CN117045587A - Preparation of brimonidine tartrate eye temperature-sensitive in-situ gel - Google Patents
Preparation of brimonidine tartrate eye temperature-sensitive in-situ gel Download PDFInfo
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- CN117045587A CN117045587A CN202210494568.8A CN202210494568A CN117045587A CN 117045587 A CN117045587 A CN 117045587A CN 202210494568 A CN202210494568 A CN 202210494568A CN 117045587 A CN117045587 A CN 117045587A
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- Prior art keywords
- brimonidine tartrate
- gel
- situ gel
- sensitive
- stirring
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- IWEGDQUCWQFKHS-UHFFFAOYSA-N 1-(1,3-dioxolan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(CC2OCCO2)N=C1 IWEGDQUCWQFKHS-UHFFFAOYSA-N 0.000 title claims abstract description 63
- 229960001724 brimonidine tartrate Drugs 0.000 title claims abstract description 63
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 239000003889 eye drop Substances 0.000 claims abstract description 13
- 230000003204 osmotic effect Effects 0.000 claims abstract description 10
- 239000011159 matrix material Substances 0.000 claims abstract description 8
- 239000002562 thickening agent Substances 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 29
- 229920001983 poloxamer Polymers 0.000 claims description 29
- 229960000502 poloxamer Drugs 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000008215 water for injection Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- 239000001509 sodium citrate Substances 0.000 claims description 15
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 15
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 12
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 12
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 238000009736 wetting Methods 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 6
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 6
- 229920001661 Chitosan Polymers 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 230000008961 swelling Effects 0.000 claims description 5
- 239000000022 bacteriostatic agent Substances 0.000 claims description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 3
- 229960002216 methylparaben Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002148 Gellan gum Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- 239000000216 gellan gum Substances 0.000 claims description 2
- 235000010492 gellan gum Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 229960003885 sodium benzoate Drugs 0.000 claims description 2
- 229940012356 eye drops Drugs 0.000 abstract description 10
- 210000004087 cornea Anatomy 0.000 abstract description 9
- 230000014759 maintenance of location Effects 0.000 abstract description 7
- 230000007547 defect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 206010067484 Adverse reaction Diseases 0.000 abstract 1
- 230000006838 adverse reaction Effects 0.000 abstract 1
- 230000007704 transition Effects 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 239000012528 membrane Substances 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 230000000694 effects Effects 0.000 description 6
- 208000010412 Glaucoma Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 238000012371 Aseptic Filling Methods 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 102000003846 Carbonic anhydrases Human genes 0.000 description 1
- 108090000209 Carbonic anhydrases Proteins 0.000 description 1
- HPQQIZGULDEVOE-UHFFFAOYSA-N OC(C(C(O)=O)(N1C2=CC=CC=C2N=CC1)O)C(O)=O Chemical compound OC(C(C(O)=O)(N1C2=CC=CC=C2N=CC1)O)C(O)=O HPQQIZGULDEVOE-UHFFFAOYSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 239000000219 Sympatholytic Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 230000004509 aqueous humor production Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229940020947 fluorescein sodium Drugs 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 230000005182 global health Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000001749 optic atrophy Diseases 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Landscapes
- 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)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to brimonidine tartrate eye temperature-sensitive in-situ gel and a preparation method thereof. The invention discloses brimonidine tartrate eye temperature sensitive in situ gel which comprises brimonidine tartrate, gel matrix, thickener, osmotic pressure regulator, pH regulator and bacteriostat. The brimonidine tartrate eye temperature-sensitive in-situ gel and the preparation method thereof are provided by optimizing the types and the proportions of auxiliary materials, solving the defects of short retention time, low bioavailability and the like of eye drops and providing the brimonidine tartrate eye temperature-sensitive in-situ gel with small adverse reaction and long cornea retention time.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to brimonidine tartrate eye temperature-sensitive in-situ gel and a preparation method thereof.
Background
Glaucoma is a group of diseases characterized by both a characteristic visual field injury and optic atrophy, which occur for a number of reasons and ultimately lead to increased ocular pressure leading to death of optic nerve cells. Glaucoma is extremely damaging to the optic nerve, is extremely blind, and is estimated by the global health organization to be a secondary blinding eye disease. According to statistics, the incidence rate of glaucoma in China is 0.22-1.60%, and blindness is about 10-20% after the glaucoma occurs.
The current clinical drugs for treating glaucoma mainly comprise the following types: carbonic anhydrase inhibitors, sympatholytic agents, prostaglandin derivatives, parasympathetic agonists, alpha 2 adrenergic receptor agonists, and the like. Brimonidine tartrate is a carbonic anhydrase inhibitor that, after absorption in the eye, acts on the cornea to reduce intraocular pressure by converting carbonic anhydrase in the ciliary body, reducing aqueous humor production. Brimonidine tartrate has the formula C 11 H 10 BrN 5 ·C 4 H 6 O 6 The molecular weight is 442.24, the chemical name is 5-bromo-6- (2-imidazole dienoamine) quinoxaline-L-tartaric acid, and the structural formula is as follows:
brimonidine tartrate is only an eye drop on the market at present, but the biological barrier effect of cornea and the high sensitivity of eyes limit the application of conventional ophthalmic preparations, so that people are promoted to research a safer, more effective and longer-acting eye administration system.
Disclosure of Invention
Based on the defects of short residence time, low bioavailability and the like of the brimonidine tartrate eye drops, the invention provides brimonidine tartrate temperature-sensitive in-situ gel, and the gel preparation comprises the following components:
the brimonidine tartrate temperature-sensitive in-situ gel comprises the following raw material components in 100 mL:
the balance of water for injection.
Preferably, the gel matrix is selected from one or more of gellan gum, poloxamer, carbomer and polyethylene glycol, preferably poloxamer;
preferably, the poloxamer is of two types, namely poloxamer P407 and poloxamer P188;
preferably, the dosage ratio of the poloxamer P188 to the poloxamer P407 is 1-3:2.55-2.75;
preferably, the viscosity of the in-situ gel is 3.0-5.0 mPa.s;
preferably, the thickener is one or more selected from sodium hyaluronate, hydroxypropyl methylcellulose, chitosan and polyvinyl alcohol;
preferably, the in situ gel has an osmotic pressure of 280-320 mOsmol/Kg;
preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, glycerol or glucose
Preferably, the bacteriostatic agent is selected from one or more of methylparaben, ethylparaben, sodium benzoate and benzalkonium chloride;
preferably, the pH regulator is selected from one or more of citrate buffer, citric acid and sodium citrate, sodium hydroxide and hydrochloric acid;
a method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
(1) Taking water for injection with the prescription amount of 70-80 wt%, adding the thickener into a container, stirring and dissolving;
(2) Adding an osmotic pressure regulator, a pH regulator and a bacteriostat into a container, stirring, mixing and dissolving;
(3) Slowly adding the gel matrix with the prescription amount into the solution, stirring and wetting, and placing in an environment of 2-8 ℃ for about 2-4 hours, waiting for full swelling to obtain a blank gel solution;
(4) Adding brimonidine tartrate in a prescription amount into a blank gel solution, stirring until the brimonidine tartrate is completely dissolved, adding water for injection to 100mL, and stirring uniformly to obtain brimonidine tartrate temperature-sensitive in-situ gel.
Compared with the traditional eye drops, the invention has the following beneficial effects:
(1) Compared with the problem of too fast metabolism of eye drops, the invention increases the bioavailability, reduces the administration times of patients and increases the compliance of the patients;
(2) The invention increases the cornea penetration capacity of brimonidine tartrate, improves the effective drug concentration and has obvious ocular hypotensive effect.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1
1. Brimonidine tartrate temperature sensitive in situ gel, 100mL, comprising the following components:
| composition of the components | Content (g/100 mL) |
| Brimonidine tartrate | 0.2 |
| Poloxamer P188 | 1 |
| Poloxamer P407 | 2.55 |
| Polyvinyl alcohol | 0.10 |
| Sodium chloride | 0.7 |
| Citric acid | 0.05 |
| Sodium citrate | 0.45 |
| Benzalkonium chloride | 0.005 |
| Sodium hydroxide or hydrochloric acid | Adjusting the pH to 5.6-6.6 |
| Water for injection | To 100mL |
The preparation method comprises the following steps:
a method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
taking 80wt% of water for injection, adding polyvinyl alcohol into a container at 20-30 ℃, stirring and dispersing, stirring at 200rpm for 10-30 min, heating to 80-90 ℃ and preserving heat and dissolving for 10-20 min;
adding sodium chloride, citric acid, sodium citrate and benzalkonium chloride into the solution, stirring, mixing and dissolving;
adding poloxamer P188 and P407 into a container, stirring and wetting, and standing for 4 hours at the temperature of 2-8 ℃ until the poloxamer P188 and P407 fully swells to obtain a blank gel solution;
cooling the blank gel solution to about 40 ℃, adding brimonidine tartrate, stirring and dissolving;
the rest water for injection is filled up, shaken up, and filtered and sterilized by a filter membrane with the pH adjusted to 5.6-6.6,0.22 mu m by sodium hydroxide or hydrochloric acid.
Example 2
2. Brimonidine tartrate temperature sensitive in situ gel, 100mL, comprising the following components:
| composition of the components | Content (g/100 mL) |
| Bromine tartrateMonitdine | 0.2 |
| Poloxamer P188 | 1.5 |
| Poloxamer P407 | 2.6 |
| Chitosan | 1.2 |
| Sodium chloride | 0.6 |
| Citric acid | 0.05 |
| Sodium citrate | 0.45 |
| Hydroxy-benzoic acid methyl ester | 0.005 |
| Sodium hydroxide or hydrochloric acid | Adjusting the pH to 5.6-6.6 |
| Water for injection | To 100mL |
Preparation method
A method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
taking 70wt% of water for injection, adding chitosan into the solution at 30-40 ℃ and stirring at 200rpm for 5-15 min until the chitosan is dissolved;
adding sodium chloride, citric acid, sodium citrate and methylparaben into a container, stirring and dissolving;
adding poloxamer bottles P188 and P407 into a container, stirring and wetting, and standing for 4 hours at the temperature of 2-8 ℃ until the poloxamer bottles P188 and P407 fully swell to obtain blank gel solution;
adding brimonidine tartrate into a container, and stirring until the brimonidine tartrate is completely dissolved;
the rest water for injection is filled up, stirred evenly, and filtered and sterilized by a filter membrane with the pH adjusted to 5.6-6.6,0.22 mu m by sodium hydroxide or hydrochloric acid.
Example 3
Brimonidine tartrate temperature sensitive in situ gel comprising the following components in 100 mL:
| composition of the components | Content (g/100 mL) |
| Brimonidine tartrate | 0.2 |
| Poloxamer P188 | 2 |
| Poloxamer P407 | 2.65 |
| Sodium hyaluronate | 1.0 |
| Potassium chloride | 0.6 |
| Citric acid | 0.05 |
| Sodium citrate | 0.45 |
| Benzalkonium chloride | 0.005 |
| Sodium hydroxide or hydrochloric acid | Adjusting the pH to 5.6-6.6 |
| Water for injection | To 100mL |
Preparation method
A method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
taking 70wt% of water for injection, adding sodium hyaluronate into a container at the temperature of 20-40 ℃, stirring at the speed of 200rpm, and stirring for 10-20 min;
adding potassium chloride, citric acid, sodium citrate and benzalkonium chloride under stirring, and stirring for dissolution;
slowly adding poloxamer P188 and P407 under stirring, stirring and wetting, standing for 4 hours at the temperature of 2-8 ℃ and waiting for full swelling, and obtaining an empty gel solution;
adding brimonidine tartrate into a container under stirring, and stirring until the brimonidine tartrate is completely dissolved;
the rest water for injection is filled up, stirred evenly, and filtered and sterilized by a filter membrane, wherein the pH value of the filter membrane is adjusted to 5.6-6.6,0.22 mu m by sodium hydroxide or hydrochloric acid.
Example 4
Brimonidine tartrate temperature sensitive in situ gel, 100mL, comprising the following components:
preparation method
A method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
taking 70wt% of water for injection, adding sodium hyaluronate into a container at the temperature of 20-40 ℃, stirring at the speed of 200rpm, and stirring for 10-20 min;
adding potassium chloride, citric acid, sodium citrate and benzalkonium chloride under stirring, and stirring for dissolution;
slowly adding poloxamer P188 and P407 under stirring, stirring and wetting, standing for 4 hours at the temperature of 2-8 ℃ and waiting for full swelling, and obtaining an empty gel solution;
adding brimonidine tartrate into a container under stirring, and stirring until the brimonidine tartrate is completely dissolved;
the rest water for injection is filled up, stirred evenly, and filtered and sterilized by a filter membrane, wherein the pH value of the filter membrane is adjusted to 5.6-6.6,0.22 mu m by sodium hydroxide or hydrochloric acid.
Example 5
Brimonidine tartrate temperature sensitive in situ gel, 100mL, comprising the following components:
preparation method
A method for preparing brimonidine tartrate temperature-sensitive in-situ gel, comprising the following steps:
taking 70wt% of water for injection, adding sodium hyaluronate into a container at the temperature of 20-40 ℃, stirring at the speed of 200rpm, and stirring for 10-20 min;
adding potassium chloride, citric acid, sodium citrate and benzalkonium chloride under stirring, and stirring for dissolution;
slowly adding poloxamer P188 and P407 under stirring, stirring and wetting, standing for 4 hours at the temperature of 2-8 ℃ and waiting for full swelling, and obtaining an empty gel solution;
adding brimonidine tartrate into a container under stirring, and stirring until the brimonidine tartrate is completely dissolved;
the rest water for injection is filled up, stirred evenly, and filtered and sterilized by a filter membrane, wherein the pH value of the filter membrane is adjusted to 5.6-6.6,0.22 mu m by sodium hydroxide or hydrochloric acid.
Comparative example 1
Brimonidine tartrate eye drops, 100mL, comprising the following components:
| composition of the components | Content (g/100 mL) |
| Brimonidine tartrate | 0.2 |
| Sodium chloride | 0.7 |
| Polyvinyl alcohol | 1.4 |
| Benzalkonium chloride | 0.005 |
| Citric acid | 0.05 |
| Sodium citrate | 0.45 |
| Sodium hydroxide or hydrochloric acid | Adjusting the pH to 5.6-6.6 |
| Water for injection | To 100mL |
Preparation method
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
taking normal-temperature water for injection, of which the prescription amount is 80 weight percent, slowly adding polyvinyl alcohol into a container, stirring at 200rpm for 10-30 min to uniformly disperse, heating to 90 ℃ and stirring for 40-60 min, stirring and dissolving, and adding sodium chloride, citric acid, sodium citrate buffer solution and benzalkonium chloride into the container;
the temperature of the solution is reduced to below 40 ℃, and the brimonidine tartrate raw material is added and stirred for dissolution;
the rest water for injection is filled up, stirred evenly, pH is regulated to 5.6-6.6 by sodium hydroxide or hydrochloric acid, filtered and sterilized by a filter membrane with the diameter of 0.22 mu m, and the injection is obtained after aseptic filling.
Comparative example 2
Brimonidine tartrate eye drops, 100mL, comprising the following components:
| composition of the components | Content (g/100 mL) |
| Bromomo tartrateNidine | 0.2 |
| Sodium chloride | 0.7 |
| Hydroxypropyl methylcellulose | 1.6 |
| Benzalkonium chloride | 0.005 |
| Citric acid | 0.05 |
| Sodium citrate | 0.45 |
| Sodium hydroxide or hydrochloric acid | Adjusting the pH to 5.6-6.6 |
| Water for injection | To 100mL |
Preparation method
A preparation method of brimonidine tartrate eye drops, which comprises the following steps:
taking 80wt% of 80-90 ℃ water for injection, slowly adding the hydroxypropyl methylcellulose into a container, stirring at 200rpm for 20-30 min to uniformly disperse, stirring until the hydroxypropyl methylcellulose is dissolved, and cooling to room temperature;
adding sodium chloride, citric acid, sodium citrate buffer solution and benzalkonium chloride into a container;
adding brimonidine tartrate into a container, stirring and dissolving;
the rest water for injection is filled up, stirred evenly, pH is regulated to 5.6-6.6 by sodium hydroxide or hydrochloric acid, filtered and sterilized by a filter membrane with the diameter of 0.22 mu m, and the injection is obtained after aseptic filling.
Verification embodiment
As a result of examining the phase transition temperatures of poloxamer P407 and P188, respectively, it was found that when P407 was used alone, the phase transition temperature of the solution decreased with increasing concentration, and when the concentration of the solution was less than 20%, the gel properties after phase transition were unstable; when the concentration of the solution is more than 28%, the gel phase transition temperature is less than 18 ℃, and the phase transition temperature is too low to carry out subsequent experiments, so the concentration of poloxamer P407 is selected to be 20% -28%. When P188 was used alone, the solution could not form a gel regardless of the increase or decrease in concentration, but when P407 was used in combination, the gel phase transition temperature increased with the increase in concentration, and when the P188 concentration was higher than 8%, the phase transition temperature was rather decreased, so the concentration of poloxamer P188 was selected in the range of 0 to 8%, and the specific results are shown in the table below.
| Gel matrix species | Concentration% | Gel case |
| P407 | ＜20％ | Unstable gel Properties |
| P407 | ＞28％ | The gel phase transition temperature is less than 18 DEG C |
| P188 | At any concentration | Failure to form a gel |
| P407+P188 | P188＜8％ | Phase transition temperature increase |
| P407+P188 | P188＞8％ | Phase transition temperature reduction |
According to the test results, the different concentrations of P407 and P188 have a significant effect on the gel temperature, so the effect of the combination prescription of P407 and P188 on the gel temperature is examined.
Wherein the concentration of P407 (X 1 Concentration of P188 (X),% w/w 2 ,%, w/w), the extreme range of concentration is X 1 :20～28,X 2 0 to 8 percent. Determining 5 levels according to a central composite design principle, and obtaining a star point design factor level table: there are 13 combinations, each of which is a prescription.
| Factors of | -1.414 | -1 | 0 | 1 | 1.414 |
| X 1 | 20 | 21.17 | 24 | 26.83 | 28 |
| X 2 | 0 | 1.17 | 4 | 6.83 | 8 |
Measuring the phase transition temperature T of brimonidine tartrate in situ gel before and after dilution by artificial simulated tear 1 、T 2 The results were as follows:
| sequence number | X 1 /％ | X 2 /％ | T 1 /℃ | T 2 /℃ |
| 1 | 21.17 | 6.83 | 40.8 | 44.2 |
| 2 | 26.83 | 6.83 | 35.4 | 39.2 |
| 3 | 26.83 | 1.17 | 24.5 | 28.6 |
| 4 | 21.17 | 1.17 | 33.8 | 36.7 |
| 5 | 28 | 1.17 | 20.2 | 26.3 |
| 6 | 20 | 4 | 45.8 | 49.2 |
| 7 | 24 | 8 | 39.3 | 44.7 |
| 8 | 24 | 0 | 32.6 | 37.8 |
| 9～11 | 24 | 4 | 31.5 | 39.6 |
Note that: repeated tests are repeated with numbers 9-11, the data of which are all average values
As a result, it was found that, when the concentration of P407 was constant, the phase transition temperature increased as the concentration of P188 increased; when the concentration of P188 is constant, the phase transition temperature decreases as the concentration of P407 increases. According to the special physiological structure of eyes, the ideal eye temperature-sensitive in-situ gel preparation is liquid at room temperature and can quickly form gel after being dripped into conjunctival sac of eyes, namely T 1 ≥25℃，T 2 The temperature is less than or equal to 34 ℃. The effect of X1 (25.5% -27%) and X2 (1% -3%) on the gel temperature was examined separately.
1. Phase transition temperature of in situ gel
The in-situ gel preparation before and after simulated tear dilution is placed in a container, and a magnetic stirrer is added. Stirring was performed on a constant temperature magnetic stirrer at a constant stirring speed, slow and uniform heating was achieved with a water bath, the gelation temperature was measured with a precision thermometer, and the temperature at which the magnetic stirrer completely stopped rotating was used as the phase transition temperature, and as a result, the average value of three repeated operations was taken.
| Examples | T 1 /℃ | T 2 /℃ |
| Example 1 | 26.6 | 32.0 |
| Example 2 | 26.3 | 31.8 |
| Example 3 | 25.8 | 31.5 |
| Example 4 | 25.6 | 21.5 |
| Example 5 | 25.3 | 31.2 |
Experimental results show that the instant gel is in a liquid state at normal temperature, and is converted into solid gel after being dropped into eyes, so that the effect of prolonging the retention effect of the medicine is achieved.
2. Influence factor test
High temperature test: placing the sample in an incubator at 50deg.C for 10 days, sampling at day 0, day 5 and day 10 respectively, and examining various indexes of the preparation.
Strong light irradiation test: the samples were placed in an illumination incubator and left under the conditions of an illuminance of 4500.+ -. 500Lx for 10 days, and sampled for 5 and 10 days, respectively, to examine each index of the samples.
Test results:
(1) High temperature test
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The results show that examples 1-5 show substantially no change in appearance, pH, content, osmotic pressure, viscosity and a slight increase in the relevant substances after 10 days of standing at a high temperature of 50℃as compared with comparative example 1.2.
(2) Strong light irradiation test
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3 animal test
(1) Cornea residence time
Sodium fluorescein was used as the chromogenic material, and the residence time of the sample in the cornea was studied. The test was divided into five groups of 6 rabbits, wherein four rabbits were instilled with 100. Mu.L of each of the samples of comparative example 1, example 2 and example 3 containing 0.10% sodium fluorescein solution in the conjunctival sac of the right eye, and 100. Mu.L of the eye drop of comparative example 2 containing 0.20% sodium fluorescein solution was instilled with the conjunctival sac of the right eye of the fifth group, and all rabbits were instilled with the same volume of sodium citrate buffer salt of pH6.45 in the left eye as a control. The eyes of the rabbits were passively closed for 30 seconds after administration. Fluorescence decay times of corneal and conjunctival sac fluorescein sodium after administration were observed and recorded with a slit lamp, and test results are shown in the following table
The results showed that the retention times of the eye drops of comparative example 1 in the cornea and conjunctival sac of the rabbit eye were about 25min and 24min, the retention times of the eye drops of comparative example 2 in the combined conjunctiva of the rabbit cornea were about 26min and 27min, and the retention times on the cornea and in the conjunctiva were significantly increased as compared with examples 1, 2, 3, 4, 5, wherein the retention time of example 3 was the longest.
(2) Ocular hypotensive effect
Rabbits were divided into 5 animals, namely, a blank group, a comparative example 1, a comparative example 2, an example 1, an example 2, an example 3, an example 4 and an example 5, 5 animals of each group were injected into the anterior chamber of the rabbits a small amount of 1.5% methylcellulose for a plurality of times to establish ocular hypertension models, and single-cage feeding was performed, wherein the blank group was used for water for injection, 3 times/d and 1 drop/time of administration, and the administration was started 12 hours after molding, and the ocular pressure was measured with a pressure-limiting tonometer every day for 10 days, and the results were shown in the following table
The results showed that, after administration for 10 days, the rabbits of each group of examples 1 to 5 were reduced to normal and the ocular hypotensive effect was better than that of comparative examples 1 and 2, compared with comparative examples 1 and 2.
Various other corresponding changes and modifications will occur to those skilled in the art from the foregoing description and the accompanying drawings, and all such changes and modifications are intended to be included within the scope of the following claims.
Claims (10)
1. The brimonidine tartrate eye temperature-sensitive in-situ gel is characterized by comprising brimonidine tartrate and pharmaceutically acceptable auxiliary materials, wherein the auxiliary materials comprise a gel matrix, a thickening agent, an osmotic pressure regulator, a pH regulator and a bacteriostatic agent.
2. The brimonidine tartrate eye temperature sensitive in situ gel of claim 1, wherein said raw and auxiliary materials are present at 100 mL: brimonidine tartrate 0.05-0.2 g, gel matrix 2-4 g, thickener 1-2 g, osmotic pressure regulator 0.3-0.8 g, bacteriostat 5-10 mg, pH regulator added to make eye drop pH 5.6-6.6, and water for injection the rest.
3. The brimonidine tartrate eye temperature sensitive in situ gel of claim 1, wherein said gel matrix is selected from one or more of gellan gum, poloxamer, carbomer, polyethylene glycol.
4. A brimonidine tartrate eye temperature sensitive in situ gel according to claim 3, wherein said poloxamer is of two types, poloxamer P407 and poloxamer P188.
5. The brimonidine tartrate eye temperature sensitive in situ gel of claim 4, wherein the mass ratio of poloxamer P188 to poloxamer P407 is between 1 and 3:2.55 and 2.75.
6. The brimonidine tartrate eye temperature sensitive in situ gel of claim 1, wherein said thickening agent is selected from one or more of sodium hyaluronate, hydroxypropyl methylcellulose, chitosan, polyvinyl alcohol; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, glycerol or glucose; the bacteriostatic agent is one or more selected from methylparaben, ethylparaben, sodium benzoate and benzalkonium chloride; the pH regulator is one or more selected from citrate buffer solution, citric acid and sodium citrate, sodium hydroxide and hydrochloric acid.
7. The brimonidine tartrate eye temperature sensitive in situ gel of claim 1, wherein said in situ gel has a viscosity of from 3.0 to 5.0 mPa-s.
8. The brimonidine tartrate eye temperature sensitive in situ gel of claim 1, wherein said in situ gel has an osmotic pressure of 280 to 320mOsmol/Kg.
9. The brimonidine tartrate eye temperature sensitive in situ gel according to any of claims 1-8, wherein said in situ gel has a suitable temperature of between 25 ℃ and 34 ℃.
10. A method of preparing a brimonidine tartrate eye temperature sensitive in situ gel according to claim 9, comprising the steps of:
(1) Taking water for injection with the prescription amount of 70-80 wt%, adding the thickener into a container, stirring and dissolving;
(2) Adding an osmotic pressure regulator, a pH regulator and a bacteriostat into a container, stirring, mixing and dissolving;
(3) Slowly adding the gel matrix with the prescription amount into the solution, stirring and wetting, and placing in an environment of 2-8 ℃ for about 2-4 hours, waiting for full swelling to obtain a blank gel solution;
(4) Adding brimonidine tartrate in a prescription amount into a blank gel solution, stirring until the brimonidine tartrate is completely dissolved, adding water for injection to 100mL, and stirring uniformly to obtain brimonidine tartrate temperature-sensitive in-situ gel.
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