are formed sediment It is selected in powder, hydroxyethyl cellulose and lecithin powder, alkali compounds is from meglumine, L-arginine and tetrapotassium pyrophosphate Selection.
5. pharmaceutical composition according to claim 4, wherein the weight ratio of ED-71 and additive is 1:50~1: 5000。
6. a kind of manufacturing method of the pharmaceutical composition comprising ED-71, it includes following processes:
The process of the oil-in-water emulsion of the aqueous solution of fat solution of the preparation comprising ED-71 and water soluble polymer；
The process for making oil-in-water emulsion adhere to or be adsorbed in excipient；And
The process for keeping oil-in-water emulsion dry,
Wherein, the water soluble polymer is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
7. according to the method described in claim 6, wherein, the weight ratio of oil-in-water emulsion and excipient is 1:4~1:20.
8. method according to claim 6 or 7, wherein excipient is selected from sugar or glycitols.
9. a kind of pharmaceutical composition comprising ED-71,
Described pharmaceutical composition is in excipient or the surface of excipient includes the particle for being wrapped by agent cladding, the covering packet Containing the water soluble polymer selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose,
The particle includes the fat solution of ED-71.
10. pharmaceutical composition according to claim 9, for by the coating tablet of HPMC film coating.
11. a kind of method for the decomposition for inhibiting ED-71, it includes following processes:
The process of the oil-in-water emulsion of the aqueous solution of fat solution of the preparation comprising ED-71 and water soluble polymer,
Wherein, the water soluble polymer is selected from hydroxypropyl methyl cellulose and hydroxypropyl cellulose.
12. also including according to the method for claim 11, following processes:
Obtained oil-in-water emulsion is dry.
CN201780081610.0A 2016-12-28 2017-12-28 The pharmaceutical composition of solid dispersions and oil dispersion comprising ED-71 Pending CN110121348A (en)

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