WO2019131515A1 - 医薬品原薬用原料又は医薬品用添加物及びこれらを用いた医薬品原薬又は医薬品 - Google Patents
医薬品原薬用原料又は医薬品用添加物及びこれらを用いた医薬品原薬又は医薬品 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
- C08G65/33337—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
- C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
- C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
Definitions
- the present invention relates to a raw material for a drug substance or drug additive, and a drug substance or drug using the same.
- polyoxyalkylene compounds such as polyethylene glycol (macrogol) are plasticizers, lubricants, stabilizers, solubilizers, bases, binders, suspending agents, brighteners, Coatings, Wetting Modifiers, Wetting Agents Emulsifiers, Coatings, Adhesion Enhancers, Thickeners, Excipients, Dispersants, Solvents, Solubilizers, Disintegrators, Moisture Proofs, Modifiers, Raw Materials for Drug Delivery Systems, etc. It is used as
- hyperbranched polyoxyalkylene derivatives have been proposed for modification of drug substances, polypeptides, physiologically active proteins and enzymes, etc., and drug delivery systems such as liposomes and polymer micelles (see, for example, Patent Document 1).
- the hyperbranched polyoxyalkylene derivative described in Patent Document 1 has a problem that the stability of the preparation after modification to drug substance, polypeptide, physiologically active protein, enzyme, etc. and stability over time of efficacy are not sufficient. is there.
- the present invention has been made in view of the above problems, and an object of the present invention is to provide a pharmaceutical which is excellent in stability of preparation after modification to drug substance, polypeptide, physiologically active protein, enzyme and the like and stability over time of efficacy.
- An object of the present invention is to provide a drug substance or a drug additive.
- the present invention is a raw material for pharmaceutical drug substance including the polyether composition (A) represented by the general formula (1) or a pharmaceutical additive, wherein the molecular weight distribution of the above (A) is monomodal, Compounds in which the ratio (Mw / Mn) of the weight average molecular weight (Mw) to the number average molecular weight (Mn) of (A) is 1.20 or less, and m in the general formula (1) is 1 in the above (A)
- OR 1 , R 2 O, R 3 O and R 4 O are each independently an oxyalkylene group having 2 to 8 carbon atoms, and when there are a plurality of OR 1 's , R 2 O and R 3 O and R 4 O may be the same or different, and their combination form may be random form or block form, and a, b, c and d are each independently an integer of 50 to 1200, and X 1 to X 4 Each independently represents a hydrogen atom, a substituent represented by the general formula (2) or a substituent represented by the general formula (3), and m is an integer of 1 to 10. ]
- R 6 represents an alkylene group having 1 to 10 carbon atoms
- R 7 is a hydrogen atom or a hydrogen atom is substituted by an alkoxy group having 1 to 10 carbon atoms
- the raw material for drug substance of the present invention and the additive for drug substance of the present invention are excellent in stability of preparation after modification to drug substance, polypeptide, physiologically active protein, enzyme and the like and stability over time of efficacy. Moreover, a drug substance or drug manufactured using the raw material for drug substance of the present invention or the additive for drug of the present invention is excellent in stability over time of formulation stability and drug efficacy.
- the raw material for drug substance according to the present invention and the additive for drug use contain the polyether composition (A) represented by the general formula (1).
- OR 1 , R 2 O, R 3 O and R 4 O in the general formula (1) are each independently an oxyalkylene group having 2 to 8 carbon atoms, and when there are a plurality of them, OR 1 , R 2 O, R 3 O And R 4 O may be the same or different.
- oxyalkylene group having 2 to 8 carbon atoms an oxyethylene group, 1,2- or 1,3-oxypropylene group, 1,2-, 1,3-, 1,4- or 2,3-oxybutylene Groups, oxypentylene groups, oxyhexylene groups, oxyoctylene groups and the like.
- the oxyalkylene group having 2 to 8 carbon atoms is preferably an oxyethylene group alone or an oxyethylene group from the viewpoint of formulation stability after modification to drug substance, polypeptide, bioactive protein and enzyme, etc. and stability over time of efficacy. It is a combined use of an ethylene group and another oxyalkylene group, more preferably an oxyethylene group alone or a combined use of an oxyethylene group and an oxypropylene group, and particularly preferably an oxyethylene group alone.
- the amount of the oxyethylene group in the case of using an oxyethylene group and another oxyalkylene group in combination is preferably 85 mol% or more based on the total number of moles of the oxyethylene group and the other oxyalkylene group.
- the bonding mode of the polyoxyalkylene group may be random or block, but after modification to the drug substance, polypeptide, physiologically active protein, enzyme, etc. From the viewpoint of formulation stability and stability over time of efficacy, block copolymers are preferable.
- A, b, c and d in the general formula (1) are each independently an integer of 50 to 1200. If it is less than 50 and more than 1,200, the stability of the preparation after modification to drug substance, polypeptide, bioactive protein, enzyme, etc. and stability over time of efficacy deteriorate.
- a, b, c and d are each preferably 50 to 1100, from the viewpoint of formulation stability after modification to drug substance, polypeptide, physiologically active protein and enzyme, etc. and stability over time of efficacy. More preferably, it is 50 to 700.
- the binding form of the oxyalkylene group is a block form (including the case of using one type of oxyalkylene group alone)
- Each of a, b, c and d is preferably 50 to 1100, more preferably 50 to 1000, and particularly preferably 50 to 700, from the viewpoint of further improving the temporal stability of the drug efficacy.
- the binding mode of the oxyalkylene group is random, from the viewpoint of further improving the stability of the preparation after modification to the drug substance, polypeptide, physiologically active protein, enzyme, etc. and temporal stability of efficacy
- Each of c, d and d is preferably 50 to 1100, more preferably 50 to 1000, and particularly preferably 50 to 650.
- the binding mode of the oxyalkylene group it is possible to determine whether it is a random mode or a block mode by assigning a signal derived from a dimer or a signal derived from a trimer by pyrolysis gas chromatography.
- the block form shows characteristic signals different from the random form. For example, in the case of the binary diblock format of monomer A and monomer B, the ratio of the signal derived from AA and the ratio of the signal derived from BB among the signals derived from the dimer increase more than in the case of random format, and are derived from AB The proportion of signal is less than in the random form.
- the ratio of the signal derived from AAA and the ratio of the signal derived from BBB among the signals derived from trimer are higher than those in the random format, and the ratio of the signals derived from other trimers (such as ABB) is greater than that in the random format. Decrease.
- the ratio of the above-mentioned signal of the random type is not limited to the method of measuring by thermal decomposition gas chromatography method, the ratio of each monomer constituting the random copolymer is calculated by 1 H-NMR, and Monte Carlo simulation It can also be derived by utilizing the law.
- the measurement by pyrolysis gas chromatography and the measurement by 1 H-NMR can be performed, for example, under the following conditions.
- ⁇ Example of measurement conditions by pyrolysis gas chromatography> Curie Point Pyrolyzer: JHP-3 (manufactured by Nippon Kagaku Kogyo Co., Ltd.) Gas chromatograph: HP-5890A (manufactured by Hewlett Packard) Mass spectrometer: JMS-DX 303 (manufactured by Nippon Denshi Co., Ltd.) Thermal decomposition temperature: 445 ° C
- Solvent Heavy methanol Device: AVANCE 300 (made by Nippon Bruker Co., Ltd.) Frequency: 300 MHz
- X 1 to X 4 in the general formula (1) each independently represent a hydrogen atom, a substituent represented by the general formula (2) or a substituent represented by the general formula (3).
- R 6 in the general formulas (2) and (3) is an alkylene group having 1 to 10 carbon atoms, and a plurality of substituents represented by the general formula (2) or (3) in the general formula (1) In certain instances, R 6 in these substituents may be the same or different.
- alkylene group having 1 to 10 carbon atoms examples include methylene, ethylene, 1,3-propylene, 1-methylethylene, 1,4-butylene, 1-ethylethylene, 1-methylpropylene, and the like.
- alkylene groups having 1 to 10 carbon atoms preferred are those having 1 to 10 carbon atoms from the viewpoint of stability of the preparation after modification to drug substance, polypeptide, bioactive protein and enzyme, etc. and stability over time of efficacy.
- Straight-chain alkylene groups more preferably ethylene, 1,3-propylene, 1,5-pentylene and 1,6-hexylene groups.
- R 7 in the general formula (2) is a hydrogen atom or a monovalent hydrocarbon group of 1 to 15 carbon atoms in which the hydrogen atom may be substituted by an alkoxy group of 1 to 10 carbon atoms, and in formula (1)
- R 7 in these substituents may be the same or different.
- the alkoxy group having 1 to 10 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and a decoxy group.
- the monovalent hydrocarbon group having 1 to 15 carbon atoms includes linear hydrocarbon groups having 1 to 15 carbon atoms (such as methyl, ethyl, iso-propyl, tert-butyl and neopentyl), carbon number 3 to 15 alicyclic hydrocarbon groups (such as cyclohexyl and adamantyl groups) and aromatic hydrocarbon groups having 1 to 15 carbon atoms (such as phenyl, benzyl, p-methylbenzyl and phenethyl groups) and the like
- linear hydrocarbon groups of 1 to 15 carbon atoms such as methyl, ethyl, iso-propyl, tert-butyl and neopentyl
- carbon number 3 to 15 alicyclic hydrocarbon groups such as cyclohexyl and adamantyl groups
- aromatic hydrocarbon groups having 1 to 15 carbon atoms such as phenyl, benzyl, p-methylbenzyl and pheneth
- X 1 to X It is preferable that 4 is a substituent represented by General formula (3).
- X 1 to X 4 are a substituent represented by the general formula (2) from the viewpoint of formulation stability and stability over time of efficacy. Is preferred.
- polyether composition (A) has m of 1 to 10
- a set comprising compounds wherein m is 1 to 7 Ones, and the and the compound of m 1 and most preferably not less than 99 wt%.
- the above-mentioned preferable range can be adjusted by removing
- the number average molecular weight (hereinafter abbreviated as Mn) of the polyether composition (A) represented by the general formula (1) is the viewpoint of the stability of the preparation after modification to physiologically active proteins and enzymes, and the temporal stability of efficacy.
- Mn number average molecular weight of the polyether composition represented by the general formula (1)
- Mn are preferably 10,000 to 200,000, more preferably 10,000 to 180,000, and particularly preferably 10,000 to 130,000.
- the molecular weight distribution of the polyether composition (A) represented by the general formula (1) is unimodal from the viewpoint of the stability of the preparation after modification to a physiologically active protein and enzyme etc. and the stability over time of efficacy. is necessary.
- “monomodal” refers to the elution of the elution peak of the compound represented by the general formula (1) when the compound represented by the general formula (1) is measured by gel permeation chromatography under the conditions described later.
- the peak which has an area of 3.5% or more with respect to the total area of a peak was made into the peak.
- the purity of the starting material (pentaerythritol etc.) in the method for producing the polyether composition (A) described later is increased, or alkylene is added to the starting material (pentaerythritol etc.)
- the ratio (Mw / Mn) of the weight average molecular weight (hereinafter abbreviated as Mw) to Mn of the polyether composition (A) is the stability of the preparation after modification to physiologically active proteins and enzymes etc. and stability over time of efficacy. Preferably, it is 1.20 or less, more preferably 1.15 or less, and particularly preferably 1.10 or less.
- the oxygen concentration in the gas phase when ring-opening polymerizing an alkylene oxide (such as ethylene oxide) to a starting material (such as pentaerythritol) is preferably 0.1% or less.
- the water content in each raw material is preferably 0.4% by weight or less
- the reaction temperature is preferably 125 to 135 ° C.
- the aging temperature is preferably 145 to 155 ° C.
- the Mn, Mw and molecular weight distribution of the polyether composition (A) in the present invention are measured, for example, by gel permeation chromatography (hereinafter abbreviated as GPC) under the following conditions, and from the obtained molecular weight distribution curve, standard polyethylene It can be obtained by calculation using a calibration curve prepared as a reference substance such as glycol.
- GPC gel permeation chromatography
- the content of the polyether composition (A) in the drug substance or drug additive of the present invention is 0.1 to 99.5% by weight based on the weight of the drug substance or drug additive. Is preferred. It is preferable that the input amount of (A) in the manufacturing method of the raw material for drug substance as described later or the additive for medicine is an amount which becomes the above ratio. Moreover, (A) of this invention may be used individually by 1 type, or may use 2 or more types together.
- polyether composition (A) represented by General formula (1) of this invention Although it does not specifically limit as a manufacturing method of the polyether composition (A) represented by General formula (1) of this invention, The following methods etc. are mentioned.
- an alkali catalyst such as potassium hydroxide
- an alkylene oxide such as ethylene oxide is simultaneously or sequentially added dropwise to a starting material (pentaerythritol etc.) under conditions of 100 to 200 ° C. under reduced pressure.
- the reaction is carried out at 0.5 ° C.
- a polyether composition in which X 1 to X 4 in the general formula (1) is a hydrogen atom is dissolved in an organic solvent (such as tetrahydrofuran and toluene), a catalyst (t-butoxy potassium and t-butoxy sodium) Etc.) in the presence of halide (compound in which a halogen atom and a carboxy group are bonded via R 6 : chloroacetic acid etc.) dropwise at 25 to 40 ° C., followed by reaction at 25 to 40 ° C.
- X 1 to X 4 in the above general formula (1) is a substituent represented by the general formula (2) (R 7 : carbon whose hydrogen atom may be substituted with an alkoxy group having 1 to 10 carbon atoms)
- the polyether composition which is a monovalent hydrocarbon group of the formulas 1 to 15 is, for example, a substituent (R 7 ) in which X 1 to X 4 in the general formula (1) are represented by the general formula (2) :
- the bonded alcohol can be produced by an esterification reaction according to a known method.
- the raw material for drug substance or drug additive of the present invention is a known active ingredient used according to the properties of the preparation and application, the above active ingredient and other additives optionally used [excipient, binder, (Solid) dispersant, thickener, nucleating agent, solubilizer, sustained release agent, disintegrant, plasticizer, coating agent, base, lubricant, stabilizer, preservative, flavoring agent, odorant, emulsifier Antioxidant, pH adjuster, flavoring agent, coloring agent, etc.] and water, etc. may be contained.
- the above-mentioned known active ingredients include the ingredients listed in the Japanese Pharmacopoeia, specifically, digestive enzymes (protease, amylase, lipase, trypsin, chymotrypsin, carboxypeptidase and ribonuclease, etc.), tamsulosin hydrochloride, ascorbic acid Acid, aspirin, acetaminophen, ethyl aminobenzoate, benzoic acid, antipyrine, iopanoic acid, isosorbide, isopropyl antipyrine, ibuprofen, indomethacin, ethensamide, ethanic acid, quinactoethyl acetate, quinine ethyl carbonate, ethosuccimide, testosterone enanthate, metenolone enanthate, epirizole , Ergocalciferol, benzalkonium chloride, benzethonium chloride, acebut
- Excipients crystalline cellulose, ethyl cellulose, low substituted hydroxypropyl cellulose, crosslinked polyvinyl pyrrolidone and the like.
- Binder hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol and the like.
- (solid) dispersant hydroxypropyl methylcellulose acetate succinate and the like.
- Thickeners methylcellulose and carboxymethylcellulose sodium and the like.
- Nucleating agent Lactose etc.
- Solubilizers polyethylene glycol, propylene glycol, glycerin, ⁇ -cyclodextrin and polyoxyethylene (polymerization degree 20) sorbitan monooleate (polysorbate 80) and the like.
- Slow release agent Ethylcellulose, cellulose acetate, copolymer of vinyl acetate and vinyl chloride, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, stearyl alcohol and the like.
- Disintegrants carmellose, carboxymethyl ethyl cellulose, low substituted hydroxypropyl cellulose, crosslinked polyvinyl pyrrolidone, hydroxypropyl starch and the like.
- Plasticizer polyethylene glycol (polymerization degree: 2 to 400), polyoxyethylene (polymerization degree: 20) sorbitan monooleate (polysorbate 80), olive oil, glycerin, sorbitol, sucrose and the like.
- Coating agents hydroxypropyl methylcellulose, ethylcellulose, polyvinyl alcohol and the like.
- Base soybean oil, bovine oil, triolein, phospholipid, dihydrocholesterol, carnauba wax, liquid paraffin, octyldodecyl myristate, dimethylpolysiloxane and the like.
- Lubricants magnesium stearate, carnauba wax, starch, silica, sucrose stearate, calcium silicate, kaolin, gypsum, borax, talc and the like.
- Stabilizers butylhydroxytoluene, butylhydroxyanisole, tocopherol, ascorbic acid and the like.
- Preservative Sodium dihydrogen phosphate etc.
- Flavoring agent saccharin, sucrose, maltose etc.
- Flavoring agents cocoa powder, peppermint oil, cinnamon powder and the like.
- Emulsifier polyoxyethylene (polymerization degree 20) sorbitan monooleate (polysorbate 80), polyoxyethylene nonylphenyl ether, sodium lauryl sulfate, triethyl citrate, tributyl citrate, polyoxyethylene glycol, acetyl triethyl citrate Acetyl tributyl citrate, glycerin monostearate, stearic acid, polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic acid and the like.
- Antioxidants dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.
- pH adjuster phosphoric acid, sodium monohydrogenphosphate, sodium dihydrogenphosphate and the like.
- Flavoring agents l-menthol and peppermint etc.
- Colorant tar dye, fluorescent dye, natural dye, titanium oxide, aluminum oxide, zinc oxide, magnesium oxide, magnesium oxide, silicon dioxide, light anhydrous silicic acid, magnesium aluminosilicate, magnesium aluminometasilicate, aluminum silicate And yellow iron oxide etc.
- the above known additives may be used alone or in combination of two or more.
- the mixing method may be such that these materials are uniformly mixed so as to be kneaded.
- a mixing device known mixing devices such as a Beck's mill, a rubber chopper, a farm mill, a mincing machine, an impact crusher, a roll crusher, a homogenizer, a propeller stirrer, a mechanical stirrer and a magnetic stirrer can be used.
- the properties of the raw material for drug substance for drug substance of the present invention or the additive for drug product there is no particular limitation on the properties of the raw material for drug substance for drug substance of the present invention or the additive for drug product, and an emulsion, an organic solvent solution, powder and the like can be mentioned.
- powder the shape thereof includes irregularly crushed, scaly, pearly, rice grains, porous spheres and the like.
- an emulsion and a powder are preferable, and in the case of a powder, an irregularly crushed, pearly and porous spheres are preferable.
- the weight ratio of the above-mentioned active ingredient is The weight ratio of the additive is preferably 0.1 to 90% by weight, more preferably 0.5 to 85% by weight, based on the weight of the drug substance or drug additive, and the weight ratio of the above additive is It is preferably 0.01 to 70% by weight, more preferably 0.03 to 65% by weight, based on the weight of the drug substance or drug additive.
- Examples of the form of the drug substance or drug of the present invention include liquid, granules and powders.
- the drug substance or drug of the present invention can be prepared, for example, using the polyether composition (A), the above-mentioned known active ingredients and other additives optionally used, for example, the following known methods (coating pan method, fluidized bed It can manufacture by the coating system, the rolling coating system, the extrusion granulation system using a screen, etc.).
- Coating Bread Method (A) of the present invention the above-mentioned known active ingredient and other additives optionally used are mixed using a coating pan, and a drug substance or drug of granular form or powder form is mixed. Get If necessary, it may be pill-shaped or tablet-like drug substance or drug by compression molding thereafter.
- Extrusion-granulation method using a screen (A) of the present invention the above-mentioned known active ingredients and other additives optionally used are extruded by using a screen-based extrusion granulator and granules A drug substance or drug in the form of a drug or powder is obtained. If necessary, it may be pill-shaped or tablet-like drug substance or drug by compression molding thereafter.
- Example 1 [Production of polyether composition (A) in which X 1 to X 4 in the general formula (1) are hydrogen atoms]
- Examples 2 to 11 and Comparative Examples 1 to 4 A polyether composition (A) was prepared in the same manner as Example 1, except that the polyol and the alkylene oxide as the starting materials were changed to the materials described in Table 1, and the charge amounts were changed to the parts as described in Table 1. -2) to (A-11) and polyether compositions for comparison (A'-1) to (A'-4) were obtained. Unreacted alkylene oxide was not detected from the obtained (A-2) to (A-11) and (A′-1) to (A′-4).
- Comparative Example 4 is an average of each value of a to d in General Formula (1). This is an example where the value is less than 50.
- Examples 12 to 22 and Comparative Examples 5 to 8 [Production of (A) wherein X 1 to X 4 in General Formula (1) is a Substituent Represented by General Formula (2)]
- the polyether compositions (A-1) to (A-11) and (A'-1) to (A'-4) obtained in Examples 1 to 11 and Comparative Examples 1 to 4 were polyethers respectively. After 5 parts of the composition and 1 part of sodium t-butoxy were dissolved in 100 parts of toluene, 1 part of sodium chloroacetate was added dropwise over 10 hours at 25 ° C., followed by stirring at 40 ° C. for 10 hours.
- Examples 45 to 55 and Comparative Examples 17 to 20> [Production of a preparation using a polyether composition (A) as a pharmaceutical additive]
- the polyether compositions (A-1) to (A-11) and (A'-1) to (A'-4) obtained in Examples 1 to 11 and Comparative Examples 1 to 4 were polyethers respectively.
- the rotating basket was rotated at 100 rpm, and the amount of eluted acetaminophen was quantified by the absorbance of UV [Shimadzu Corporation "UV-1800", 244 nm], and the time for which 80% by weight of the drug granules were eluted was indicated .
- the raw material for drug substance of the present invention or the additive for a drug of the present invention is superior to the raw material for drug substance for comparison or the additive for drug, with respect to the stability of the preparation stability and the efficacy over time. I understand that.
- it is difficult to determine the dissolution end point of the drug if it occurs when the drug is dissolved in physiological saline, so that when the drug is used as an injection preparation, the above-mentioned blur may be small. preferable.
- the pharmaceutical composition of the present invention is substantially free of haze when dissolved in physiological saline, and such a polyether composition (A) is particularly excellent as a raw material for drug substance or as an additive for drug I understand.
- a drug substance or a drug additive which improves the stability of the preparation after modification to the drug substance, polypeptide, physiologically active protein, enzyme and the like and stability over time of efficacy.
- the drug substance or drug containing the drug substance for the drug substance of the present invention or the additive for the drug has stability of the preparation after modification to the drug substance, polypeptide, physiologically active protein, enzyme, etc. and stability over time of efficacy.
- the quality of the medicine can be improved to improve it.
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Abstract
Description
オキシエチレン基とその他のオキシアルキレン基とを併用する場合のオキシエチレン基の量は、オキシエチレン基とその他のオキシアルキレン基との合計モル数に基づいて、85モル%以上であることが好ましい。
50未満の場合及び1200を超える場合、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性が悪化する。
また、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性の観点から、a、b、c及びdはそれぞれ50~1100であることが好ましく、50~700であることが更に好ましい。
また、オキシアルキレン基の結合形式がブロック形式(1種単独のオキシアルキレン基を用いる場合を含む。)の場合、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性を更に向上させる観点から、a、b、c及びdはそれぞれ、50~1100であることが好ましく、50~1000であることが更に好ましく、50~700であることが特に好ましい。
また、オキシアルキレン基の結合形式がランダム形式の場合、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性を更に向上させる観点から、a、b、c及びdはそれぞれ、50~1100であることが好ましく、50~1000であることが更に好ましく、50~650であることが特に好ましい。
ブロック形式は、ランダム形式と異なる特徴的なシグナルを示す。例えば、モノマーA及びモノマーBの2成分系ジブロック形式の場合、ダイマー由来のシグナルの内、AA由来のシグナルの割合及びBB由来のシグナルの割合は、ランダム形式の場合より増加し、AB由来のシグナルの割合は、ランダム形式の場合より減少する。
また、トリマー由来のシグナルの内、AAA由来のシグナルの割合及びBBB由来のシグナルの割合はランダム形式の場合より増加し、その他のトリマー由来のシグナル(ABB等)の割合は、ランダム形式の場合より減少する。
尚、ランダム形式の上記のシグナルの割合は、熱分解ガスクロマトグラフィー法で測定する方法以外に、1H-NMRによって、ランダム共重合体を構成する各モノマーの比率を算出し、モンテカルロシミューレション法を活用することでも導出できる。
<熱分解ガスクロマトグラフィー法での測定条件例>
キューリーポイントパイロライザ:JHP-3型(日本分析工業(株)製)
ガスクロマトグラフ:HP-5890A(Hewlett Packard社製)
質量分析計:JMS-DX303(日本電子(株)製)
熱分解温度:445℃
<1H-NMRでの測定条件例>
溶媒:重メタノール
装置:AVANCE300(日本ブルカー(株)製)
周波数:300MHz
炭素数1~10のアルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、ブトキシ基及びデコキシ基等が挙げられる。
炭素数1~15の1価の炭化水素基としては、炭素数1~15の鎖状炭化水素基(メチル基、エチル基、iso-プロピル基、tert-ブチル基及びネオペンチル基等)、炭素数3~15の脂環式炭化水素基(シクロヘキシル基及びアダマンチル基等)及び炭素数1~15の芳香族炭化水素基(フェニル基、ベンジル基、p-メチルベンジル基及びフェネチル基等)等が挙げられる。
炭素数1~15の1価の炭化水素基の内、好ましいのは、炭素数1~15の鎖状炭化水素基であり、更に好ましいのはtert-ブチル基である。上記の好ましい基であると、後に詳述する一般式(1)におけるX1~X4が一般式(2)で表される置換基であるポリエーテル組成物を用いて、一般式(1)におけるX1~X4が一般式(3)で表される置換基であるポリエーテル組成物を合成する反応を効率よく進めることができる。
ポリエーテル組成物(A)は、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性の観点から、上記(A)の重量を基準として、m=1の化合物を90重量%以上含有し、m=1の化合物を92重量%以上含有することが好ましく、m=1の化合物を94重量%以上含有することが更に好ましく、m=1の化合物を95重量%以上含有することが特に好ましく、m=1の化合物を98重量%以上含有することがとりわけ好ましく、m=1の化合物を99重量%以上含有することが最も好ましい。
特に、m=1の化合物を95重量%以上含有する場合は、ポリエーテル組成物(A)を生理食塩水に溶解させた際におけるかすみの発生を抑制できる点で好ましい。
また、原薬、ポリペプチド、生理活性蛋白質及び酵素等への修飾後の製剤安定性並びに薬効の経時安定性を更に向上させる観点から、ポリエーテル組成物(A)は、mが1~10の化合物を含む組成物であり、かつ、m=1の化合物を90重量%以上含有し、mが1~8の化合物を含む組成物であり、かつ、m=1の化合物を92重量%以上含有することが好ましく、mが1~7の化合物を含む組成物であり、かつ、m=1の化合物を94重量%以上含有することが更に好ましく、mが1~7の化合物を含む組成物であり、かつ、m=1の化合物を95重量%以上含有することが特に好ましく、mが1~7の化合物を含む組成物であり、かつ、m=1の化合物を98重量%以上含有することがとりわけ好ましく、mが1~7の化合物を含む組成物であり、かつ、m=1の化合物を99重量%以上含有することが最も好ましい。
また、m=1の化合物の含量は、後述のポリエーテル組成物(A)の製造方法で用いる出発物質(ペンタエリスリトール等)について、反応前の精製(カラムクロマトグラフィー等)により、ジペンタエリスリトール等を除去することにより、上記の好ましい範囲に調整することができる。
本発明において一峰性とは、一般式(1)で表される化合物を、後述の条件のゲルパーミエーションクロマトグラフィーで測定した際に、一般式(1)で表される化合物の溶出ピークの溶出時間を横軸に、その示差屈折率(RI)を縦軸にしたグラフに、溶出時間毎の示差屈折率(RI)をプロットした場合に、極大を示すピークが1つの場合を言う。なお、ピークの総面積に対して、3.5%以上の面積を有するピークを峰とした。
分子量分布を一峰性にするためには、後述のポリエーテル組成物(A)の製造方法における(A)の出発物質(ペンタエリスリトール等)の純度を上げたり、出発物質(ペンタエリスリトール等)にアルキレンオキサイド(エチレンオキサイド等)を開環重合させる際に、出発物質に対して0.05~5倍重量のポリエーテル組成物(A)を分散媒として共存させることが好ましい。
Mw/Mnを1.20以下にするためには、出発物質(ペンタエリスリトール等)にアルキレンオキサイド(エチレンオキサイド等)を開環重合させる際の気相の酸素濃度は0.1%以下が好ましく、各原料中の含水量は0.4重量%以下が好ましく、反応温度は125~135℃が好ましく、熟成温度は145~155℃が好ましい。
・装置:「HLC-8320GPC」[東ソー(株)製]
・カラム:「TSK gel Super AW」[東ソー(株)製]
・試料溶液:0.25重量%のN,N-ジメチルホルムアミド(DMF)溶液
・溶液注入量:10μL
・流量:0.6mL/分
・測定温度:40℃
・移動相:DMF
・検出装置:屈折率検出器
後述の医薬品原薬用原料又は医薬品用添加物の製造方法における(A)の投入量は、上記の割合となる量であることが好ましい。また、本発明の(A)は、1種を単独で用いても、2種以上を併用してもよい。
例えば、水酸化カリウム等のアルカリ触媒存在下、エチレンオキサイド等のアルキレンオキサイドを減圧下で100~200℃の条件で同時又は逐次的に出発物質(ペンタエリスリトール等)中に滴下し、更に100~200℃で0.5~10時間反応させ、必要により、未反応のエチレンオキサイドを減圧下で除去した後、触媒を吸着処理又はリン酸中和し、固形物を濾去して、一般式(1)におけるX1~X4が水素原子のポリエーテル組成物を得ることができる。
また、上記の一般式(1)におけるX1~X4が一般式(2)で表される置換基(R7:水素原子が炭素数1~10のアルコキシ基で置換されていてもよい炭素数1~15の1価の炭化水素基)であるポリエーテル組成物は、例えば、上記の一般式(1)におけるX1~X4が一般式(2)で表される置換基(R7:水素原子)であるポリエーテル組成物が有するカルボキシ基と、水素原子が炭素数1~10のアルコキシ基で置換されていてもよい炭素数1~15の1価の炭化水素基及びヒドロキシ基が結合したアルコールとを、公知の方法でエステル化反応させることで製造することができる。
なお、一般式(2)において、R7が、水素原子の場合は、一般式(2)が有するカルボキシ基と、N-ヒドロキシスクシンイミドが有する水酸基とのエステル化反応が進行する。また、一般式(2)において、R7が、水素原子が炭素数1~10のアルコキシ基で置換されていてもよい炭素数1~15の1価の炭化水素基の場合は、一般式(2)が有するエステル基において、エステル交換反応が進行する。
上記の公知の有効成分は、1種を単独で用いても2種以上を併用してもよい。
(1)賦形剤:結晶セルロース、エチルセルロース、低置換ヒドロキシプロピルセルロース及び架橋ポリビニルピロリドン等。
(2)結合剤:ヒドロキシプロピルセルロース、ポリビニルピロリドン及びポリビニルアルコール等。
(3)(固体)分散剤:ヒドロキシプロピルメチルセルロースアセテートスクシネート等。
(4)増粘剤:メチルセルロース及びカルボキシメチルセルロースナトリウム等。
(5)核剤:乳糖等。
(6)可溶化剤:ポリエチレングリコール、プロピレングリコール、グリセリン、α-シクロデキストリン及びポリオキシエチレン(重合度20)モノオレイン酸ソルビタン(ポリソルベート80)等。
(7)徐放剤:エチルセルロース、酢酸セルロース、酢酸ビニルと塩化ビニルとの共重合体、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム及びステアリルアルコール等。
(8)崩壊剤:カルメロース、カルボキシメチルエチルセルロース、低置換度ヒドロキシプロピルセルロース、架橋ポリビニルピロリドン及びヒドロキシプロピルスターチ等。
(9)可塑剤:ポリエチレングリコール(重合度2~400)、ポリオキシエチレン(重合度20)モノオレイン酸ソルビタン(ポリソルベート80)、オリーブ油、グリセリン、ソルビトール及びショ糖等。
(10)コーティング剤:ヒドロキシプロピルメチルセルロース、エチルセルロース及びポリビニルアルコール等。
(11)基剤:大豆油、牛油、トリオレイン、リン脂質、ジヒドロコレステロール、カルナウバロウ、流動パラフィン、ミリスチン酸オクチルドデシル及びジメチルポリシロキサン等。
(12)滑沢剤:ステアリン酸マグネシウム、カルナウバロウ、デンプン、シリカ、ショ糖ステアリン酸エステル、ケイ酸カルシウム、カオリン、セッコウ、ホウ砂及びタルク等。
(13)安定剤:ブチルヒドロキシトルエン、ブチルヒドロキシアニソール、トコフェロール及びアスコルビン酸等。
(14)保存剤:リン酸二水素ナトリウム等
(15)矯味剤:サッカリン、ショ糖及びマルトース等。
(16)矯臭剤:ココア末、ハッカ油及び桂皮末等。
(17)乳化剤:ポリオキシエチレン(重合度20)モノオレイン酸ソルビタン(ポリソルベート80)、ポリオキシエチレンノニルフェニルエーテル、ラウリル硫酸ナトリウム、クエン酸トリエチル、クエン酸トリブチル、ポリオキシエチレングリコール、クエン酸アセチルトリエチル、クエン酸アセチルトリブチル、モノステアリン酸グリセリン、ステアリン酸、ポリビニルピロリドン、ポリビニルアルコール、カルボキシメチルセルロース、レシチン、ゼラチン及びヒアルロン酸等。
(18)酸化防止剤:ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、ソルビン酸、亜硫酸ナトリウム、アスコルビン酸、エリソルビン酸及びL-システイン塩酸塩等。
(19)pH調整剤:リン酸、リン酸一水素ナトリウム及びリン酸二水素ナトリウム等。
(20)着香剤:l-メントール及びペパーミント等。
(21)着色剤:タール色素、蛍光染料、天然色素、酸化チタン、酸化アルミニウム、酸化亜鉛、酸化マグネシウム、二酸化ケイ素、軽質無水ケイ酸、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミニウム及び黄酸化鉄等。
上記の公知の添加剤は、1種を単独で用いても、2種以上を併用してもよい。
(1)コーティングパン方式
本発明の(A)、上記の公知の有効成分及び必要により用いられるその他の添加剤を、コーティングパンを用いて混合し、顆粒剤状又は散剤状の医薬品原薬又は医薬品を得る。必要により、その後圧縮成型することで、丸剤状又は錠剤状の医薬品原薬又は医薬品としてもよい。
(2)流動層コーティング方式
本発明の(A)、上記の公知の有効成分及び必要により用いられるその他の添加剤を、流動造粒機を用いて、空気流によって流動、造粒させ、顆粒剤状又は散剤状の医薬品原薬又は医薬品を得る。必要により、その後圧縮成型することで、丸剤状又は錠剤状の医薬品原薬又は医薬品としてもよい。
(3)転動コーティング方式
本発明の(A)、上記の公知の有効成分及び必要により用いられるその他の添加剤を、転動造粒機を用いて、水平の円盤を回転させ、円盤上面を転動運動によって流動、造粒させ、顆粒剤状又は散剤状の医薬品原薬又は医薬品を得る。必要により、その後圧縮成型することで、丸剤状又は錠剤状の医薬品原薬又は医薬品としてもよい。
(4)スクリーンを用いた押出造粒方式
本発明の(A)、上記の公知の有効成分及び必要により用いられるその他の添加剤を、スクリーンを用いた押出造粒機を用いて、押し出して顆粒剤状又は散剤状の医薬品原薬又は医薬品を得る。必要により、その後圧縮成型することで、丸剤状又は錠剤状の医薬品原薬又は医薬品としてもよい。
出発物質であるポリオールとして、ペンタエリスリトール[Perstorp社製:上記の式(1)におけるm=1の原料となる化合物を99重量%含有、上記の式(1)におけるm=2の原料となる化合物を1重量%含有]2.9部、ペンタエリスリトールエチレンオキサイド4モル付加物[日本乳化剤工業(株)製「PNT-40」:上記の式(1)におけるm=1となる化合物を100重量%含有]1.2部及び水酸化ナトリウム0.027部をオートクレーブに仕込み、アルゴンガスで置換してから減圧にし、95℃に昇温した。
0.001~0.003MPa、95℃で1時間脱水を行なった後、130℃に温度を下げて、アルキレンオキサイドとして、エチレンオキサイド996部をオートクレーブ内圧が0.2MPa以上にならないようにして、125~135℃の範囲で18時間かけて徐々に滴下した。滴下終了後、145~155℃でオートクレーブの内圧が滴下開始時と同じ圧力を示すまで2時間熟成させ、ポリエーテル組成物(A-1)1000部を得た。
得られた(A-1)からは未反応のエチレンオキサイドは検出されず、(A-1)は一般式(1)のm=1の化合物を99重量%[(A)の重量を基準とした重量割合]含有し、下記GPC測定から、(A-1)の分子量分布の形状は一峰性であり、(A-1)のMnは3.6万[一般式(1)におけるa~dの各値の平均値は225]、Mw/Mn=1.06であった。
・装置:「HLC-8320GPC」[東ソー(株)製]
・カラム:「TSK gel Super AW」[東ソー(株)製]
・試料溶液:0.25重量%のN,N-ジメチルホルムアミド(DMF)溶液
・溶液注入量:10μL
・流量:0.6mL/分
・測定温度:40℃
・移動相:DMF
・検出装置:屈折率検出器
・基準物質:標準ポリエチレングリコール
出発原料となるポリオール及びアルキレンオキサイドを表1に記載の原料に変更し、仕込量を表1に記載の通りの部数に変更した以外は、実施例1と同様にして、ポリエーテル組成物(A-2)~(A-11)及び比較用のポリエーテル組成物(A’-1)~(A’-4)を得た。
得られた(A-2)~(A-11)及び(A’-1)~(A’-4)からは未反応のアルキレンオキサイドは検出されなかった。
(A-2)~(A-11)及び(A’-1)~(A’-4)の分子量分布の形状、Mn、Mw/Mn、一般式(1)におけるa~dの各値の平均値及び一般式(1)におけるm=1の化合物の含有量[(A)の重量を基準とした重量割合]を表1に示す。
また、比較例3は、一般式(1)のm=1化合物の含有率が90重量%よりも小さい例であり、比較例4は、一般式(1)におけるa~dの各値の平均値が50より小さい例である。
実施例1~11及び比較例1~4で得られたポリエーテル組成物(A-1)~(A-11)及び(A’-1)~(A’-4)のそれぞれについて、ポリエーテル組成物5部及びt-ブトキシナトリウム1部をトルエン100部に溶解させた後、クロロ酢酸ナトリウム1部を25℃にて10時間かけて滴下した後、40℃にて10時間撹拌した。その後、1Mの塩酸水溶液を加え分液にて有機相を回収し、飽和食塩水溶液で有機相を3回洗浄し、トルエンを減圧留去した後、イソプロパノールで再結晶することで、ポリエーテル組成物(A-12)~(A-22)及び比較用のポリエーテル組成物(A’-5)~(A’-8)各5.1部を得た。
実施例12~22及び比較例5~8で得られたポリエーテル組成物(A-12)~(A-22)及び(A’-5)~(A’-8)のそれぞれについて、ポリエーテル組成物5部、ジシクロヘキシルカルボジイミド1部及びN-ヒドロキシスクシンイミド1部をN,N-ジメチルホルムアミド100部に溶解させた後、40℃にて10時間撹拌した。その後、不溶物を濾去し、イソプロパノール100部を加え、5℃まで冷却し、析出物を濾取した。再度イソプロパノール100部を加え、5℃まで冷却し、析出物を濾取し、ポリエーテル組成物(A-23)~(A-33)及び比較用のポリエーテル組成物(A’-9)~(A’-12)各4部を得た。
(A-23)~(A-33)及び(A’-9)~(A’-12)の分子量分布の形状、Mw/Mn、及び一般式(1)におけるm=1の化合物の含有量[(A)の重量を基準とした重量割合]を表2に示す。
実施例23~33及び比較例9~12で得られたポリエーテル組成物(A-23)~(A-33)及び(A’-9)~(A’-12)のそれぞれについて、ポリエーテル組成物5部、メマンチン塩酸塩[東京化成(株)製]3部及びトリエチルアミン2部をテトラヒドロフラン100部に溶解させ、40℃、5時間撹拌した。溶剤を留去した後、イソプロパノール100部を加え、5℃まで冷却し、析出物を濾取し、本発明の医薬品原薬用原料で修飾された医薬品原薬(B-1)~(B-11)及び比較用の医薬品原薬(B’-1)~(B’-4)各4部を得た。
上記で得られた医薬品原薬(B-1)~(B-11)及び(B’-1)~(B’-4)を、殺菌したイオン交換水に濃度10重量%で溶解させた。25℃の温度で1カ月保存後又は3カ月保存後の各水溶液の外観を目視で確認して下記水準で評価した結果を表2に示す。
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上記製剤安定性の評価を行った各水溶液について、下記条件にて高圧送液タイプ高速液体クロマトグラフィー(UPLC)を用いて加水分解されたメマンチンを定量して、測定試料の重量に対する加水分解によって生成したメマンチンの重量の比率(重量%)を算出した結果を表2に示す。この比率が小さい程、加水分解されておらず、修飾後の薬効の経時安定性に優れる。
LCシステム:ACQUITY UPLC H-Class
カラム:ACQUITY UPLC CORTECS C+18、1.6μm、2.1×50mm
カラム温度:45℃
流速:0.6mL/分
注入量:1.0μL
溶媒:メタノール/水=1/1
MS検出器:ACQUITY QDa検出器
イオン化モード:ESI(+)
Single Ion Recording:180.2Da
サンプリングレート:10ポイント/秒
キャピラリー電圧:0.8kV
コーン電圧:15V
プローブ温度:600℃
上記で得られた医薬品原薬(B-1)~(B-11)及び(B’-1)~(B’-4)1.0gを、25℃の生理食塩水10mLに加え、30分間撹拌し溶解させ評価用試料を作成した。
濁度計[品名:WA6000、日本電色工業(株)製]を用いて、セル中[光路長:10mm]の評価用試料について、25℃での散乱透過光量(Td)及び全透過光量(Tt)を測定し、以下の計算式からヘイズ値(Hz)を算出した。結果を表2に示す。
ヘイズ値が小さいほどかすみが少なく、生理食塩水への溶解性が高いことを示す。
HZ=Td/Tt×100
実施例1~11及び比較例1~4で得られたポリエーテル組成物(A-1)~(A-11)及び(A’-1)~(A’-4)のそれぞれについて、ポリエーテル組成物10部とアセトアミノフェン[東京化成(株)製]1部を粉体混合した後、1mmのスクリーンを用いて押出造粒し、本発明の医薬品顆粒(C-1)~(C-11)及び比較用の医薬品顆粒(C’-1)~(C’-4)を各11部得た。
上記で得られた医薬品顆粒(C-1)~(C-11)及び(C’-1)~(C’-4)を、湿度が50%RHで温度が25℃又は40℃に保たれた恒温恒湿器内に静置した。1ヶ月後、3ヶ月後の各顆粒の外観を目視で確認して下記水準で評価した結果を表3に示す。
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作製初期並びに湿度50%RH、温度25℃で1カ月間又は3カ月間静置した本発明の医薬品顆粒(C-1)~(C-11)及び比較用の医薬品顆粒(C’-1)~(C’-4)について、下記の評価方法にて溶出速度を評価した結果を表3に示す。作製初期から溶出速度が変化していないことが好ましい。
日本薬局方の溶出試験機(回転バスケット法)を用い、37℃の0.05mol/Lリン酸緩衝液(pH6.8)500mL中に評価用の医薬品顆粒(C又はC’)40mgを投入した。回転バスケットを100rpmで回転させ、溶出したアセトアミノフェン量をUVの吸光度[(株)島津製作所「UV-1800」、244nm]で定量し、医薬品顆粒中の80重量%が溶出した時間を表記した。
上記で得られた医薬品顆粒(C-1)~(C-11)及び(C’-1)~(C’-4)の生理食塩水への溶解性評価は、医薬品原薬(B-1)~(B-11)及び(B’-1)~(B’-4)の生理食塩水への溶解性評価と同様の方法で実施した。結果を表3に示す。
また、医薬品を生理食塩水に溶解させた際にかすみが生じてしまうと、医薬品の溶解終点の判断が困難となるため、特に医薬品を注射製剤として用いる場合には、上記のかすみが少ないことが好ましい。ここで、本発明におけるポリエーテル組成物(A)が、一般式(1)においてm=1の化合物を上記(A)の重量を基準として95重量%以上含有する場合、上記(A)を用いてなる医薬品は、生理食塩水に溶解させた際にかすみがほぼ生じておらず、このようなポリエーテル組成物(A)は、医薬品原薬用原料又は医薬品用添加物として特に優れていることが分かる。
Claims (4)
- 一般式(1)で表されるポリエーテル組成物(A)を含有する医薬品原薬用原料又は医薬品用添加物であって、
前記(A)の分子量分布が一峰性であり、
前記(A)の数平均分子量(Mn)に対する重量平均分子量(Mw)の比率(Mw/Mn)が1.20以下であり、
前記(A)が一般式(1)におけるmが1である化合物を前記(A)の重量を基準として90重量%以上含有する医薬品原薬用原料又は医薬品用添加物。
- 前記一般式(1)におけるOR1、R2O、R3O及びR4Oが、いずれもオキシエチレン基である請求項1記載の医薬品原薬用原料又は医薬品用添加物。
- 前記ポリエーテル組成物(A)の含有量が、医薬品原薬用原料又は医薬品用添加物の重量を基準として0.1~99.5重量%である請求項1又は2記載の医薬品原薬用原料又は医薬品用添加物。
- 請求項1又は2記載の医薬品原薬用原料又は医薬品用添加物を用いてなる医薬品原薬又は医薬品。
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