CN116421555A - Brimonidine tartrate eye drops and preparation method thereof - Google Patents
Brimonidine tartrate eye drops and preparation method thereof Download PDFInfo
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- CN116421555A CN116421555A CN202310470895.4A CN202310470895A CN116421555A CN 116421555 A CN116421555 A CN 116421555A CN 202310470895 A CN202310470895 A CN 202310470895A CN 116421555 A CN116421555 A CN 116421555A
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- brimonidine tartrate
- eye drops
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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 87
- 229960001724 brimonidine tartrate Drugs 0.000 title claims abstract description 87
- 239000003889 eye drop Substances 0.000 title claims abstract description 57
- 229940012356 eye drops Drugs 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 239000000243 solution Substances 0.000 claims abstract description 103
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000008215 water for injection Substances 0.000 claims abstract description 35
- 238000003756 stirring Methods 0.000 claims abstract description 33
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 21
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 21
- 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 abstract description 21
- 239000002562 thickening agent Substances 0.000 claims abstract description 21
- 230000003204 osmotic effect Effects 0.000 claims abstract description 12
- 239000003755 preservative agent Substances 0.000 claims abstract description 11
- 230000002335 preservative effect Effects 0.000 claims abstract description 9
- 239000002585 base Substances 0.000 claims abstract description 8
- 239000000872 buffer Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 3
- 239000007853 buffer solution Substances 0.000 claims abstract description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 26
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 23
- 239000001632 sodium acetate Substances 0.000 claims description 23
- 235000017281 sodium acetate Nutrition 0.000 claims description 23
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 21
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims description 17
- 229940014041 hyaluronate Drugs 0.000 claims description 17
- 229960000583 acetic acid Drugs 0.000 claims description 16
- 239000012362 glacial acetic acid Substances 0.000 claims description 16
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 229910052700 potassium Inorganic materials 0.000 claims description 11
- 239000011591 potassium Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 239000001509 sodium citrate Substances 0.000 claims description 8
- 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 8
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 7
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000007794 irritation Effects 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000005286 illumination Methods 0.000 abstract description 5
- 230000000052 comparative effect Effects 0.000 description 18
- 230000001105 regulatory effect Effects 0.000 description 9
- 210000001508 eye Anatomy 0.000 description 8
- 235000011187 glycerol Nutrition 0.000 description 8
- 229960004249 sodium acetate Drugs 0.000 description 6
- 229960004063 propylene glycol Drugs 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (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-carboxylic acid Chemical class 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 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 229920002148 Gellan gum Polymers 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 229960001790 sodium citrate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940003677 alphagan Drugs 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 230000004509 aqueous humor production Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 231100001032 irritation of the eye Toxicity 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000013112 stability test Methods 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
- A61K9/08—Solutions
-
- 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
- A61K47/06—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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to brimonidine tartrate eye drops and a preparation method thereof, wherein the eye drops comprise the following components in 1000 ml: 1-2g of brimonidine tartrate, 0.04-0.06g of preservative, 1g of thickener, 6-8g of osmotic pressure regulator, 4-6g of acid-base buffer and the balance of water; taking 100ml of water for injection, uniformly scattering 1g of sodium hyaluronate, and stirring until the sodium hyaluronate is completely dissolved to obtain a solution a; taking 800ml of water for injection, sequentially adding brimonidine tartrate, preservative, osmotic pressure regulator and alkali in an acid-alkali buffer, and stirring until the mixture is completely dissolved to obtain a solution b; pouring the solution b into the solution a, and stirring for 30min to obtain a solution c; adjusting the pH value of the solution c to 4.5-5.5 by using a solution prepared by acid in an acid-base buffer solution; adding water for injection to 1000ml; the resulting solution was filtered through 2 0.22 μm cartridges and filled. The invention solves the problem that the impurity of the brimonidine tartrate eye drops grows faster under the illumination condition, and has lower irritation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to brimonidine tartrate eye drops and a preparation method thereof.
Background
Brimonidine tartrate eye drops were originally developed by the company ai built and approved for sale in the united states in 1996 under the trade name alfagen (ALPHAGAN) and later marketed in japan, china and europe, respectively. Brimonidine tartrate is a highly selective alpha 2 adrenergic receptor agonist and has a dual mechanism of action that reduces intraocular pressure by reducing aqueous humor production and increasing uveal scleral fluid outflow. Brimonidine tartrate eye drops are commonly used clinically to lower ocular pressure in open angle glaucoma or ocular hypertension patients.
Through early-stage researches, the commercial product of the brimonidine tartrate eye drops has faster impurity growth under the illumination condition, and the brimonidine tartrate raw material and the preservative used in the eye drops have certain irritation; for example, the Chinese invention patent No. CN115068416A is brimonidine tartrate eye drops and a preparation method thereof, wherein polyethylene glycol and glycerin are matched in a formula, so that the irritation to eyes of patients is reduced, but the influence on the growth of impurities under the illumination condition is not mentioned; for example, the invention of China with the patent number of CN109966245A is brimonidine tartrate gellan type in-situ gel eye drops and a preparation method thereof, wherein the gellan gel type in-situ gel technology is used in the formula to increase the residence time of the medicine in aqueous humor, but more cellulose thickening agent is added in the formula to increase the growth of impurities and have certain irritation to eyes.
Disclosure of Invention
The technical problem to be solved by the invention is to provide brimonidine tartrate eye drops for solving the problems.
In order to solve the technical problems, the invention adopts the following technical scheme: brimonidine tartrate eye drops, comprising the following components in 1000 ml:
brimonidine tartrate 1-2g
Preservative 0.04-0.06g
Thickener 1g
Osmotic pressure regulator 6-8g
Acid-base buffer 4-6g
The balance being water.
As a further scheme of the invention, the pH range of the brimonidine tartrate eye drops is 4.5-5.5.
As a further aspect of the present invention, the thickener is hyaluronate.
As a further aspect of the present invention, the hyaluronate is sodium hyaluronate or potassium hyaluronate.
As a further scheme of the invention, the preservative is one or more of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoate and benzyl alcohol.
As a further scheme of the invention, the osmotic pressure regulator is one or more of glycerol, sodium chloride and propylene glycol.
As a further scheme of the invention, the acid-base buffer is one or more of glacial acetic acid, sodium acetate, citric acid and sodium citrate.
As a further aspect of the invention, the brimonidine tartrate eye-drops have an osmotic pressure of 280-330mOsmol/kg.
A preparation method of brimonidine tartrate eye drops comprises the following steps:
taking 100ml of water for injection, uniformly scattering 1g of sodium hyaluronate, and stirring until the sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding the brimonidine tartrate, the preservative, the osmotic pressure regulator and the alkali in the acid-alkali buffer, and stirring until the mixture is completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, adjusting the pH value of the solution c to 4.5-5.5 by using a solution prepared by acid in an acid-base buffer solution;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
As a further aspect of the invention, the brimonidine tartrate eye-drops have an osmotic pressure of 280-330mOsmol/kg.
As the technical scheme is adopted, the invention has the advantages and positive effects that:
1. the hyaluronic acid salt is adopted, and the pH range is controlled to be 4.5-5.5, so that the rising of impurities under the illumination condition of the brimonidine tartrate eye drops can be obviously slowed down, the stability is higher, and the irritation of the eye drops to eyes can be reduced;
2. the sodium hyaluronate can increase the viscosity of the preparation and increase the bioavailability, has better function of protecting cornea, and can relieve the irritation caused by raw materials, preservatives and the like in eye drops.
Detailed Description
Example 1
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Sodium hyaluronate 1g
Glycerol 6.5g
Citric acid 0.5g
Sodium citrate 5.5g
0.04g of benzalkonium chloride. The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickener sodium hyaluronate, and stirring until the thickener sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium chloride, glycerol and sodium citrate, and stirring until the brimonidine tartrate, the benzalkonium chloride, the glycerol and the sodium citrate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing citric acid into a 20% solution, and regulating the pH value of the solution c to 4.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Example 2
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Potassium hyaluronate 1g
Sodium chloride 7g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.05g of benzalkonium bromide.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickening agent potassium hyaluronate, and stirring until the thickening agent potassium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium bromide, sodium chloride and sodium acetate, and stirring until the brimonidine tartrate, the benzalkonium bromide, the sodium chloride and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 5.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Example 3
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Potassium hyaluronate 1g
Propylene glycol 7.5g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.05g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickening agent potassium hyaluronate, and stirring until the thickening agent potassium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium chloride, propylene glycol and sodium acetate, and stirring until the brimonidine tartrate, the benzalkonium chloride, the propylene glycol and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 5.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Example 4
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 1g
Sodium hyaluronate 1g
Propylene glycol 7.8g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.06g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickener sodium hyaluronate, and stirring until the thickener sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium chloride, propylene glycol and sodium acetate, and stirring until the brimonidine tartrate, the benzalkonium chloride, the propylene glycol and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 5.0;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Example 5
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 1.5g
Sodium hyaluronate 1g
Propylene glycol 7.8g
Glacial acetic acid 0.5g sodium acetate 5g
0.04g of parahydroxybenzoate.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickener sodium hyaluronate, and stirring until the thickener sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, parahydroxybenzoate, propylene glycol and sodium acetate, and stirring until the brimonidine tartrate, the parahydroxybenzoate, the propylene glycol and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 5.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Comparative example 1
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Sodium hyaluronate 1g
Glycerol 6.5g
Citric acid 0.5g
Sodium citrate 5.5g
0.05g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickener sodium hyaluronate, and stirring until the thickener sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium chloride, glycerol and sodium citrate, and stirring until the brimonidine tartrate, the benzalkonium chloride, the glycerol and the sodium citrate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing citric acid into a 20% solution, and regulating the pH value of the solution c to 6.0;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Comparative example 2
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Potassium hyaluronate 1g
Sodium chloride 7g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.05g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of thickening agent potassium hyaluronate, and stirring until the thickening agent potassium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium bromide, sodium chloride and sodium acetate, and stirring until the brimonidine tartrate, the benzalkonium bromide, the sodium chloride and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 7.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Comparative example 3
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 2g
Propylene glycol 7.5g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.05g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
step one, 800ml of water for injection is added with brimonidine tartrate, benzalkonium chloride, propylene glycol and sodium acetate in sequence, and stirred until the brimonidine tartrate, the benzalkonium chloride, the propylene glycol and the sodium acetate are completely dissolved, so as to obtain a solution a;
step two, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution a to 5.0;
step three, adding water for injection into the solution obtained in the step two to 1000ml;
and step four, filtering the solution obtained in the step three through 2 filter cores with the diameter of 0.22 mu m, and filling.
Comparative example 4
Brimonidine tartrate eye drops comprising the following components by weight of 1000ml water:
brimonidine tartrate 1g
10g of polyvinyl alcohol
Propylene glycol 7.8g
Glacial acetic acid 0.5g
Sodium acetate 4.5g
0.06g of benzalkonium chloride.
The preparation method of the brimonidine tartrate eye drops comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 10g of polyvinyl alcohol, and stirring until the polyvinyl alcohol is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding brimonidine tartrate, benzalkonium chloride, propylene glycol and sodium acetate, and stirring until the brimonidine tartrate, the benzalkonium chloride, the propylene glycol and the sodium acetate are completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, preparing glacial acetic acid into a 20% solution, and regulating the pH value of the solution c to 5.5;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
Stability test
Samples prepared in reference preparations afara (pH 6.3) and examples 1-5 and comparative examples 1-2 were sampled under light intensity of 4500 lx.+ -. 500lx for 30d, and samples were sampled at 10d and 30d, respectively, to examine the color, content and related substances, and the experimental results were as follows:
table 1 shows color comparisons of samples of examples 1-5 and comparative examples 1-2
Table 2 shows the comparison of the sample contents of examples 1-5 and comparative examples 1-2
Table 3 shows comparison of substances related to the samples of examples 1-5 and comparative examples 1-2
From the above data, the color and content of each of examples 1-5, comparative examples 1-2 and reference formulations did not change significantly in the light for 30 days. The inventor finds that the brimonidine tartrate eye drops increase in the light condition along with the increase of pH in the range of pH4.5-pH 7.5. The samples prepared in the embodiments 1-5 of the invention have slow impurity growth under the illumination condition when the pH value is 4.5-5.5, and the total impurities in 30d are less than 0.5%, even better than the reference preparation; whereas the comparative examples 1-2 samples were at a higher pH, they showed a significant increase in impurities under light conditions. The control of the pH of the brimonidine tartrate eye drops within the range of 4.5-5.5 is demonstrated to significantly slow the growth of impurities, has higher stability, and the pH range is within the tolerance range of human eyes.
Irritation test:
healthy New Zealand rabbits were taken, randomly divided into 7 groups of 3 as test and control groups. Each rabbit was given a sample for the left eye and a saline control for the right eye. The samples obtained in examples 1 to 5 and the samples obtained in comparative examples 3 to 4 were respectively dropped into conjunctiva of rabbit eyes as test groups 1 to 5 and comparative groups 1 to 2, once every 30 minutes, and administered 10 times in total. Scoring is carried out after the 3 rd, the 5 th and the 10 th times of administration according to the eye irritation response score standard in the guidelines for research on drug irritation, allergy and hemolysis, issued by the drug evaluation center of the national drug administration: the scores were no-stimulus in the range of 0-3, mild-stimulus in the range of 4-8, moderate-stimulus in the range of 9-12, and heavy-stimulus in the range of 13-16.
Table 4 shows the stimulation response scores after the 3 rd dosing of examples 1-5 and comparative examples 3-4
Table 5 shows the comparison of the stimulation response scores after the 5 th administration of examples 1-5 and comparative examples 3-4
Table 6 shows the comparison of the stimulation response scores after the 10 th dosing of examples 1-5 and comparative examples 3-4
As can be seen from tables 4-6, the control saline was not irritating; examples 1-5 using hyaluronate were all non-irritating after 10 administrations; the samples of comparative examples 3 and 4 showed slight irritation in 3 and 2 cases, respectively, after 5 administrations; after 10 administrations, comparative example 3 showed moderate irritation, and comparative example 4 showed mild irritation; brimonidine tartrate eye drops using hyaluronate as a thickener have lower irritation; hyaluronic acid is a natural polysaccharide macromolecule, and can improve the stability of the tear film on the surface of an eyeball, keep more moisture in the eyes and relieve the irritation of medicines or preservatives in eye drops through being combined and connected with proteins.
While particular embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many variations or modifications may be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined only by the appended claims.
Claims (10)
1. Brimonidine tartrate eye drops, characterized in that: the composition comprises the following components in 1000 ml:
brimonidine tartrate 1-2g
Preservative 0.04-0.06g
Thickener 1g
Osmotic pressure regulator 6-8g
Acid-base buffer 4-6g
The balance being water.
2. The brimonidine tartrate eye drops as defined in claim 1, wherein: the pH range of the brimonidine tartrate eye drops is 4.5-5.5.
3. The brimonidine tartrate eye drops as defined in claim 1, wherein: the thickener is hyaluronate.
4. The brimonidine tartrate eye drops as defined in claim 1, wherein: the hyaluronate is sodium hyaluronate or potassium hyaluronate.
5. The brimonidine tartrate eye drops as defined in claim 1, wherein: the preservative is one or more of benzalkonium chloride, benzalkonium bromide, parahydroxybenzoate and benzyl alcohol.
6. The brimonidine tartrate eye drops as defined in claim 1, wherein: the osmotic pressure regulator is one or more of glycerol, sodium chloride and propylene glycol.
7. The brimonidine tartrate eye drops as defined in claim 1, wherein: the acid-base buffer is one or more of glacial acetic acid, sodium acetate, citric acid and sodium citrate.
8. The brimonidine tartrate eye drops as defined in claim 1, wherein: the osmotic pressure of the brimonidine tartrate eye drops is 280-330mOsmol/kg.
9. A process for preparing brimonidine tartrate eye drops, for preparing the brimonidine tartrate eye drops as defined in any one of claims 1 to 8, characterized in that: the method comprises the following specific steps:
taking 100ml of water for injection, uniformly scattering 1g of sodium hyaluronate, and stirring until the sodium hyaluronate is completely dissolved to obtain a solution a;
taking 800ml of water for injection, sequentially adding the brimonidine tartrate, the preservative, the osmotic pressure regulator and the alkali in the acid-alkali buffer, and stirring until the mixture is completely dissolved to obtain a solution b;
pouring the solution b into the solution a, and stirring for 30min to obtain a solution c;
step four, adjusting the pH value of the solution c to 4.5-5.5 by using a solution prepared by acid in an acid-base buffer solution;
step five, adding the solution obtained in the step four to 1000ml of water for injection;
and step six, filtering the solution obtained in the step five through 2 filter cores with the diameter of 0.22 mu m, and filling.
10. The method for preparing brimonidine tartrate eye drops as defined in claim 9, wherein the method comprises the steps of: the osmotic pressure of the brimonidine tartrate eye drops is 280-330mOsmol/kg.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090069345A1 (en) * | 2007-09-12 | 2009-03-12 | Arturo Jimenez Bayardo | Pharmaceutically Stable Compound Consisting of Timolol, Dorzolamide and Brimonidine |
| KR20110100370A (en) * | 2010-03-04 | 2011-09-14 | 한림제약(주) | Ophthalmic soultion comprising brimonidine tartrate |
| US20160331745A1 (en) * | 2013-12-24 | 2016-11-17 | Sentiss Pharma Private Limited | Topical Brimonidine Tartrate Ophthalmic Solution |
| CN108261390A (en) * | 2017-06-12 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of brinzolamide Brimonidine eye drops and preparation method thereof |
| CN114306226A (en) * | 2022-01-21 | 2022-04-12 | 山东诺明康药物研究院有限公司 | Compound nanometer eye drops and preparation method thereof |
-
2023
- 2023-04-27 CN CN202310470895.4A patent/CN116421555A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090069345A1 (en) * | 2007-09-12 | 2009-03-12 | Arturo Jimenez Bayardo | Pharmaceutically Stable Compound Consisting of Timolol, Dorzolamide and Brimonidine |
| KR20110100370A (en) * | 2010-03-04 | 2011-09-14 | 한림제약(주) | Ophthalmic soultion comprising brimonidine tartrate |
| US20160331745A1 (en) * | 2013-12-24 | 2016-11-17 | Sentiss Pharma Private Limited | Topical Brimonidine Tartrate Ophthalmic Solution |
| CN108261390A (en) * | 2017-06-12 | 2018-07-10 | 上海昊海生物科技股份有限公司 | A kind of brinzolamide Brimonidine eye drops and preparation method thereof |
| CN114306226A (en) * | 2022-01-21 | 2022-04-12 | 山东诺明康药物研究院有限公司 | Compound nanometer eye drops and preparation method thereof |
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