CN111632025A - Temperature-sensitive in-situ gel for bimatoprost eyes and preparation method and application thereof - Google Patents
Temperature-sensitive in-situ gel for bimatoprost eyes and preparation method and application thereof Download PDFInfo
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- CN111632025A CN111632025A CN202010149340.6A CN202010149340A CN111632025A CN 111632025 A CN111632025 A CN 111632025A CN 202010149340 A CN202010149340 A CN 202010149340A CN 111632025 A CN111632025 A CN 111632025A
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- poloxamer
- bimatoprost
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- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 title claims abstract description 103
- 229960002470 bimatoprost Drugs 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 36
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 82
- 239000000203 mixture Substances 0.000 claims abstract description 76
- 229920001992 poloxamer 407 Polymers 0.000 claims abstract description 39
- 229940044476 poloxamer 407 Drugs 0.000 claims abstract description 39
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 36
- 229940044519 poloxamer 188 Drugs 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229920001983 poloxamer Polymers 0.000 claims abstract description 12
- 239000006184 cosolvent Substances 0.000 claims abstract description 11
- 229960000502 poloxamer Drugs 0.000 claims abstract description 7
- 206010030043 Ocular hypertension Diseases 0.000 claims abstract description 4
- 206010030348 Open-Angle Glaucoma Diseases 0.000 claims abstract description 4
- 201000006366 primary open angle glaucoma Diseases 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 84
- 238000004090 dissolution Methods 0.000 claims description 26
- 239000012154 double-distilled water Substances 0.000 claims description 25
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 24
- 229920000053 polysorbate 80 Polymers 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 238000007789 sealing Methods 0.000 claims description 12
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 10
- 229920000136 polysorbate Polymers 0.000 claims description 7
- -1 polyethylene Polymers 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 229920001400 block copolymer Polymers 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 239000004632 polycaprolactone Substances 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004626 polylactic acid Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 230000001954 sterilising effect Effects 0.000 claims description 2
- 239000000080 wetting agent Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims 3
- 239000012153 distilled water Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 10
- 239000003889 eye drop Substances 0.000 abstract description 6
- 229940012356 eye drops Drugs 0.000 abstract description 5
- 206010015946 Eye irritation Diseases 0.000 abstract description 2
- 208000010412 Glaucoma Diseases 0.000 abstract description 2
- 210000004087 cornea Anatomy 0.000 abstract description 2
- 239000002552 dosage form Substances 0.000 abstract description 2
- 231100000013 eye irritation Toxicity 0.000 abstract description 2
- 239000000607 artificial tear Substances 0.000 description 30
- 238000010790 dilution Methods 0.000 description 22
- 239000012895 dilution Substances 0.000 description 22
- 238000001879 gelation Methods 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 14
- 239000012085 test solution Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 10
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- 230000003628 erosive effect Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000003093 cationic surfactant Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical class C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229960002233 benzalkonium bromide Drugs 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 229940100655 ophthalmic gel Drugs 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DARPYRSDRJYGIF-PTNGSMBKSA-N (Z)-3-ethoxy-2-naphthalen-2-ylsulfonylprop-2-enenitrile Chemical compound C1=CC=CC2=CC(S(=O)(=O)C(\C#N)=C/OCC)=CC=C21 DARPYRSDRJYGIF-PTNGSMBKSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- HDTIFOGXOGLRCB-VVGYGEMISA-N 2-[2-[(2r,3r)-3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCOCC(OCCO)[C@H]1OCC(OCCO)[C@H]1OCCO HDTIFOGXOGLRCB-VVGYGEMISA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004283 Sodium sorbate Substances 0.000 description 1
- 238000011111 UV-scan method Methods 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000004424 eye movement Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 description 1
- 235000019250 sodium sorbate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000004520 water soluble gel Substances 0.000 description 1
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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
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a temperature-sensitive in-situ gel for bimatoprost eyes and a preparation method and application thereof. The ophthalmic bimatoprost composition comprises: bimatoprost, poloxamer, cosolvent and water; wherein the poloxamers include poloxamer 407 and poloxamer 188. The composition is suitable for primary open-angle glaucoma and ocular hypertension with high incidence rate. The composition is liquid at normal temperature, forms a semisolid gel state when being dripped into eyes, adheres to the surfaces of cornea and conjunctival sac to delay the release of the medicine, not only can solve the problems of short residence time and low bioavailability of the eye part of the conventional eye drops, but also overcomes the problems of poor spreadability and difficult dose control of the common eye gel preparation, can avoid eye irritation caused by using dosage forms such as emulsifiable paste and the like, and is an eye preparation for treating glaucoma with great economic benefit and development potential.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a temperature-sensitive in-situ gel for bimatoprost eyes, and a preparation method and application thereof.
Background
Bemeprostil (British name: Bimatoprost; chemical name: (Z) -7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- [ (1E,3S) -3-hydroxy-5-phenyl-1-pentenyl ] cyclopentyl ] -5-N-ethylheptenamide) is a unique drug, which is a synthetic prostamide that selectively mimics the action of naturally occurring prostamides, which has a dual mechanism of pressure reduction that reduces intraocular pressure by increasing outflow of aqueous humor through the trabecular meshwork and the grape sclera. The prostaglandin fatty acid amide analogue developed by Allergan company of the Beimeiprost system is firstly marketed in the United states in 3 months in 2001, is clinically used for treating glaucoma, and has good intraocular pressure reducing effect and safety.
Currently, the eye drop preparations of the bimatoprost are eye drops. Due to winks and eye movements, the conventional eye drops have short eye retention time and low bioavailability. The temperature-sensitive gel preparation is a preparation which can immediately generate phase change along with the change of temperature at an application part after being administrated in a solution state and is converted into semisolid gel from a liquid state. For example, an ophthalmic temperature-sensitive gel is in a solution state at room temperature, and after administration in a liquid conjunctival sac, a phase transition occurs in time in the eye to form a semisolid gel.
At present, clinical bimatoprost pharmaceutical preparations mainly comprise eye drops, and no ophthalmic temperature-sensitive in-situ gel preparation exists, and no related literature reports about the preparation.
Disclosure of Invention
In order to improve the above problems, the present invention provides a bimatoprost ophthalmic composition comprising: bimatoprost, poloxamer, cosolvent and water;
wherein the poloxamers include poloxamer 407 and poloxamer 188.
According to an embodiment of the invention, the concentration of bimatoprost in the composition is 0.01-0.1%, for example 0.02-0.06%, exemplarily 0.03%, by mass volume percentage.
According to an embodiment of the invention, the concentration of poloxamer 407 in the composition is 17-25%, such as 18-24%, exemplarily 18%, 19.17%, 20%, 21%, 22%, 23%, 24.83% in mass volume percentage.
According to an embodiment of the invention, the concentration of poloxamer 188 in the composition is 0-8%, such as 1-6%, exemplarily 1.17%, 2%, 3%, 4%, 5%, 6.83% in mass volume percentage.
According to an embodiment of the invention, the mass ratio of poloxamer 407 to poloxamer 188 in the composition is (2-20):1, e.g. (3-12):1, exemplarily 24.83:6.83, 5.5:1, 21:2, 19.17: 1.17.
According to an embodiment of the present invention, the cosolvent may be selected from at least one of tween (polysorbate), polyethylene glycol-polylactic acid block copolymer (PEG-PLA), polyethylene glycol/polycaprolactone multi-block copolymer, chitosan, and the like, for example, tween, exemplified by tween 80. Wherein the concentration of co-solvent in the composition is 0.1-5%, such as 0.5-3%, exemplary 0.8%, 1%, 1.5% by mass volume.
According to an embodiment of the present invention, other pharmaceutical excipients, such as at least one of preservatives, wetting agents, and buffers, etc., may also be included in the composition. Preferably, these pharmaceutical excipients do not have an effect on the essential properties of the composition, in particular the phase transition temperature. For example, the other pharmaceutical excipients may be selected from excipients known in the art for ophthalmic formulations.
For example, the preservative may be selected from at least one of cationic surfactants, alcohol compounds, ester compounds, sorbic acid, sorbate salts, and the like, for example, from cationic surfactants. The cationic surfactant may be selected from quaternary ammonium compounds, and may be at least one of benzalkonium chloride and benzalkonium bromide, for example. Wherein, the alcohol compound can be at least one selected from benzyl alcohol and chlorobutanol; wherein the ester compound may be selected from hydroxyphenyl esters, such as at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, n-propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.; wherein the sorbate may be at least one selected from potassium sorbate and sodium sorbate. Illustratively, the preservative may be selected from benzalkonium chloride or benzalkonium bromide.
For example, the humectant may be selected from at least one of glycerin, ethanol, propylene glycol, and the like;
for example, the buffer may be selected from at least one of phosphate buffer, borate buffer, and the like.
The concentration of the pharmaceutical excipients can be selected from the known concentrations in the field, and the skilled person can understand that the content of each pharmaceutical excipient can be adjusted within the range that the pharmaceutical excipient can exert the corresponding effect.
According to an embodiment of the invention, the water may be selected from redistilled water or purified water, preferably redistilled water, exemplified by double distilled water.
According to an embodiment of the invention, the composition comprises, in mass volume percent: bimatoprost at a concentration of 0.03%, poloxamer 407 at a concentration of 24.83%, poloxamer 188 at a concentration of 6.83%, tween 80 at a concentration of 1%, and the balance of double distilled water.
According to an embodiment of the invention, the composition comprises, in mass volume percent: 0.03% of bemesectin, 21% of poloxamer 407, 2% of poloxamer 188, 1% of tween 80 and the balance of double distilled water.
According to an embodiment of the invention, the composition comprises, in mass volume percent: bimatoprost at a concentration of 0.03%, poloxamer 407 at a concentration of 22%, poloxamer 188 at a concentration of 4%, tween 80 at a concentration of 1%, and the balance double distilled water.
According to an embodiment of the invention, the composition comprises, in mass volume percent: bimatoprost at a concentration of 0.03%, poloxamer 407 at a concentration of 19.17%, poloxamer 188 at a concentration of 1.17%, tween 80 at a concentration of 1%, and the balance double distilled water.
According to an embodiment of the invention, the composition has temperature-sensitive properties, is liquid at no more than normal temperature (e.g. no more than 25 ℃), and is capable of phase transition in the eye to form a gel in a semi-solid state after being administered in the liquid form into the conjunctival sac. For example, the composition has a gelling temperature T prior to tear dilution1，25℃<T1<34 ℃ C, e.g. T1At 27-33 deg.C, illustratively 30.23 deg.C, 30.87 deg.C, 31.15 deg.C, 31.86 deg.C, 32.16 deg.C. For example, the composition has a gelling temperature T after dilution of the tear fluid2，T2>T1(ii) a Preferably, T2Preferably close to body temperature, e.g. T1<T2<39 ℃, preferably 34 ℃ T or less2<38 ℃, more preferably 35 ℃ T or less2<36.5 ℃ exemplary T2At 35.12 deg.C, 36.5 deg.C, 37.12 deg.C, 37.54 deg.C, 38.55 deg.C.
The invention also provides application of the composition in preparing preparations for treating primary open-angle glaucoma and ocular hypertension. Preferably, the preparation is a temperature-sensitive in-situ gel preparation for the bimatoprost eye.
The invention also provides a preparation method of the bimatoprost ophthalmic composition, which comprises the following steps: uniformly mixing the bimatoprost, the poloxamer, the cosolvent, water and optionally pharmaceutical excipients to obtain a mixture, and performing cold dissolution to ensure that the poloxamer fully absorbs water to swell and gradually dissolves until the solution is clear to obtain the composition;
wherein the poloxamers include poloxamer 407 and poloxamer 188.
According to an embodiment of the present invention, bemepiride may be prepared into a bemepiride solution, and then poloxamer 407 or poloxamer 407 and poloxamer 188 may be added into the bemepiride solution to obtain a mixture. Wherein the bimatoprost solution also contains a cosolvent, water and optionally a pharmaceutical adjuvant; for example, the bevacizin solution further contains tween and double distilled water. Further, the concentration of bemepiride in the bemepiride solution is 0.01-0.1%, for example 0.02-0.06%, exemplarily 0.03%, by mass volume percent. Further, the concentration of tween in the bimatoprost solution is 0.1-5%, for example 0.5-3%, exemplarily 1%, by mass volume percentage.
According to an embodiment of the invention, the mass concentration of poloxamer 407 in the mixture is 17-25%, such as 18-24%, exemplarily 18%, 19.17%, 20%, 21%, 22%, 23%, 24.83% in mass volume percentage.
According to an embodiment of the invention, the mass concentration of poloxamer 188 in the mixture is 0-8%, such as 1-6%, exemplarily 1.17%, 2%, 3%, 4%, 5% in mass volume percentage.
According to an embodiment of the invention, the temperature of the cold melt is 1-8 ℃, such as 2-5 ℃, exemplary 4 ℃.
According to an embodiment of the invention, the time of the cold dissolution is 6 to 36h, such as 10 to 30h, exemplary 24 h.
According to an embodiment of the invention, the pharmaceutical excipient has the meaning and concentration as described above.
According to an embodiment of the present invention, the method for preparing the ophthalmic bimatoprost composition comprises the following steps:
(1) dissolving bemesenteric with tween 80, adding double distilled water to obtain bemesenteric solution, and adding poloxamer 407(P407) and poloxamer 188(P188) into the bemesenteric solution according to the above ratio to obtain mixture;
(2) and (2) sealing the mixture in the step (1), then performing cold dissolution, fully absorbing water, expanding, and gradually dissolving until the solution is clear to obtain the composition.
The invention also provides a temperature-sensitive in-situ gel preparation containing the composition for the bemeprostone eye.
The invention also provides a preparation method of the bimatoprost ophthalmic temperature-sensitive in-situ gel preparation, and the preparation method comprises a preparation process of the composition. Furthermore, the preparation method also comprises the processes of sterilizing and packaging the product prepared from the composition.
The invention also provides the application of the composition and/or the bimatoprost ophthalmic temperature-sensitive in-situ gel preparation in preventing and/or treating primary open-angle glaucoma and ocular hypertension.
Advantageous effects
The inventor unexpectedly discovers that in the composition taking the bimatoprost as an active ingredient, the concentration of poloxamer 407 and poloxamer 188 in the composition and the mass ratio of the poloxamer 407 and the poloxamer 188 are strictly controlled, so that the phase transition temperature of the composition can be precisely adjusted, the composition/preparation has intelligence, namely the composition/preparation can be liquid at normal temperature, can be in an in-situ semisolid gel state after being dripped into eyes, can still keep the gel state after being diluted by tears, can be adhered to the surfaces of cornea and conjunctival sac, delays the release of medicines, improves the bioavailability of the preparation, and is suitable for nighttime administration. Meanwhile, the combination of the components in the composition enables the composition to have good spreadability, and when the composition is used as an ophthalmic gel preparation, the application dosage is easier to control.
The temperature-sensitive in-situ gel composition/preparation for bemepiride provided by the invention can solve the problems of short eye retention time and low bioavailability of the conventional eye drops, overcomes the problems of poor spreadability and difficulty in dose control of the common eye gel preparation, and can avoid eye irritation caused by using dosage forms such as emulsifiable paste and the like.
Description of terms:
in the present invention, "phase transition temperature" has the same meaning as "gelling temperature". The phase transition temperature refers to the environmental temperature measured when the bimatoprost ophthalmic composition, the bimatoprost temperature-sensitive in-situ gel or the preparation thereof is completely changed from liquid state to gel state in situ.
"mass volume percent" in the context of the present invention refers to the mass volume content of a component per 100mL of a composition or formulation, such as: 0.03% means that the composition contains 0.03g/mL of the component per 100mL of the composition or formulation.
Drawings
FIG. 1 is a UV scan of test example 1.
FIG. 2 is an HPLC chromatogram of the control solution (A), the test solution (B) and the blank solvent (C) in test example 2.
FIG. 3 is a graph showing the effect of the artificial tear in test example 3 on the erosion of the gel in example 3.
FIG. 4 is a graph showing the results of examining the release rate of the temperature-sensitive in-situ gel of bimatoprost in example 3.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The following examples and test examples used instruments and materials:
AX224ZH electronic balance (aohaos instruments ltd., actual division d 0.0001 g); smart series ultra pure water machines (shanghai and tai instruments ltd); PS-40 ultrasonic cleaner (Shenzhen super technology limited); shimadzu 16A high performance liquid chromatograph (Shimadzu corporation, japan); IKEA constant temperature magnetic stirrer (IKEA, Germany); TS-200B model constant temperature shaking table (Changzhou Nuoji instruments Co., Ltd.); shimadzu UV-160A ultraviolet spectrophotometer (Shimadzu corporation, Japan).
Bemeprost (Shanghai Jinghe pharmaceutical science and technology Co., Ltd., product batch No. 155206-00-1); tween 80 (product batch number: 9005-65-6, Dalochi chemical reagent factory, Tianjin); poloxamer 188 (abbreviation P188, BASF, Germany, product batch: WPHC 625E); poloxamer 407 (abbreviation P407, BASF, Germany, product batch: WPAH 516D); sodium chloride (Beijing chemical plant, product lot: 20190107); sodium bicarbonate (Beijing chemical plant, product lot: 20080108); calcium chloride (VETEC, Shanghai Baiyan Biotech Co., Ltd., product batch No.: WXSC 0624V); potassium chloride (Beijing chemical plant, product batch: 20160126); methanol-HPLC was chromatographically pure (TEDIA, USA), and other reagents were analytically pure.
According to the reference (Zhao Yuna, Hao Xijuan, pH sensitive chloramphenicol ophthalmic in situ gel preparation and Release degree Observation [ J ]. northwest J.Pharmacology, 2018,33(06): 793-. Clinically, the ophthalmic preparation temperature sensitive in-situ gel is clinically specified to be liquid at normal temperature (25 ℃), and can become a semisolid gel at body temperature (34 ℃) after being diluted by tears when being dripped into eyes, and it is noted that the phase transition temperature before being diluted by tears is lower than that after being diluted by tears, so the phase transition temperature before being diluted by tears needs to be controlled to be more than 25 ℃.
The components of the simulated artificial tears used contained: 6.78g of sodium chloride, 1.38g of potassium chloride, 2.18g of sodium bicarbonate and 0.084g of calcium chloride.
The manufacturing process of the artificial tears comprises the following steps: precisely weighing the medicines, adding a proper amount of double distilled water, transferring the mixture into a 1000mL volumetric flask after the double distilled water is completely dissolved, fixing the volume to a scale mark by using the double distilled water, shaking up to obtain the artificial tear, and adjusting the pH value to be about 7.1 by using boric acid.
Example 1
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
And (3) determining the gelling temperature: placing 4 deg.C temperature sensitive type in-situ gel of bimatoprost in test tube (uniformly heated, large heated area, good space fluidity), placing the test tube in beaker inserted with electronic thermometer, and heating in water bath at 0.5 deg.C/min-1The temperature of the water bath beaker is slowly increased at the temperature rising rate, the test tube is slightly inclined for 45 degrees every 10s until the liquid is completely changed into gel and the gel does not flow any more, and the corresponding temperature is the gelation temperature before the artificial tear is diluted.
When the gelation temperature of the preparation after dilution of artificial tears is tested, the gel in the test tube is mixed according to the volume ratio of 50:7 of the gel to the artificial tears, and the temperature is continuously increased by 0.5 ℃ min-1The temperature of the water bath beaker is slowly increased at the temperature rising rate, the test tube is slightly inclined for 45 degrees every 10s until the liquid is completely changed into gel and the gel does not flow any more, and the corresponding temperature is the gelling temperature of the diluted artificial tears. The measurement was repeated 3 times for each phase transition temperature, and the average value was taken.
In this embodiment, the gelling temperature of the bemesectin temperature-sensitive in-situ gel before the dilution of the artificial tear is about 31.86 ± 0.312 ℃, and the gelling temperature of the diluted artificial tear is about 38.55 ± 0.257 ℃.
Example 2
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in-situ gel prepared in this example was about 32.16 ± 0.127 ℃ before the dilution of the artificial tear and about 37.54 ± 0.366 ℃ after the dilution of the artificial tear.
Example 3
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in-situ gel prepared in this example was about 31.15 + -0.375 deg.C before the dilution of the artificial tear and about 37.12 + -0.311 deg.C after the dilution of the artificial tear.
Example 4
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in-situ gel prepared in this example was about 42.27 + -0.378 ℃ before the dilution of the artificial tear and about 61.27 + -0.414 ℃ after the dilution of the artificial tear.
Example 5
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 into the bimatoprost solution, sealing, putting into a refrigerator at 4 ℃ for cold dissolution for 24 hours, fully absorbing water, expanding and gradually dissolving until the solution is clear, and obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured in the same manner as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in-situ gel prepared in this example was about 24.10 ± 0.261 ℃ before the dilution of the artificial tear and about 30.03 ± 0.349 ℃ after the dilution of the artificial tear.
Example 6
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the method comprises the following steps of precisely weighing the bimatoprost powder, adding the bimatoprost powder into tween 80, ultrasonically dissolving, and then adding double distilled water to prepare a 0.03% bimatoprost solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in this example was about 30.23 ± 0.132 ℃ before the dilution of the artificial tear and about 40.82 ± 0.271 ℃ after the dilution of the artificial tear.
Example 7
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in this example was about 23.73 ± 0.322 ℃ before the dilution of the artificial tear and about 33.13 ± 0.421 ℃ after the dilution of the artificial tear.
Example 8
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in this example was about 37.43 + -0.561 deg.C before the dilution of the artificial tear and about 54.80 + -0.398 deg.C after the dilution of the artificial tear.
Example 9
The formula (in percentage by mass and volume) is as follows:
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in this example was about 40.80 + -0.344 ℃ before the dilution of the artificial tear and about 52.47 + -0.326 ℃ after the dilution of the artificial tear.
Example 10
Formula (by mass volume concentration):
the preparation process comprises the following steps: the bemepiride powder is precisely weighed, added into tween 80 for ultrasonic dissolution, and then added with double distilled water to prepare a 0.03% bemepiride solution. And adding poloxamer 407 and poloxamer 188 into the bimatoprost solution according to the proportion, sealing, and then putting the sealed bimatoprost solution into a refrigerator at 4 ℃ for cold dissolution for 24 hours to ensure that the bimatoprost solution fully absorbs water to swell and gradually dissolves until the solution is clear, thus obtaining the bimatoprost ophthalmic thermo-sensitive in-situ gel.
The gelation temperature was measured as in example 1, and the gelation temperature of the ophthalmic temperature sensitive type bimatoprost in this example was about 22.60 + -0.178 deg.C before the dilution of the artificial tear and about 27.63 + -0.472 deg.C after the dilution of the artificial tear.
Test example 1
Ultraviolet spectrophotometry for measuring maximum absorption wavelength: precisely weighing a proper amount of bimatoprost powder by using an electronic balance, putting the weighed bimatoprost powder into a 10mL volumetric flask, adding a proper amount of methanol, carrying out ultrasonic dissolution, fixing the volume, and shaking up to obtain the bimatoprost with the concentration of 0.03 mg/mL-1The solution of (1). Taking a proper amount of solution to perform full-wavelength scanning within the range of 190-900 nm, determining the maximum absorption wavelength of the bimatoprost solution, taking the maximum absorption wavelength as a detection wavelength, and then determining the gel content by adopting an HPLC method.
From the UV absorption curve, bemeprostil solution has a maximum absorption wavelength at 261nm, therefore 261nm was experimentally selected as the detection wavelength, see fig. 1.
Test example 2 determination of temperature-sensitive in situ gel content of bimatoprost for eye
(1) Preparation of the solution
Test solution: precisely weighing the prescription of example 3 in a volumetric flask of 1mL to 10mL, dissolving the volumetric flask with methanol and fixing the volume to the scale mark to obtain 0.3 mg/mL-1The solution of (1).
Control solution: precisely weighing 3mg bemepiride medicine powder, placing in a 10mL volumetric flask, dissolving with methanol, and fixing volume to scale mark to obtain the final product with concentration of 0.3 mg/mL-1The control solution of (4).
Blank solvent: and adding poloxamer 407 with the final concentration of 21% and poloxamer 188 with the final concentration of 2% into 300mL of methanol containing 3mL of Tween 80, and swelling at 4 ℃ for 24 hours to obtain a gel solution which is a blank solvent.
(2) Chromatographic conditions are as follows:
a chromatographic column: Shimadzu-GL, Wondasil C18-WR (4.6X 150mm 5 μm);
mobile phase: 0.1% phosphoric acid as phase A (aqueous phase), methanol as phase B (organic phase), volume ratio of phase A: phase B is 30: 70;
flow rate: 20 μ L/min-1；
Detection wavelength: 261 nm; column temperature: 35 ℃;
sample introduction amount: 20 μ L.
(3) Specificity testing
And respectively sucking 1000 mu L of the blank solvent, the reference solution and the sample solution by using a pipette, sequentially injecting 20 mu L of the sample according to the chromatographic conditions, recording an HPLC chromatogram, and analyzing whether the blank reference interferes with the peak position of the bimatoprost or not by observing the chromatogram.
The HPLC chromatograms of the control solution (a in fig. 2), the test solution (B in fig. 2) and the blank solvent (C in fig. 2) under the above chromatographic conditions show that: the bemepiride in the test solution can be well separated, and the blank solvent has no interference at the peak position of the bemepiride. The retention time of the bimatoprost in the test solution is about 7.134min, the chromatographic peak has good shape, the retention time of the chromatographic peak is consistent with that of the control solution, and the chromatographic peak of the bimatoprost in the blank solvent is not found.
(4) The linear relationship is: precisely measuring 5 parts of 1mL of the above control solution, and diluting with mobile phase to 0.2. mu.g/mL-1、1.0μg·mL-1、5.0μg·mL-1、25.0μg·mL-1、100.0μg·mL-1(ii) a And (3) according to the chromatographic conditions, sequentially injecting into a liquid chromatograph for measurement, recording peak areas, drawing a standard curve by taking the chromatographic peak area (Y) of the reference substance as a vertical coordinate and the chromatographic peak area (X) of the reference substance as a horizontal coordinate, and solving a regression equation. According to the results, the content of the bevacizin in the range of 0.2-100 mu g/mL-1Linear relationship over the concentration range.
The linear regression of the concentration (X) of the bimatoprost is carried out by the chromatographic peak area (Y), and the result shows that: the content of bemepiridin is 0.2-100 mu g/mL-1A good linear relationship is present in the concentration range. The regression equation is: y ═450X-213.2(R2＝0.9996)。
(5) And (3) precision experiment: respectively taking test solution with different bemepiride contents: (1) the test solution in (1), the test solution with the content of bemeprostone being 80% of the content of the test solution in (1), and the test solution with the content of bemeprostone being 120% of the content of the test solution in (1). Taking 1mL of each sample solution, repeatedly injecting samples for 5 times in one day according to the chromatographic conditions, injecting 20 mu L of each sample solution, measuring the precision within one day, and calculating the relative standard deviation within one day. Each sample solution was measured once a day for five days, 20. mu.L of each sample was injected, the precision between days was measured, and the relative standard deviation between days was calculated.
The daily and daytime precision of the test solution of 3 concentrations of bemesedin was calculated according to the hplc chromatogram, see table 1, and the Relative Standard Deviation (RSD) value was calculated. The results show that the RSD is less than 2 percent, and the method has good repeatability and good instrument precision.
Table 1 precision of bevacet assay (Mean ± SD, n ═ 5)
(6) Recovery rate test:
tween 80, poloxamer 407 and 188 were added according to the formulation composition of example 3, and gel samples containing bemeseprost at 3 concentrations, low (80%), medium (100% based on the content of bemeseprost in the formulation of example 3), and high (120%), respectively, were prepared as controls. Precisely measuring the reference substance 3 parts and the test substance 9 parts of the test sample solution in the test example 1, injecting sample according to the chromatographic conditions provided by the test example 1, recording the chromatogram, calculating the concentration of the bemeprobamate by using the peak area according to an external standard method, and calculating the average recovery rate. Recovery is expressed as accuracy, which refers to the degree to which the results determined by the method are close to the true or reference value.
In the formula: a represents the peak area measured by high performance liquid chromatography, and C represents the solution concentration.
According to a spectrum obtained by a high performance liquid chromatograph, the average recovery rate of the bimatoprost is calculated to be 97.51%, the methodological requirements are met, and the measurement results are shown in table 2.
Table 2 recovery rate of bemeseprost content determination method
Test example 3
Examination of in vitro Release
Tear in the conjunctival sac is continuously updated, and the release of the medicine can be influenced by the actions of rotation, blinking and the like of eyes. The filmless dissolution model provides a choice for researching drug release accompanied with gel erosion, the method adopts simulated tears to generate a shearing effect similar to wink on the surface of the gel under the oscillation condition, erosion of the water-soluble gel and drug release are carried out synchronously, and the method conforms to the real process of the in-vivo ophthalmic gel.
Precisely measuring 3 parts of the composition prepared in example 3 by using a pipette, weighing 1.0g of each part, placing the weighed parts in a 1.5mL penicillin bottle, preheating the penicillin bottle in an oscillator at 37 ℃ for 10min, adding 0.5mL of artificial tears preheated in advance as release media after the solution completely forms a gel state, and carrying out gel permeation at 200 r.min-1Oscillating at constant temperature at the rotating speed of (1), and measuring the temperature to be 37 ℃. Pouring out all release medium immediately after every 20 minutes, putting the penicillin bottle into the oscillator again for balancing for 10 minutes, supplementing 0.5mL of artificial tears and continuing to shake for 20 minutes. The operation is repeated in this way. The poured release medium was placed in a 10mL volumetric flask, diluted with methanol and brought to the mark, and 20 μ L of the diluted release medium was subjected to HPLC to determine the content of bimatoprost in the release medium under the same chromatographic conditions as in test example 1.
According to data measured by HPLC, linear regression analysis is carried out on the gel cumulative erosion amount (A) and the bevacet prost cumulative release amount (B) with respect to time (see FIG. 3), and the results show a good relationship and accord with zero-order kinetic characteristics. With shellfishThe cumulative amount of released mepiquat chloride was linearly regressed against the cumulative amount of erosion of the gel and the results were good (see fig. 4), with the regression equation: Y0.9265X +6.8112 (R)20.9964). The results show that: example 3 the release of the drug and the erosion of the gel proceeded at the same rate, and it was found that the main factors determining the release were the erosion of the gel, the erosion amount at 5h was 95.14%, the cumulative release amount of bemepiride was 272.72 μ g, and the cumulative release rate of bemepiride was 90.91%.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A bimatoprost ophthalmic composition, comprising: bimatoprost, poloxamer, cosolvent and water;
wherein the poloxamers include poloxamer 407 and poloxamer 188.
2. The composition according to claim 1, wherein the concentration of bimatoprost in the composition is 0.01-0.1%, such as 0.02-0.06%, illustratively 0.03%, by mass volume percent;
preferably, the concentration of poloxamer 407 in the composition is 17-25%, such as 18-24%, illustratively 18%, 19.17%, 20%, 21%, 22%, 23%, 24.83%;
preferably, the concentration of poloxamer 188 in the composition is 0-8%, such as 1-6%, exemplary 1.17%, 2%, 3%, 4%, 5%, 6.83%.
3. The composition according to claim 1 or 2, wherein the mass to volume concentration ratio of poloxamer 407 to poloxamer 188 is (2-20):1, preferably (3-12): 1.
4. The composition according to any one of claims 1 to 3, wherein the cosolvent is selected from at least one of Tween, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol/polycaprolactone multi-block copolymer, chitosan, etc., such as Tween;
preferably, the concentration of the cosolvent in the composition is 0.1-5% in percentage by mass and volume;
preferably, the water is selected from the group consisting of distilled water or purified water;
the composition also includes other pharmaceutical excipients, such as at least one of preservatives, wetting agents and buffers.
5. The composition according to any one of claims 1 to 4, wherein the composition comprises, in mass volume percent: 0.03% of bemepiridin, 21% of poloxamer 407, 2% of poloxamer 188, 1% of tween 80 and the balance of double distilled water;
preferably, the composition comprises, in mass volume percent: bimatoprost with a concentration of 0.03%, poloxamer 407 with a concentration of 24.83%, poloxamer 188 with a concentration of 6.83%, tween 80 with a concentration of 1%, and the balance of double distilled water;
preferably, the composition comprises, in mass volume percent: bimatoprost with a concentration of 0.03%, poloxamer 407 with a concentration of 22%, poloxamer 188 with a concentration of 4%, tween 80 with a concentration of 1%, and the balance of double distilled water;
preferably, the composition comprises, in mass volume percent: bimatoprost at a concentration of 0.03%, poloxamer 407 at a concentration of 19.17%, poloxamer 188 at a concentration of 1.17%, tween 80 at a concentration of 1%, and the balance double distilled water.
6. Use of a composition according to any one of claims 1 to 5 for the preparation of a preparation for the treatment of primary open angle glaucoma, ocular hypertension;
preferably, the preparation is a temperature-sensitive in-situ gel preparation for the bimatoprost eye.
7. A method of making a bimatoprost ophthalmic composition of any one of claims 1-5, said method of making comprising the steps of: uniformly mixing the bimatoprost, the poloxamer, the cosolvent, water and optional pharmaceutic adjuvants, and performing cold dissolution on the obtained mixture to ensure that the poloxamer fully absorbs water to swell and gradually dissolves until the solution is clear to obtain the composition;
wherein the poloxamers include poloxamer 407 and poloxamer 188;
preferably, the bimatoprost is prepared into a bimatoprost solution, and then poloxamer 407 or poloxamer 407 and poloxamer 188 are added into the bimatoprost solution to obtain a mixture; preferably, the bemepiride solution also contains a cosolvent and water;
preferably, the concentration of the bemepiride in the bemepiride solution is 0.01-0.1%;
preferably, the temperature of the cold dissolving is 1-8 ℃;
preferably, the cold dissolving time is 6-36 h;
the pharmaceutical excipient has the meaning and concentration as defined in claim 4.
8. The method of claim 7, comprising the steps of:
(1) dissolving bemesenteric with tween 80, adding double distilled water to obtain bemesenteric solution, and adding poloxamer 407 and poloxamer 188 into the bemesenteric solution according to a certain proportion to obtain mixed solution;
(2) sealing the mixed solution obtained in the step (1) and then carrying out cold dissolution to ensure that the mixed solution fully absorbs water and expands to gradually dissolve until the solution is clear, thus obtaining the composition.
9. The ophthalmic temperature-sensitive in situ gel formulation of bemeprostin, which comprises the composition according to any one of claims 1-5.
10. The method for preparing the ophthalmic temperature-sensitive in-situ gel preparation of the bemeprostone according to claim 9, wherein the preparation method comprises the preparation method according to claim 7 or 8;
preferably, the preparation method further comprises the processes of sterilizing and packaging the composition of any one of claims 1 to 5 or the composition prepared by the preparation method of claim 7 or 8.
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