WO2016148201A1 - ポリペプチドを含有する医薬組成物 - Google Patents
ポリペプチドを含有する医薬組成物 Download PDFInfo
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- WO2016148201A1 WO2016148201A1 PCT/JP2016/058359 JP2016058359W WO2016148201A1 WO 2016148201 A1 WO2016148201 A1 WO 2016148201A1 JP 2016058359 W JP2016058359 W JP 2016058359W WO 2016148201 A1 WO2016148201 A1 WO 2016148201A1
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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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- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
- C07C317/04—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
-
- 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
- C08L71/08—Polyethers derived from hydroxy compounds or from their metallic derivatives
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a drug, a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -NH 2 , and a specific organic solvent, the polypeptide and a specific organic solvent And a method for imparting sustained release to a drug.
- Patent Document 1 and Non-Patent Document 1 are water-soluble drugs using a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -CONH 2 (SEQ ID NO: 1) as a self-assembling peptide.
- a sustained release formulation of insulin is disclosed.
- Non-Patent Document 2 discloses a sustained-release preparation comprising a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -CONH 2 and containing pindolol, quinine and timolol maleate as drugs.
- the polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -CONH 2 is PuraMatrix (registered trademark), but PuraMatrix (registered trademark) is Ac- (Arg).
- An object of the present invention is to find a pharmaceutical composition that releases a drug over a long period of time after being administered into the body.
- the present inventors have conducted extensive research on a gelling agent for forming a hydrogel, a solvent for dissolving the drug, and the like, and as a result, the drug and Ac- (Arg-Ala-Asp- the polypeptide represented by ala) 4 -NH 2, polyethylene glycol, dimethyl sulfoxide, pharmaceutical composition mixed with at least one organic solvent selected from the group consisting of glycofurol and N- methylpyrrolidone, drug
- the present invention was completed by finding that the release was sustained.
- a pharmaceutical composition comprising a drug, a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 —NH 2 , and an organic solvent, A pharmaceutical composition, wherein the organic solvent is at least one organic solvent selected from the group consisting of polyethylene glycol, dimethyl sulfoxide, glycofurol and N-methylpyrrolidone.
- the pharmaceutical composition according to the above [1] further comprising water.
- the drug is represented by the formula (1): [Where: R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-6 alkyl group, one or a plurality of C 1-6 alkyl group substituted with a halogen atom, C 1-6 alkoxy group, or one or a plurality A C 1-6 alkoxy group substituted with a halogen atom of R 2 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkylcarbonyl group, or a C 1-6 alkylcarbonyl group substituted with one or more hydroxyl groups.
- the drug is 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide or a salt thereof
- the pharmaceutical composition according to the above [13] which is for intravitreal or anterior chamber administration.
- a sustained release agent for a drug comprising a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 —NH 2 and an organic solvent, wherein the organic solvent is polyethylene glycol ,
- a sustained release imparting agent which is at least one organic solvent selected from the group consisting of dimethyl sulfoxide, glycofurol and N-methylpyrrolidone.
- a method of imparting sustained release to a drug comprising adding a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 —NH 2 and an organic solvent to the drug,
- the organic solvent is at least one organic solvent selected from the group consisting of polyethylene glycol, dimethyl sulfoxide, glycofurol and N-methylpyrrolidone.
- the pharmaceutical composition of the present invention dissolves a drug and administers it into the body, then depots it to release the drug slowly. Furthermore, the pharmaceutical composition of the present invention has sufficient safety as a pharmaceutical product.
- the sustained release agent of the present invention is suitable for imparting a good sustained release property to a drug.
- the method for imparting sustained release to the drug of the present invention can impart good sustained release to the drug.
- a polypeptide in the present invention is a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -NH 2 (SEQ ID NO: 1) (hereinafter also referred to as polypeptide A) as PuraMatrix (registered trademark). Sold by 3D Matrix Co., Ltd. The C-terminal carboxyl group (COOH) is amidated (CONH 2 ).
- the content of the polypeptide A is not particularly limited, but is preferably 0.001 to 5% (w / v), more preferably 0.005 to 3% (w / v), 0.01 to 2% (W / v) is more preferable, 0.05 to 1% (w / v) is particularly preferable, and 0.1 to 0.5% (w / v) is most preferable.
- “% (W / v)” means the mass (g) of the target component (here, polypeptide A) contained in 100 mL of the pharmaceutical composition of the present invention. The same applies hereinafter unless otherwise specified.
- a hydrophobic drug is a drug that is difficult to dissolve in water, and the degree of hydrophobicity is expressed using a partition coefficient CLogP or the like as an index.
- CLogP is a value obtained by calculating the logarithm of a 1-octanol / water distribution coefficient of a chemical substance, and details thereof are described in JP-A-2009-298878.
- a hydrophobic drug having a distribution coefficient CLogP of 0.5 or more is preferable, a drug with CLogP of 1 to 20 is more preferable, a drug with 1.5 to 15 is more preferable, and 2 or more is preferable. 12 or less drugs are more preferred, compounds of 2.2 to 9 are particularly preferred, and compounds of 2.5 to 8 are most preferred.
- the drug in the present invention include Tafetinib, SIM-817378, ACTB-1003, Chiauranib, CT-53608, Cinnamon, chim4G8-SDIE, CEP-5214, IMC-1C11, CEP-7055, 3- [5- [ 2- [N- (2-Methoxyethyl) -N-methylamino] ethoxy] -1H-indol-2-yl] quinolin-2 (1H) -one, hF4-3C5, ZK-CDK, IMC-EB10, LS-104 , CYC-116, OSI-930, PF-337210, JNJ-26483327, SSR-106462, R-1530, PRS-050, TG-02, SC-71710, SB-1578, AMG-191, AMG-820, Sulfatinib , Lucitanib hydrochloride, JNJ-28312141, Ilorasertib, PLX-5622,
- VEGF inhibitors described in JP-A-2011-37844, JP-A-2005-232149, JP-A-2006-2733851, JP-A-2006-306861, JP-A-2008-266294, JP-A-2007-230993, JP-A-2008-074829 A compound having a glucocorticoid receptor binding activity described in JP-A-2008-14389, JP-A-2008-143890, JP-A-2008-143891, JP-A-2009-007344, JP-A-2009-084274, and the like, and a selective glucose such as RU24858 Corticoid receptor agonists, anticancer agents such as fluorouracil, Janus kinase inhibitors such as tofacitinib, protein kinase inhibitors such as ruboxistaurine mesylate, and the like.
- anticancer agents such as fluorouracil, Janus kinase inhibitors such
- R 1 is a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-6 alkyl group, one or a plurality of C 1-6 alkyl group substituted with a halogen atom, C 1-6 alkoxy group, or one or a plurality
- a C 1-6 alkoxy group substituted with a halogen atom of R 2 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkylcarbonyl group, or a C 1-6 alkylcarbonyl group substituted with one or more hydroxyl groups. It is preferable to use a compound represented by the formula or a salt thereof.
- R 1 is, C 1-6 an alkoxy group, or one or a plurality of C 1-6 alkoxy group substituted by a halogen atom
- R 2 is C 1-6 alkyl carbonyl group or one or A compound of the above formula (1) or a salt thereof showing a C 1-6 alkylcarbonyl group substituted with a plurality of hydroxyl groups, more preferably R 1 is substituted with one or more halogen atoms.
- Halogen atom refers to fluorine, chlorine, bromine or iodine.
- the “C 1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and a linear or branched alkyl group having 1 to 4 carbon atoms is preferable. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and the like. It is done.
- C 1-6 alkoxy group refers to a group in which a hydrogen atom of a hydroxyl group is substituted with the C 1-6 alkyl group. Specific examples include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentoxy group, n-hexyloxy group, isopropoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, isopentyloxy. Group and the like.
- C 1-6 alkylcarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with the C 1-6 alkyl group.
- Specific examples include methylcarbonyl group (acetyl group), ethylcarbonyl group, n-propylcarbonyl group, n-butylcarbonyl group, n-pentylcarbonyl group, n-hexylcarbonyl group, isopropylcarbonyl group, isobutylcarbonyl group, sec-butyl.
- Examples thereof include a carbonyl group, a tert-butylcarbonyl group, and an isopentylcarbonyl group.
- “Substituted with one or a plurality of halogen atoms” means that the C 1-6 alkyl group is substituted with one or more halogen atoms in the number that can be substituted. Each halogen atom may be the same or different, and the number of halogen atoms is preferably 2 or 3, particularly preferably 3. “Substituted with one or a plurality of hydroxyl groups” means that the C 1-6 alkyl group is substituted with one or more hydroxyl groups of the number that can be substituted. The number of hydroxyl groups is preferably 1 or 2, particularly preferably 1.
- a particularly preferred specific example of the drug in the present invention is represented by the formula (2): 2-[[[2-[(hydroxyacetyl) amino] -4-pyridinyl] methyl] thio] -N- [4- (trifluoromethoxy) phenyl] -3-pyridinecarboxamide or a salt thereof .
- 2007/0149574 discloses that a compound represented by formula (2) exhibits a cell growth inhibitory action in a test system using a VEGF-induced HUVEC proliferation reaction evaluation system, Inhibition of tumor growth in test system using model, Inhibition of foot edema in test system using rat adjuvant arthritis model, Inhibition of choroidal neovascularization in test system using rat choroidal neovascularization model It is described to show. Furthermore, the compound represented by the formula (2) from their pharmacological action is useful as a medicine, and in particular, prevention or treatment of diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.
- diseases such as cancer, rheumatoid arthritis, age-related macular degeneration, diabetic retinopathy, and diabetic macular edema.
- U.S. Patent Application Publication No. 2012/0116088 describes a benzenesulfonate salt of a compound represented by the formula (2), a crystal thereof, a crystal polymorph thereof, and a production method thereof. It is described that the benzenesulfonate salt of the compound represented by (2) has excellent storage stability and no mineral deposits are observed in the stomach even after repeated oral administration.
- the compound represented by the formula (2) or a salt thereof contained in the pharmaceutical composition of the present invention is in accordance with a usual method in the art such as a method described in US Patent Application Publication No. 2007/0149574. Can be manufactured.
- the drug in the present invention includes derivatives such as esters and amides.
- the ester include an ester obtained by condensing a hydroxyl group in a drug and a carboxylic acid such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid.
- Specific examples of amides include amides obtained by condensing amino groups in drugs and carboxylic acids such as acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, and pivalic acid.
- the drug in the present invention may take the form of a hydrate or a solvate.
- geometrical isomers, tautomers or optical isomers in the drug of the present invention these isomers are also included in the scope of the present invention.
- crystalline polymorph exists in the drug of the present invention, the crystalline polymorph is also included in the scope of the present invention.
- the drug in the present invention may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
- Salts include inorganic acid salts, organic acid salts, quaternary ammonium salts, halogen ion salts, alkali metal salts, alkaline earth metal salts, metal salts, organic amine salts, etc. Can be mentioned.
- Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.
- Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like.
- Salts with halogen ions include salts with chloride ions, bromide ions, iodide ions, etc.
- Salts with alkali metals include salts with lithium, sodium, potassium, etc., alkaline earths
- Examples of the salt with metal include salts with calcium, magnesium and the like, and examples of the metal salt include salts with iron, zinc and the like.
- Salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like.
- the content of the drug in the present invention is not particularly limited as long as it is an amount sufficient to achieve a desired drug effect, but is preferably 0.01 to 30% (w / v), and preferably 0.1 to 25% (w / v). v) is more preferred, 0.5-20% (w / v) is more preferred, 1-15% (w / v) is even more preferred, 1-12% (w / v) is particularly preferred, 1% (W / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v ), 4% (w / v), 5% (w / v), 6% (w / v), 7% (w / v), 8% (w / v), 9% (w / v), Most preferred is 10% (w / v), 11% (w / v) or 12% (w / v).
- the organic solvent in the present invention is selected from the group consisting of polyethylene glycol (PEG), dimethyl sulfoxide, glycofurol and N-methylpyrrolidone.
- PEG polyethylene glycol
- Polyethylene glycol (PEG) as the organic solvent is a polyether in which ethylene glycol is polymerized, and is represented by the chemical formula HO (CH 2 CH 2 O) n H, where n is the number of polymerizations.
- the average molecular weight of polyethylene glycol as the organic solvent is preferably 90 to 2200, more preferably 100 to 2000, further preferably 100 to 1500, more preferably 100 to 1000, still more preferably 200 to 800, and more preferably 300 to 660. Much preferred, 400-600 is even more preferred, 400 and 600 are particularly preferred, and 400 is most preferred. Specific examples of polyethylene glycol include PEG100, PEG200, PEG300, PEG400, PEG600, PEG800, PEG1000, and the like. Dimethyl sulfoxide (DMSO) as the organic solvent is a compound represented by the chemical formula CH 3 SOCH 3 .
- DMSO Dimethyl sulfoxide
- Glycofurol as the organic solvent is a compound represented by the following formula (3) composed of tetrahydrofuran and polyethylene glycol.
- N in the formula (3) is the number of polymerizations, preferably 1 to 20, more preferably 1 to 10, still more preferably 1 to 6, particularly preferably 1 to 4, and most preferably 1 to 2.
- N-methylpyrrolidone as the organic solvent is a compound represented by the following formula (4) composed of tetrahydrofuran and polyethylene glycol.
- a solvent that can be used as a pharmaceutical additive such as water, ethanol, N, N-dimethylacetamide, etc. Can be contained. In particular, from the viewpoint of dissolving polypeptide A, it is preferable to contain water.
- the volume ratio of water to an organic solvent particularly preferably polyethylene glycol selected from the group consisting of polyethylene glycol, dimethyl sulfoxide, glycofurol and N-methylpyrrolidone is particularly high.
- an organic solvent particularly preferably polyethylene glycol
- 99: 1 to 60:40 is preferable, 97: 3 to 70:30 is more preferable, 95: 5 to 75:25 is more preferable, and 90:10 to 80:20 is most preferable.
- the total content of the solvent in the pharmaceutical composition of the present invention is not particularly limited, but is 70 to 99.99% as a value of mass% of the solvent when the pharmaceutical composition of the present invention is 100 mass% ( w / w) is preferable, 80 to 99.95% (w / w) is more preferable, 85 to 99.9% (w / w) is more preferable, and 90 to 99.5% (w / w) is particularly preferable Preferably, 92 to 99% (w / w) is most preferable.
- the pharmaceutical composition of the present invention can use additives as necessary.
- the additives include surfactants, buffering agents, tonicity agents, stabilizers, preservatives, antioxidants, Molecular weight polymers and the like can be added.
- a cationic surfactant for example, a cationic surfactant, an anionic surfactant, and a nonionic surfactant can be blended.
- anionic surfactants include phospholipids, and examples of phospholipids include lecithin.
- cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyltrimethylammonium salts, dialkyldimethylammonium salts.
- Alkyldimethylbenzylammonium salt alkylpyridinium salt, acylaminoalkyl-type ammonium salt, acylaminoalkylpyridinium salt, diacyloxyethylammonium salt, alkylimidazoline, 1-acylaminoethyl-2-alkylimidazoline, 1-hydroxylethyl-2 -Alkyl imidazolines and the like.
- alkyldimethylbenzylammonium salt include benzalkonium chloride and cetalkonium chloride.
- nonionic surfactants include polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, Vitamin E TPGS (tocopherol polyethylene glycol 1000 succinate, CAS 9002-96-4) and the like can be mentioned.
- polyoxyethylene fatty acid ester examples include polyoxyl 40 stearate.
- polyoxyethylene sorbitan fatty acid ester examples include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and the like.
- polyoxyethylene hydrogenated castor oil various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, ⁇ 70 are particularly preferred and 60 is most preferred.
- Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like.
- polyoxyethylene castor oil various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, more preferably 20 to 50, and more preferably 30 to 40 Is particularly preferred and 35 is most preferred.
- polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.
- polyoxyethylene polyoxypropylene glycol polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) And glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like.
- sucrose fatty acid ester examples include sucrose stearate ester.
- the content of the surfactant when blended with the surfactant in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but is 0.001 to 10% (w / v).
- w / v a weight average of the surfactant
- 0.01 to 5% (w / v) is more preferable
- 0.05 to 3% (w / v) is more preferable
- 0.1 to 2% (w / v) is most preferable.
- Buffers that can be used as the additive include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ⁇ -aminocaproic acid, Examples include trometamol.
- the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the borate includes borax.
- examples of the tartrate include sodium carbonate and sodium hydrogencarbonate
- examples of the tartrate include sodium tartrate and potassium tartrate.
- the content of the buffer when blending the buffer with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer, etc., but is preferably 0.001 to 10% (w / v), 0 0.01 to 5% (w / v) is more preferable, 0.05 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is most preferable.
- tonicity agents examples include ionic tonicity agents and nonionic tonicity agents.
- ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and nonionic tonicity agents include glycerin, propylene glycol, sorbitol, mannitol, trehalose, sucrose, glucose, and the like. Can be mentioned.
- the content of the tonicity agent when blended with the tonicity agent in the pharmaceutical composition of the present invention can be adjusted as appropriate depending on the type of the tonicity agent and the like, but is 0.001 to 10% (w / v) is preferred, 0.01 to 5% (w / v) is more preferred, 0.05 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is most preferred.
- Examples of the stabilizer that can be used as the additive include edetic acid, sodium edetate, sodium citrate and the like.
- the content of the stabilizer when the stabilizer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the stabilizer, etc., but is 0.001 to 10% (w / v).
- w / v a weight average of the stabilizer
- 0.01 to 5% (w / v) is more preferable
- 0.05 to 3% (w / v) is more preferable
- 0.1 to 2% (w / v) is most preferable.
- preservative examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, and chlorobutanol. .
- the content of the preservative when blended with the preservative in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the preservative, but is preferably 0.0001 to 10% (w / v), 0 0.001 to 5% (w / v) is more preferable, 0.005 to 3% (w / v) is still more preferable, and 0.01 to 2% (w / v) is most preferable.
- Antioxidants that can be used as the above-mentioned additives include ascorbic acid derivatives such as ascorbic acid and ascorbyl palmitate, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.
- ascorbic acid derivatives such as ascorbic acid and ascorbyl palmitate
- tocopherol dibutylhydroxytoluene
- butylhydroxyanisole sodium erythorbate
- propyl gallate sodium sulfite
- the content of the antioxidant when the antioxidant is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the antioxidant, etc., but is 0.001 to 10% (w / v).
- w / v 0.05 to 3%
- w / v 0.1 to 2%
- Examples of the high molecular weight polymer that can be used as the additive include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, Examples thereof include hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, and carboxyvinyl polymer.
- the content of the high molecular weight polymer in the case where the high molecular weight polymer is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the high molecular weight polymer, etc., but is 0.001-10% (w / v) is preferred, 0.01 to 5% (w / v) is more preferred, 0.05 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is most preferred.
- the content of the additive that can be used as the additive can be appropriately adjusted depending on the type of the additive, and the total amount is preferably 0.0001 to 30% (w / v), preferably 0.001 to 25% (w / v) is more preferable, 0.01 to 20% (w / v) is more preferable, 0.1 to 15% (w / v) is particularly preferable, and 1 to 10% (w / v) Is most preferred.
- a preferred specific embodiment of the pharmaceutical composition of the present invention is substantially composed of a drug, a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -NH 2 , polyethylene glycol, and water only.
- a pharmaceutical composition comprising:
- a preferred specific embodiment of the pharmaceutical composition of the present invention is substantially represented by the compound represented by the formula (1) or a salt thereof, Ac- (Arg-Ala-Asp-Ala) 4 -NH 2.
- a pharmaceutical composition comprising only a polypeptide, polyethylene glycol, and water.
- a preferred specific embodiment of the pharmaceutical composition in the present invention is substantially represented by the compound represented by the formula (2) or a salt thereof, Ac- (Arg-Ala-Asp-Ala) 4 -NH 2.
- a pharmaceutical composition comprising only a polypeptide, polyethylene glycol, and water.
- a preferred specific embodiment of the pharmaceutical composition of the present invention consists essentially of a drug, a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -NH 2 , and dimethyl sulfoxide. It is a pharmaceutical composition.
- a preferred specific embodiment of the pharmaceutical composition of the present invention is substantially represented by the compound represented by the formula (1) or a salt thereof, Ac- (Arg-Ala-Asp-Ala) 4 -NH 2.
- a pharmaceutical composition comprising only a polypeptide and dimethyl sulfoxide.
- a preferred specific embodiment of the pharmaceutical composition in the present invention is substantially represented by the compound represented by the formula (2) or a salt thereof, Ac- (Arg-Ala-Asp-Ala) 4 -NH 2.
- a pharmaceutical composition comprising only a polypeptide and dimethyl sulfoxide.
- the pharmaceutical composition of the present invention can be administered orally or parenterally.
- the dosage form of the pharmaceutical composition in the present invention is not particularly limited as long as it can be used as a pharmaceutical product.
- Examples of the dosage form include liquid preparations for oral preparations, and injection preparations, infusion solutions, nasal drops, ear drops, eye drops and the like for parenteral preparations.
- Preferred are ophthalmic injections and eye drops, more preferred are ophthalmic injections, and most preferred are intravitreal, intracameral or subconjunctival injections. These can be produced according to conventional methods in the art.
- the pharmaceutical composition in the present invention can be appropriately administered according to its dosage form.
- an ophthalmic injection it can be administered intravitreally, near the retrosclera, around the orbit, and between the sclera and the conjunctiva.
- the dose is not particularly limited as long as it is sufficient to achieve the desired drug effect, but preferably 1 to 100 ⁇ L per dose.
- the dose of the drug is preferably 0.001 to 30 mg / eye, more preferably 0.01 to 10 mg / eye, further preferably 0.1 to 5 mg / eye, and particularly preferably 0.2 to 1.6 mg / eye.
- the administration interval is not particularly limited as long as it is sufficient to achieve a desired drug effect, but once a week to 3 years.
- the administration interval is administered at one time interval, once a week, once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months More preferably once every six months, once every year, once every two years or once every three years, once every two months, once every three months, Most preferably, it is administered once every 4 months, once every 5 months, once every 6 months or once a year.
- the administration interval can be appropriately changed according to the type of drug, sustained release of the drug, patient symptoms, and the like.
- the composition of the present invention is useful as a medicine, and particularly useful for preventing or treating eye diseases.
- Specific diseases that can be prevented and treated by the composition of the present invention include age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, retinal artery occlusion, polypoidal choroidal vasculopathy, retina Hemangiomatous growth, myopic choroidal neovascularization, diabetic macular edema, eye tumor, radiation retinopathy, iris rubeosis, neovascular glaucoma, proliferative vitreoretinopathy (PVR), primary open-angle glaucoma, secondary Open-angle glaucoma, normal-tension glaucoma, aqueous production hyperglaucoma, primary occlusion angle glaucoma, secondary occlusion angle glaucoma, plateau iris glaucoma, mixed glaucoma, developmental glaucoma,
- the pharmaceutical composition of the present invention has a sustained release property and can release the administered drug of the present invention slowly in the body, so-called sustained release of the drug.
- the sustained release can be evaluated, for example, by measuring the drug release rate over time.
- the release rate is, for example, preferably 60% or less after 1 day, more preferably 1 to 50%, still more preferably 1 to 45%. Further, the release rate after 6 days is preferably 97% or less, more preferably 5 to 95%, and even more preferably 10 to 90%.
- sustained-release property is obtained by producing a lump or, in other words, a so-called “depot” when the pharmaceutical composition of the present invention or the sustained-release agent for drugs described below is administered into the body. This is achieved by slowly releasing the drug present in the object etc. from the depot.
- the sustained release agent for drugs of the present invention is capable of imparting sustained release to a drug, and comprises a polypeptide represented by Ac- (Arg-Ala-Asp-Ala) 4 -NH 2 , Containing an organic solvent.
- the organic solvent is at least one organic solvent selected from the group consisting of polyethylene glycol, dimethyl sulfoxide, glycofurol and N-methylpyrrolidone.
- the description of the above-mentioned pharmaceutical composition can be applied to this sustained release agent as it is.
- the ratio of the sustained-release imparting agent of the present invention to the drug is, for example, 0.01: 99.99 to 30:70, preferably 0.1: 99.9 to 25:75, more preferably, by mass ratio. 0.5: 99.5 to 20:80, more preferably 1:99 to 15:85, and particularly preferably 1:99 to 12:88.
- Formulation Example A typical formulation example of the present invention is shown below.
- the compounding amount of each component is the content in 100 mL of the composition.
- a desired composition can be obtained by appropriately adjusting the compounding amounts of the drug, polypeptide A, and solvent in Preparation Examples 1 to 6.
- Table 1 shows the test results. As can be seen from Table 1, a solution containing DMSO or PEG400 can dissolve drugs that are not soluble in water.
- polypeptide A formed a depot when DMSO, PEG200, PEG400, glycofurol (a mixture having a polymerization number of 1 to 4 mainly) and N-methylpyrrolidone were used as solvents.
- DMSO, PEG200, PEG400, glycofurol (a mixture having a polymerization number of 1 to 4 mainly) and N-methylpyrrolidone were used as solvents.
- ethanol and N, N-dimethylacetamide were used as solvents, no depot was formed. Therefore, it was shown that the sustained release imparting agent of the present invention forms a depot when administered into the body together with a drug, and can release the drug slowly.
- test composition 0.25 g of drug A was added to 8 mL of PEG400 (Nacalai Tesque) and dissolved by stirring to obtain composition A. 0.4 mL of water was added to 1.6 mL of Composition A, and dissolved by stirring to obtain Composition B. 1 mL of a 1% (w / v) aqueous solution of polypeptide A (containing 1% by mass of polypeptide A with respect to 100 mL of water) is collected in a standard bottle and lyophilized at ⁇ 35 to 30 ° C.
- Composition C A1.6 mL of A and 0.4 mL of water were added and mixed by stirring to obtain Composition C.
- Composition B 0.7mL was added to composition C0.7mL, and it stirred and mixed, and obtained the composition D.
- Composition B 0.8mL was added to composition C0.2mL, it stirred and mixed, and the composition E was obtained.
- 25 mg of Drug A was added to 1 mL of PEG400 (Nacalai Tesque), and dissolved by stirring to obtain Composition F.
- Test method Water was added to 10 g of polyoxyl 40 stearate (Nikko Chemicals) and 9.6 g of Dulbecco's phosphate buffer (Sigma Aldrich) to make the total volume 1 L (release solvent). 20 mL of the release solvent heated to 37 ° C. was put into a standard bottle, 0.01 mL of each of Composition C to F test solutions was added, and then stirred at 37 ° C. and 86 rpm for 6 days. The amount of drug A released into the release solvent was quantified using high performance liquid chromatography (HPLC) to calculate the release rate (%). The release rate was calculated based on the following formula.
- HPLC high performance liquid chromatography
- Release rate (%) [Drug release (mass)] / [Initial dose (dose) (mass)] ⁇ 100
- the release rate is calculated as follows: [Initial dose of drug (administration (Amount) (mass)] is the amount of drug input at the time of drug input (day 0), and “drug release amount (mass)” is the amount of drug released after 1 day.
- compositions C to E formed a depot after being introduced into the release solvent, and sustained release of drug A over 1 to 6 days.
- the pharmaceutical composition of the present invention dissolves a drug and forms a depot when administered into the body to release the drug slowly.
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Abstract
Description
特許文献1及び非特許文献1には、自己組織化ペプチドとしてAc-(Arg-Ala-Asp-Ala)4-CONH2(配列番号1)で表されるポリペプチドを使用した水溶性薬剤であるインスリンの徐放製剤が開示されている。また、非特許文献2には、Ac-(Arg-Ala-Asp-Ala)4-CONH2で表されるポリペプチドを用い、薬物としてピンドロール、キニン及びマレイン酸チモロールを包含した徐放製剤が開示されている。ここで、上記文献中、Ac-(Arg-Ala-Asp-Ala)4-CONH2で表されるポリペプチドは、PuraMatrix(登録商標)であるが、PuraMatrix(登録商標)は、Ac-(Arg-Ala-Asp-Ala)4-NH2とも表されることから、本明細書では、PuraMatrix(登録商標)をAc-(Arg-Ala-Asp-Ala)4-NH2と記載する(配列番号1)。
しかしながら、これら文献に記載の徐放製剤は、水のみが溶媒として使用されており、いずれの文献にも、薬物及びAc-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドを含有する医薬組成物の溶媒として、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される有機溶媒を使用することは記載されておらず、該医薬組成物が薬物の徐放製剤として有用であることも一切記載されていない。
〔1〕薬物と、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドと、有機溶媒とを含有する医薬組成物であって、
前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、医薬組成物。
〔2〕さらに、水を含有する、前記〔1〕記載の医薬組成物。
〔3〕前記有機溶媒と水の体積比が99:1~60:40である、前記〔2〕記載の医薬組成物。
〔4〕前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールの平均分子量が90から2200の範囲内である、前記〔1〕~〔3〕のいずれか一項に記載の医薬組成物。
〔5〕前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールがPEG400である、前記〔1〕~〔3〕のいずれか一項に記載の医薬組成物。
〔6〕前記薬物の含有量が、0.01~30%(w/v)である、前記〔1〕~〔5〕のいずれか一項に記載の医薬組成物。
〔7〕前記Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドの含有量が、0.001~5%(w/v)である、前記〔1〕~〔6〕のいずれか一項に記載の医薬組成物。
〔8〕前記有機溶媒の含有量が70~99.99%(w/w)である、前記〔1〕~〔7〕のいずれか一項に記載の医薬組成物。
〔9〕薬物、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、ポリエチレングリコール、及び水のみから実質的になる、前記〔1〕~〔8〕のいずれか一項に記載の医薬組成物。
〔10〕薬物、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、及びジメチルスルホキシドのみから実質的になる、前記〔1〕に記載の医薬組成物。
〔11〕薬物が、式(1):
[式中、
R1は水素原子、ハロゲン原子、ヒドロキシル基、C1-6アルキル基、1個若しくは複数個のハロゲン原子で置換されたC1-6アルキル基、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、;
R2は水素原子、C1-6アルキル基、C1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す]
で表される化合物又はその塩である、前記〔1〕~〔10〕のいずれか一項に記載の医薬組成物。
〔12〕薬物が、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミド又はその塩である、前記〔1〕~〔10〕のいずれか一項に記載の医薬組成物。
〔13〕眼疾患を予防又は治療するための、前記〔1〕~〔12〕のいずれか一項に記載の医薬組成物。
〔14〕硝子体内又は前房内投与用である、前記〔13〕に記載の医薬組成物。
〔15〕薬物徐放用である、前記〔13〕又は〔14〕に記載の医薬組成物。
〔16〕Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドと、有機溶媒とを含有する薬物用徐放性付与剤であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、徐放性付与剤。
〔17〕薬物に、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド及び有機溶媒を添加する工程を含む、薬物に徐放性を付与する方法であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、方法。
本発明の徐放性付与剤は、薬物に良好な徐放性を付与するのに適している。
本発明の薬物に徐放性を付与する方法は、薬物に良好な徐放性を付与することができる。
<ポリペプチド>
本発明におけるポリペプチドは、Ac-(Arg-Ala-Asp-Ala)4-NH2(配列番号1)で表されるポリペプチド(以下、ポリペプチドAともいう)は、PuraMatrix(登録商標)として株式会社スリー・ディー・マトリックスより販売されている。C末端のカルボキシル基(COOH)はアミド化(CONH2)されている。
当該ポリペプチドAの含有量は、特に制限はないが、0.001~5%(w/v)が好ましく、0.005~3%(w/v)がより好ましく、0.01~2%(w/v)がさらに好ましく、0.05~1%(w/v)が特に好ましく、0.1~0.5%(w/v)が最も好ましい。なお、「%(w/v)」は、本発明の医薬組成物100mL中に含まれる対象成分(ここでは、ポリペプチドA)の質量(g)を意味する。以下、特に断りがない限り同様とする。
本発明における薬物に特に制限はないが、疎水性薬物であることが好ましい。疎水性薬物とは、水に溶解しにくい薬物のことであり、疎水性の程度は分配係数CLogP等を指標にして表される。CLogPとは、化学物質の1-オクタノール/水系の分配係数の対数を計算により求めた値であり、その詳細は特開2009-298878号公報などに記載されている。本発明における薬物として、分配係数CLogPが0.5以上で規定される疎水性薬物が好ましく、CLogPが1以上20以下の薬物がより好ましく、1.5以上15以下の薬物がさらに好ましく、2以上12以下の薬物さらに好ましく、2.2以上9以下の化合物が特に好ましく、2.5以上8以下の化合物が最も好ましい。本発明における薬物の具体例としては、Tafetinib、SIM-817378、ACTB-1003、Chiauranib、CT-53608、Cinnamon、chim4G8-SDIE、CEP-5214、IMC-1C11、CEP-7055、3-[5-[2-[N-(2-Methoxyethyl)-N-methylamino]ethoxy]-1H-indol-2-yl]quinolin-2(1H)-one、hF4-3C5、ZK-CDK、IMC-EB10、LS-104、CYC-116、OSI-930、PF-337210、JNJ-26483327、SSR-106462、R-1530、PRS-050、TG-02、SC-71710、SB-1578、AMG-191、AMG-820、Sulfatinib、Lucitanib hydrochloride、JNJ-28312141、Ilorasertib、PLX-5622、ARRY-382、TAS-115、Tanibirumab、Henatinib、LY-2457546、PLX-7486、FPA-008、NVP-AEE-788、cgi-1842、RAF-265、MK-2461、SG-00529、Rebastinib、Golvatinib、Roniciclib、BVT-II、X-82、XV-615、KD-020、Lestaurtinib、Delphinidin、Semaxanib、Vatalanib、OSI-632、Telatinib、Alacizumab pegol、ATN-224、Tivozanib、XL-999、Icrucumab、Foretinib、Crenolanib besylate、R-406、Brivanib、Pegdinetanib、TG-100572、Olaratumab、Fostamatinib disodium、BMS-690514、AT-9283、MGCD-265、Quizartinib、ENMD-981693、Famitinib、Anlotinib、Tovetumab、PLX-3397、Fruquintinib、(-)-Epigallocatechin、Midostaurin、NSC-706456、Orantinib、Cediranib、Dovitinib、XL-647、Motesanib、Linifanib、Brivanib、Cediranib、Apatinib、Fedratinib、Pacritinib、Ramucirumab、Intedanib、Masitinib、Elemene、Dihydroartemisinin、WS-1442、Itranazole、Leflunomide、Dihydroartemisinin、Imatinib、Sorafenib、Sunitinib、Dasatinib、Pazopanib、Vandetanib、Axitinib、Regorafenib、Cabozantinib及びPonatinib等のチロシンキナーゼ阻害剤、ハイドロコルチゾン、トリアムシノロン、フルオシノロン、デキサメタゾン、ベタメタゾン等のステロイド、イソプロピルウノプロストン、ラタノプロスト、ビマトプロスト、トラボプロスト等のプロスタグランジン誘導体、シクロスポリン、シロリムス、FK506等の免疫抑制剤、アゼラスチン等の抗アレルギー剤、インドメタシン、ブロムフェナク、ジクロフェナク等の非ステロイド性抗炎症剤、パゾパニブ、SU5416、バラチニブ、ラニビズマブ、ベバシズマブなどの血管新生阻害薬、ニカルジピン、ニトレンジピン等の循環改善薬、ビタミンEなどの抗酸化剤、アセタゾラミド、ブリンゾラミドなどの炭酸脱水酵素阻害剤、チモロール、カルテオロール等のβ受容体遮断薬、ビタミンA誘導体等のビジュアルサイクルモジュレーター、毛様体栄養因子(CNTF)、脳由来神経栄養因子(BDNF)等の栄養因子や神経成長因子(NGF)、幹細胞増殖因子(HGF)等の成長因子、ペガプタニブのようなアプタマー、各種アンチセンス核酸、siRNAのような核酸医薬、ルセンティス、IgGなどの抗体・ペプチド製剤、特開2006-96739、特開2011-37844、特開2005-232149、特開2006-273851、特開2006-306861、特開2008-266294などに記載のVEGF阻害剤、特開2007-230993、特開2008-074829、特開2008-143889、特開2008-143890、特開2008-143891、特開2009-007344、特開2009-084274などに記載のグルココルチコイド受容体結合活性を有する化合物、RU24858などの選択的グルココルチコイド受容体アゴニスト、フルオロウラシルなどの抗癌剤、トファシチニブなどのヤヌスキナーゼ阻害剤、ルボキシスタウリンメシレートなどのプロテインキナーゼ阻害剤、等が挙げられる。
[式中、
R1は水素原子、ハロゲン原子、ヒドロキシル基、C1-6アルキル基、1個若しくは複数個のハロゲン原子で置換されたC1-6アルキル基、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、;
R2は水素原子、C1-6アルキル基、C1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す]
で表される化合物又はその塩を使用することが好適である。より好ましくは、R1が、C1-6アルコキシ基又は1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、R2がC1-6アルキルカルボニル基又は1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す上記式(1)の化合物またはその塩であり、さらに好ましくは、R1が、1個若しくは複数個のハロゲン原子で置換されたC1-6アルコキシ基を示し、R2が1個若しくは複数個のヒドロキシル基で置換されたC1-6アルキルカルボニル基を示す上記式(1)の化合物またはその塩である。
「C1-6アルキル基」とは、炭素原子数1~6個の直鎖又は分枝のアルキル基を示し、炭素原子数が1~4個の直鎖又は分枝のアルキル基が好ましい。具体例としてメチル基、エチル基、n-プロピル基、n-ブチル基、n-ペンチル基、n-ヘキシル基、イソプロピル基、イソブチル基、sec-ブチル基、tert-ブチル基、イソペンチル基などが挙げられる。
「1個若しくは複数個のヒドロキシル基で置換された」とは、前記C1-6アルキル基が、1個以上、置換可能な数以下の個数のヒドロキシル基で置換されていることを示す。ヒドロキシル基の個数は1又は2個の場合が好ましく、1個の場合が特に好ましい。
で表される2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミド又はその塩である。米国特許出願公開第2007/0149574号明細書には、式(2)で表される化合物などが、VEGF誘発HUVEC増殖反応評価系を用いた試験系において細胞増殖阻害作用を示すこと、マウス担癌モデルを用いた試験系において腫瘍増殖抑制作用を示すこと、ラットアジュバント関節炎モデルを用いた試験系において足浮腫抑制作用を示すこと、ラット脈絡膜血管新生モデルを用いた試験系において脈絡膜血管新生阻害作用を示すことが記載されている。さらに、それらの薬理作用から式(2)で表される化合物は、医薬として有用であり、特に癌、関節リウマチ、加齢性黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫などの疾患の予防または治療剤として期待されることが記載されている。
また、米国特許出願公開第2012/0116088号明細書には、式(2)で表される化合物のベンゼンスルホン酸塩、その結晶、その結晶多形およびそれらの製造方法が記載されており、式(2)で表される化合物のベンゼンスルホン酸塩は、保存安定性に優れ、反復経口投与を行っても胃に鉱質沈着が認められないことが記載されている。
本発明における薬物に幾何異性体、互変異性又は光学異性体が存在する場合は、それらの異性体も本発明の範囲に含まれる。
さらに本発明における薬物に結晶多形が存在する場合は、結晶多形体も本発明の範囲に含まれる。
本発明における有機溶媒は、ポリエチレングリコール(PEG)、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される。
上記有機溶媒としてのポリエチレングリコール(PEG)は、エチレングリコールが重合したポリエーテルであり、化学式HO(CH2CH2O)nHで表され、nは重合数である。
上記有機溶媒としてのジメチルスルホキシド(DMSO)は、化学式CH3SOCH3で表される化合物である。
上記有機溶媒としてのN-メチルピロリドンは、テトラヒドロフランとポリエチレングリコールからなる下記式(4)で表される化合物である。
上記ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される有機溶媒のほか、さらに、水、エタノール、N,N-ジメチルアセトアミド等の医薬品の添加物として使用可能な溶媒を含有することができる。特に、ポリペプチドAを溶解する観点から、水を含有することが好ましい。
本発明における医薬組成物は、必要に応じて添加剤を用いることができ、添加剤としては、界面活性剤、緩衝化剤、等張化剤、安定化剤、防腐剤、抗酸化剤、高分子量重合体等を加えることができる。
ショ糖脂肪酸エステルとしては、ショ糖ステアリン酸エステル等が挙げられる。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(1)で表される化合物又はその塩、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、ポリエチレングリコール、及び、水のみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(2)で表される化合物又はその塩、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、ポリエチレングリコール、及び、水のみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、薬物、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(1)で表される化合物又はその塩、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
本発明における医薬組成物の、好ましい具体的な態様は、実質的に、式(2)で表される化合物又はその塩、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、及び、ジメチルスルホキシドのみからなる医薬組成物である。
放出率(%)=[薬物の放出量(質量)]/[薬物の初期量(投与量)(質量)]×100
放出率としては、例えば1日経過後の放出率が、60%以下であることが好ましく、1~50%であることがより好ましく、1~45%であることがさらに好ましい。また、6日後の放出率が、97%以下であることが好ましく、5~95%であることがより好ましく、10~90%であることがさらに好ましい。
上記徐放性は、本発明の医薬組成物や後述する薬物用徐放性付与剤が体内に投与された場合、塊、いいかえると、いわゆる「デポ(depot)」を生じることにより、これら医薬組成物等に存在する薬物がデポからゆっくりと放出されることで達成される。
本発明の薬物用徐放性付与剤は、薬物に徐放性を付与することができるものであり、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドと、有機溶媒とを含有する。当該有機溶媒は、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である。各成分及び追加の添加剤等の詳細に関しては、上述した医薬組成物の記載をそのままこの徐放性付与剤に適用できる。例えば、ポリペプチド及び溶媒の詳細は、上述したとおりであり、上述した添加剤を加えることができる点も上記医薬組成物の説明と同様である。本発明の徐放性付与剤:薬物の割合が、例えば、質量比で、0.01:99.99~30:70、好ましくは、0.1:99.9~25:75、より好ましくは、0.5:99.5~20:80、さらに好ましくは、1:99~15:85、特に好ましくは、1:99~12:88であることが適当である。
以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は組成物100mL中の含量である。
薬物 4g
ポリペプチドA 0.1g
PEG400/水(体積比9/1) 適量
薬物 4g
ポリペプチドA 0.5g
PEG400/水(体積比9/1) 適量
薬物 4g
ポリペプチドA 0.1g
PEG400/水(体積比8/2) 適量
薬物 4g
ポリペプチドA 0.5g
PEG400/水(体積比8/2) 適量
薬物 4g
ポリペプチドA 0.1g
DMSO 適量
薬物 4g
ポリペプチドA 0.5g
DMSO 適量
各種溶液の薬物溶解能を検討した。
1-1.試験方法
上記式(2)で表される化合物(2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミド、以下、薬物Aともいう;米国特許出願公開第2007/0149574号明細書記載の方法に準じて調製した)をDMSO(GAYLORD)、PEG400(ナカライテスク)又は水からなる各種溶媒(合計1mL)に加え、室温(25℃)で終夜(8時間)撹拌したときの性状を目視にて確認した。
各種ゲル化剤のデポ(塊)の形成を検討した。
2-1.試験方法
各種ゲル化剤を0.1%(w/v)となるようにDMSO/水(体積比9:1)の溶媒に配合し(100mLのDMSO/水に対してゲル化剤が0.1質量%含有)、組成物1~6を調製した。ダルベッコリン酸緩衝液(-)(Sigma-Aldrich製、製品番号D-5652)に塩化カルシウム二水和物及び塩化マグネシウム六水和物を溶解させてダルベッコリン酸緩衝液(+)を調製した。各組成物0.005mLをダルベッコリン酸緩衝液(+)1mLに投与し、デポの形成を目視にて確認した。デポの形成は、塊ができていたらデポが形成されているものと評価した。
2-2.試験結果及び考察
試験結果を表2に示す。表2から分かるように、各種ゲル化剤のなかで、ポリペプチドAのみが体積比でDMSO/水(9:1)溶液でもデポを形成した。従って、本発明の徐放性付与剤は、薬物と共に体内に投与されるとデポを形成して、当該薬物を徐放し得ることが示された。
ポリペプチドAの溶媒を検討した。
3-1.試験方法
各種溶媒0.09mLに1%(w/v)ポリペプチドA水溶液(水100mLに対してポリペプチドAが1質量%含有)を0.01mL加えて撹拌し、組成物2~6及び比較例6~7を調製した。そのうち0.005mLをダルベッコリン酸緩衝液(+)1mLに投与し、デポの形成を目視にて確認した。
3-2.試験結果及び考察
試験結果を表3に示す。表3から分かるように、ポリペプチドAは、DMSO、PEG200、PEG400、グリコフロール(重合数が主に1~4の混合物)及びN-メチルピロリドンを溶媒として用いた場合にデポを形成した。一方、エタノール及びN,N-ジメチルアセトアミドを溶媒用いた場合には、デポを形成しなかった。従って、本発明の徐放性付与剤は、薬物と共に体内に投与されるとデポを形成して、当該薬物を徐放し得ることが示された。
デポからの薬物徐放性を検討した。
4-1.被験組成物の調製
薬物A0.25gをPEG400(ナカライテスク)8mLに加え、撹拌溶解し、組成物Aを得た。
組成物A1.6mLに水0.4mLを加え、撹拌溶解し、組成物Bを得た。
1%(w/v)のポリペプチドA水溶液(水100mLに対してポリペプチドAが1質量%含有)1mLを規格瓶に1mL採取し、-35~30℃にて凍結乾燥して、組成物A1.6mL及び水0.4mLを加え、撹拌混合し、組成物Cを得た。
組成物C0.7mLに組成物B0.7mLを加え、撹拌混合し、組成物Dを得た。
組成物C0.2mLに組成物B0.8mLを加え、撹拌混合し、組成物Eを得た。
薬物Aを25mgをPEG400(ナカライテスク)1mLに加え、撹拌溶解し、組成物Fを得た。
10gのステアリン酸ポリオキシル40(日光ケミカルズ)とダルベッコリン酸緩衝液(シグマアルドリッチ)9.6gに水を加え、全量を1Lとした(放出溶媒)。
37℃に加温した放出溶媒を20mLずつ規格瓶に投入し、組成物C~F試験液を0.01mLずつ投入した後、37℃、86rpmで6日間撹拌した。放出溶媒中に放出された薬物Aの量を高速液体クロマトグラフィー(HPLC)を用いて定量し、放出率(%)を算出した。放出率は、以下の式に基づいて算出した。
放出率(%)=[薬物の放出量(質量)]/[薬物の初期量(投与量)(質量)]×100
上記式において、例えば、各組成物の試験液を放出溶媒に投入した日を0日とし、1日(24時間)経過後を1日後として放出率を算出する場合、[薬物の初期量(投与量)(質量)]は、薬物投入時(0日)の薬物の投入量であり、「薬物の放出量(質量)」は、1日経過後の薬物の放出量である。
試験結果を表4に示す。表4から分かるように、組成物C~Eは、放出溶媒に投入後、デポを形成し、1日~6日間かけて薬物Aを徐放した。
Claims (17)
- 薬物と、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドと、有機溶媒とを含有する医薬組成物であって、
前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、医薬組成物。 - さらに、水を含有する、請求項1記載の医薬組成物。
- 前記有機溶媒と水の体積比が99:1~60:40である、請求項2記載の医薬組成物。
- 前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールの平均分子量が90から2200の範囲内である、請求項1~3のいずれか一項に記載の医薬組成物。
- 前記有機溶媒がポリエチレングリコールであり、該ポリエチレングリコールがPEG400である、請求項1~3のいずれか一項に記載の医薬組成物。
- 前記薬物の含有量が、0.01~30%(w/v)である、請求項1~5のいずれか一項に記載の医薬組成物。
- 前記Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドの含有量が、0.001~5%(w/v)である、請求項1~6のいずれか一項に記載の医薬組成物。
- 前記有機溶媒の含有量が70~99.99%(w/w)である、請求項1~7のいずれか一項に記載の医薬組成物。
- 薬物、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、ポリエチレングリコール、及び水のみから実質的になる、請求項1~8のいずれか一項に記載の医薬組成物。
- 薬物、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド、及びジメチルスルホキシドのみから実質的になる、請求項1に記載の医薬組成物。
- 薬物が、2-[[[2-[(ヒドロキシアセチル)アミノ]-4-ピリジニル]メチル]チオ]-N-[4-(トリフルオロメトキシ)フェニル]-3-ピリジンカルボキサミド又はその塩である、請求項1~10のいずれか一項に記載の医薬組成物。
- 眼疾患を予防又は治療するための、請求項1~12のいずれか一項に記載の医薬組成物。
- 硝子体内又は前房内投与用である、請求項13に記載の医薬組成物。
- 薬物徐放用である、請求項13又は14に記載の医薬組成物。
- Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチドと、有機溶媒とを含有する薬物用徐放性付与剤であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、徐放性付与剤。
- 薬物に、Ac-(Arg-Ala-Asp-Ala)4-NH2で表されるポリペプチド及び有機溶媒を添加する工程を含む、薬物に徐放性を付与する方法であって、前記有機溶媒が、ポリエチレングリコール、ジメチルスルホキシド、グリコフロール及びN-メチルピロリドンからなる群より選択される少なくとも1種の有機溶媒である、方法。
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CA2979802A CA2979802C (en) | 2015-03-17 | 2016-03-16 | Pharmaceutical composition comprising polypeptide |
KR1020177029851A KR102538806B1 (ko) | 2015-03-17 | 2016-03-16 | 폴리펩티드를 함유하는 의약 조성물 |
ES16765030T ES2935917T3 (es) | 2015-03-17 | 2016-03-16 | Composición farmacéutica que comprende polipéptidos |
CN201680015948.1A CN108064171B (zh) | 2015-03-17 | 2016-03-16 | 含有多肽的医药组合物 |
US15/558,893 US9987368B2 (en) | 2015-03-17 | 2016-03-16 | Pharmaceutical composition comprising polypeptide |
EP16765030.8A EP3272360B1 (en) | 2015-03-17 | 2016-03-16 | Pharmaceutical composition comprising polypeptide |
RU2017134594A RU2726625C2 (ru) | 2015-03-17 | 2016-03-16 | Фармацевтическая композиция, включающая полипептид |
HK18102936.3A HK1243347A1 (zh) | 2015-03-17 | 2018-02-28 | 含有多肽的藥物組合物 |
HK18114714.6A HK1255586A1 (zh) | 2015-03-17 | 2018-11-16 | 含有多肽的醫藥組合物 |
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EP (1) | EP3272360B1 (ja) |
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HK (2) | HK1243347A1 (ja) |
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ES2368153T3 (es) * | 2004-02-17 | 2011-11-14 | Santen Pharmaceutical Co., Ltd. | Nuevo compuesto cíclico que presenta un grupo 4-piridilalquiltio que presenta amino (no) sustituido introducido en el mismo. |
EA019689B1 (ru) * | 2009-07-17 | 2014-05-30 | Сантен Фармасьютикал Ко., Лтд. | Бензолсульфонат 2-[[[2-[(гидроксиацетил)амино]-4-пиридинил]метил]тио]-n-[4-(трифторметокси)фенил]-3-пиридинкарбоксамида, его кристаллы, его полиморфы и способы их получения |
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CA2979802A1 (en) | 2016-09-22 |
US20180064818A1 (en) | 2018-03-08 |
EP3272360A1 (en) | 2018-01-24 |
RU2017134594A3 (ja) | 2019-08-23 |
HK1243347A1 (zh) | 2018-07-13 |
CA2979802C (en) | 2023-06-27 |
RU2726625C2 (ru) | 2020-07-15 |
ES2935917T3 (es) | 2023-03-13 |
KR102538806B1 (ko) | 2023-05-31 |
CN108064171A (zh) | 2018-05-22 |
TW201639589A (zh) | 2016-11-16 |
JP6709088B2 (ja) | 2020-06-10 |
TWI677346B (zh) | 2019-11-21 |
US9987368B2 (en) | 2018-06-05 |
EP3272360B1 (en) | 2022-11-23 |
CN108064171B (zh) | 2021-07-13 |
EP3272360A4 (en) | 2018-05-02 |
JP2016172730A (ja) | 2016-09-29 |
RU2017134594A (ru) | 2019-04-05 |
HK1255586A1 (zh) | 2019-08-23 |
KR20170129832A (ko) | 2017-11-27 |
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