CN115671042A - Acatadine eye drops - Google Patents
Acatadine eye drops Download PDFInfo
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- CN115671042A CN115671042A CN202211306801.1A CN202211306801A CN115671042A CN 115671042 A CN115671042 A CN 115671042A CN 202211306801 A CN202211306801 A CN 202211306801A CN 115671042 A CN115671042 A CN 115671042A
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Abstract
The invention relates to alcaftadine eye drops. Specifically, the invention provides an alcaftadine eye drop which comprises alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water. The alcaftadine eye drops disclosed by the invention have high ocular administration compliance and excellent stability.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to alcaftadine eye drops.
Background
The alcaftadine eye drops are used for treating eye diseases such as pruritus by means of eye drop administration, have the advantages of simple and convenient administration mode and the like, and the structural formula of the alcaftadine is as follows:
however, the existing alcaftadine eye drops have the side effect of strong eye stimulation, the eye medication acceptance of patients is reduced, and the eye medication compliance of the patients is poor. Therefore, the application value of the alcaftadine eye drops can be improved by improving the compliance and stability of ocular administration of the alcaftadine eye drops.
Disclosure of Invention
The invention aims to provide alcaftadine eye drops with high ocular administration compliance and excellent stability.
The invention provides an alcaftadine eye drop, which comprises alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water.
Preferably, the alcaftadine is 1-10 parts by weight, preferably 1-5 parts by weight, more preferably 2-3 parts by weight, most preferably 2.5 parts by weight.
Preferably, the alcaftadine is present in an amount of 1-10mg/ml, preferably 1-5mg/ml, more preferably 2-3mg/ml, most preferably 2.5mg/ml.
Preferably, the glycerol is present in an amount of 1 to 8 parts by weight, preferably 2 to 4 parts by weight, more preferably 2.5 to 3.5 parts by weight, most preferably 3.0 parts by weight.
Preferably, the glycerol is present in an amount of 1-8mg/ml, preferably 2-4mg/ml, more preferably 2.5-3.5mg/ml, most preferably 3.0mg/ml.
Preferably, the poloxamer 188 is present in an amount of 1-8 parts by weight, preferably 3-5 parts by weight, more preferably 3.5-4.5 parts by weight, most preferably 4.0 parts by weight.
Preferably, the poloxamer 188 is present in an amount of 1-8mg/ml, preferably 3-5mg/ml, more preferably 3.5-4.5mg/ml, most preferably 4.0mg/ml.
Preferably, the polyvinyl alcohol is 0.1 to 3.0 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, most preferably 1.0 part by weight.
Preferably, the polyvinyl alcohol is present in an amount of 0.1-3.0mg/ml, preferably 0.5-1.5mg/ml, more preferably 0.8-1.2mg/ml, most preferably 1.0mg/ml.
Preferably, the tartaric acid is 0.5 to 5 parts by weight, preferably 1 to 2 parts by weight, more preferably 1.3 to 1.7 parts by weight, most preferably 1.5 parts by weight.
Preferably, the tartaric acid is present in an amount of 0.5-5mg/ml, preferably 1-2mg/ml, more preferably 1.3-1.7mg/ml, most preferably 1.5mg/ml.
Preferably, the mannitol is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, most preferably 2.0 parts by weight.
Preferably, the mannitol is present in an amount of 1-3mg/ml, preferably 1.5-2.5mg/ml, more preferably 1.8-2.2mg/ml, most preferably 2.0mg/ml.
Preferably, the disodium hydrogen phosphate is present in an amount of 0.1 to 1.2 parts by weight, preferably 0.2 to 0.8 parts by weight, more preferably 0.3 to 0.7 parts by weight, most preferably 0.5 parts by weight.
Preferably, the disodium hydrogen phosphate is present in an amount of 0.1 to 1.2mg/ml, preferably 0.2 to 0.8mg/ml, more preferably 0.3 to 0.7mg/ml, most preferably 0.5mg/ml.
Preferably, the sodium chloride is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, most preferably 2.0 parts by weight.
Preferably, the sodium chloride is present in an amount of 1-3mg/ml, preferably 1.5-2.5mg/ml, more preferably 1.8-2.2mg/ml, most preferably 2.0mg/ml.
Preferably, the EDTA-2Na is 0.05 to 0.3 parts by weight, preferably 0.05 to 0.15 parts by weight, more preferably 0.08 to 0.12 parts by weight, and most preferably 0.1 parts by weight.
Preferably, the EDTA-2Na is present in an amount of 0.05-0.3mg/ml, preferably 0.05-0.15mg/ml, more preferably 0.08-0.12mg/ml, most preferably 0.1mg/ml.
Preferably, the water is 900 to 1100 parts by weight, preferably 950 to 1050 parts by weight, more preferably 980 to 1020 parts by weight, more preferably 990 to 1010 parts by weight, most preferably 1000 parts by weight.
Preferably, the water is water for injection.
Preferably, the alcaftadine eye drop comprises:
| components | Dosage of |
| Alcaftadine | 2.0 to 3.0 parts by weight |
| Glycerol | 2.0 to 4.0 parts by weight |
| Poloxamer 188 | 3.0 to 5.0 portions by weight |
| Polyvinyl alcohol | 0.5 to 1.5 parts by weight of |
| Tartaric acid | 1.0 to 2.0 parts by weight |
| Mannitol | 1.0 to 3.0 parts by weight |
| Disodium hydrogen phosphate | 0.2 to 0.8 weight portion |
| Sodium chloride | 1.0 to 3.0 parts by weight |
| EDTA-2Na | 0.05-0.2 weight parts; and |
| water (W) | 970-1030 parts by weight. |
Preferably, the alcaftadine eye drops comprise:
preferably, the alcaftadine eye drops comprise:
| components | Dosage of |
| Acatadine | 2.5 parts by weight of |
| Glycerol | 3.0 parts by weight |
| Poloxamer 188 | 4.0 parts by weight |
| Polyvinyl alcohol | 1.0 part by weight |
| Tartaric acid | 1.5 parts by weight |
| Mannitol | 2.0 parts by weight |
| Disodium hydrogen phosphate | 0.5 part by weight |
| Sodium chloride | 2.0 parts by weight |
| EDTA-2Na | 0.1 part by weight; and |
| water (I) | 1000 parts by weight. |
Preferably, the alcaftadine eye drop comprises:
| components | Dosage of |
| Acatadine | 2.5g |
| Glycerol | 3.0g |
| Poloxamer 188 | 4.0g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 1.5g |
| Mannitol | 2.0g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium chloride | 2.0g |
| EDTA-2Na | 0.1g |
| Adding water to | 1000ml。 |
In a second aspect, the present invention provides a method for preparing an alcaftadine ophthalmic solution according to the first aspect of the present invention, said method comprising the steps of:
mixing alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water to obtain the alcaftadine eye drops.
Preferably, the method comprises the steps of:
stirring and mixing 80-90% of water, glycerol, poloxamer 188 and polyvinyl alcohol according to the prescription amount, dissolving, adding tartaric acid and disodium hydrogen phosphate, stirring and dissolving, adding alcaftadine, stirring and dissolving, adding mannitol, sodium chloride and EDTA-2Na, stirring and dissolving, adding water to the dosage volume, and filtering to obtain the alcaftadine eye drops.
Preferably, said filtration comprises filtration through 0.45 μm and 0.22 μm microporous filter membranes in that order.
In a third aspect, the invention provides a kit comprising an alcaftadine ophthalmic solution according to the first aspect of the invention and a container.
Preferably, the container comprises a transparent container.
Preferably, the container comprises a transparent glass or transparent plastic container
Preferably, the container comprises a transparent PET bottle
In a fourth aspect, the present invention provides a use of the alcaftadine eye drops according to the first aspect of the invention for preparing a medicament for preventing and/or treating an ocular disease.
Preferably, the ocular disease is selected from the group consisting of: itch, choroidal neovascularization complications, or a combination thereof.
Preferably, the choroidal neovascular complication comprises macular degeneration.
Preferably, the prevention and/or treatment of choroidal neovascularization comprises prevention and/or treatment of choroidal neovascularization formation and growth.
Preferably, the dosage form of the medicament is eye drops.
Preferably, the eye drops are eye drops.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments.
Detailed Description
The invention provides an alcaftadine eye drop which comprises alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water. The acatadine eye drops disclosed by the invention are small in irritation of eye administration, high in compliance of eye administration of patients, and excellent in illumination, high temperature and high temperature stability, so that the medication safety of the acatadine eye drops is effectively ensured. The alcaftadine eye drops have excellent treatment effect on eye diseases such as choroidal neovascularization and the like.
Term(s)
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of 8230; \8230; composition;" consisting essentially of 8230; \8230; composition 8230).
As used herein, the term "EDTA-2Na" refers to disodium ethylenediaminetetraacetic acid.
As used herein, the term "Polyvinyl Alcohol" is given its english designation Polyvinyl Alcohol.
As used herein, the term "Poloxamer 188" is in English the Poloxamer 188.
As used herein, the term "part by weight" can be any fixed weight expressed in milligrams, grams, or kilograms (e.g., 1mg, 1g, or 1kg, etc.). For example, a composition consisting of 1 part by weight of component a and 9 parts by weight of component b may be a composition consisting of 1g of component a +9 g of component b, or 10 g of component a +90 g of component b. In the alcaftadine eye drops, the percentage content of a certain component = (the weight part of the component/the sum of the weight parts of all the components) × 100%, and therefore, in a composition composed of 1 part by weight of the component a and 9 parts by weight of the component b, the content of the component a is 10%, and the content of the component b is 90%.
In the present invention, the term "prevention" means a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease.
In the present invention, the term "treatment" includes inhibiting, reducing, alleviating, reversing or eradicating the progression of the disease, and does not require 100% inhibition, eradication or reversal. In some embodiments, the alcaftadine ophthalmic solutions of the present invention reduce, inhibit, and/or reverse disease, e.g., by at least about 30%, at least about 50%, or at least about 80%, or at least about 90%, or at least about 95% or 100%, as compared to the levels observed in the absence of the alcaftadine ophthalmic solutions of the present invention.
Acatadine eye drops and preparation method thereof
The invention provides an alcaftadine eye drop, which comprises alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water.
In a preferred embodiment of the present invention, the alcaftadine is 1 to 10 parts by weight, preferably 1 to 5 parts by weight, more preferably 2 to 3 parts by weight, most preferably 2.5 parts by weight.
Preferably, the alcaftadine is present in an amount of 1-10mg/ml, preferably 1-5mg/ml, more preferably 2-3mg/ml, most preferably 2.5mg/ml.
In a preferred embodiment of the present invention, the glycerin is 1 to 8 parts by weight, preferably 2 to 4 parts by weight, more preferably 2.5 to 3.5 parts by weight, and most preferably 3.0 parts by weight.
Preferably, the glycerol is present in an amount of 1-8mg/ml, preferably 2-4mg/ml, more preferably 2.5-3.5mg/ml, most preferably 3.0mg/ml.
In a preferred embodiment of the invention, the poloxamer 188 is present in an amount of 1-8 parts by weight, preferably 3-5 parts by weight, more preferably 3.5-4.5 parts by weight, most preferably 4.0 parts by weight.
Preferably, the poloxamer 188 is present in an amount of 1-8mg/ml, preferably 3-5mg/ml, more preferably 3.5-4.5mg/ml, most preferably 4.0mg/ml.
In a preferred embodiment of the present invention, the polyvinyl alcohol is 0.1 to 3.0 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, and most preferably 1.0 part by weight.
Preferably, the polyvinyl alcohol is present in an amount of 0.1-3.0mg/ml, preferably 0.5-1.5mg/ml, more preferably 0.8-1.2mg/ml, most preferably 1.0mg/ml.
In a preferred embodiment of the present invention, the tartaric acid is 0.5 to 5 parts by weight, preferably 1 to 2 parts by weight, more preferably 1.3 to 1.7 parts by weight, and most preferably 1.5 parts by weight.
Preferably, the tartaric acid is present in an amount of 0.5-5mg/ml, preferably 1-2mg/ml, more preferably 1.3-1.7mg/ml, most preferably 1.5mg/ml.
In a preferred embodiment of the present invention, the mannitol is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, and most preferably 2.0 parts by weight.
Preferably, the mannitol is present in an amount of 1-3mg/ml, preferably 1.5-2.5mg/ml, more preferably 1.8-2.2mg/ml, most preferably 2.0mg/ml.
In a preferred embodiment of the present invention, the disodium hydrogen phosphate is 0.1 to 1.2 parts by weight, preferably 0.2 to 0.8 parts by weight, more preferably 0.3 to 0.7 parts by weight, and most preferably 0.5 parts by weight.
Preferably, the disodium hydrogen phosphate is present in an amount of 0.1 to 1.2mg/ml, preferably 0.2 to 0.8mg/ml, more preferably 0.3 to 0.7mg/ml, most preferably 0.5mg/ml.
In a preferred embodiment of the present invention, the sodium chloride is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, and most preferably 2.0 parts by weight.
Preferably, the sodium chloride is present in an amount of 1-3mg/ml, preferably 1.5-2.5mg/ml, more preferably 1.8-2.2mg/ml, most preferably 2.0mg/ml.
In a preferred embodiment of the present invention, the EDTA-2Na is present in an amount of 0.05 to 0.3 parts by weight, preferably 0.05 to 0.15 parts by weight, more preferably 0.08 to 0.12 parts by weight, most preferably 0.1 parts by weight.
Preferably, the EDTA-2Na is present in an amount of 0.05-0.3mg/ml, preferably 0.05-0.15mg/ml, more preferably 0.08-0.12mg/ml, most preferably 0.1mg/ml.
In a preferred embodiment of the present invention, the amount of water is 900 to 1100 parts by weight, preferably 950 to 1050 parts by weight, more preferably 980 to 1020 parts by weight, still more preferably 990 to 1010 parts by weight, and most preferably 1000 parts by weight.
Preferably, the water is water for injection.
Typically, the alcaftadine eye drops comprise:
typically, the alcaftadine eye drops comprise:
| components | Amount of the composition |
| Acatadine | 2.3-2.7 parts by weight |
| Glycerol | 2.8 to 3.2 parts by weight of |
| Poloxamer 188 | 3.8 to 4.2 parts by weight of |
| Polyvinyl alcohol | 0.8 to 1.2 parts by weight of |
| Tartaric acid | 1.3-1.7 parts by weight |
| Mannitol | 1.8-2.2 parts by weight |
| Disodium hydrogen phosphate | 0.3 to 0.7 part by weight |
| Sodium chloride | 1.8-2.2 parts by weight |
| EDTA-2Na | 0.08 to 0.12 part by weight; and |
| water (I) | 980-1020 parts by weight. |
Typically, the alcaftadine eye drops comprise:
| components | Dosage of |
| Alcaftadine | 2.5g |
| Glycerol | 3.0g |
| Poloxamer 188 | 4.0g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 1.5g |
| Mannitol | 2.0g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium chloride | 2.0g |
| EDTA-2Na | 0.1g |
| Adding water to | 1000ml。 |
The invention also provides a method for preparing the alcaftadine eye drops, which comprises the following steps:
mixing alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water to obtain the alcaftadine eye drops.
In a preferred embodiment of the present invention, the method comprises the steps of:
mixing and dissolving 80-90% of water, glycerol, poloxamer 188 and polyvinyl alcohol by stirring, adding tartaric acid and disodium hydrogen phosphate, stirring for dissolving, adding alcaftadine, stirring for dissolving, adding mannitol, sodium chloride and EDTA-2Na, stirring for dissolving, adding water to the dosage volume, and filtering to obtain the alcaftadine eye drops.
Preferably, said filtration comprises filtration through 0.45 μm and 0.22 μm microporous filter membranes in that order.
Use of
The invention provides an application of the alcaftadine eye drops, which is used for preparing a medicament for preventing and/or treating eye diseases.
In a preferred embodiment of the present invention, the ocular disease is selected from the group consisting of: itch, choroidal neovascularization complications, or a combination thereof.
Preferably, the choroidal neovascular complication comprises macular degeneration.
Preferably, said preventing and/or treating choroidal neovascularization comprises preventing and/or treating choroidal neovascularization formation and growth.
In a preferred embodiment of the invention, the dosage form of the medicament is eye drops.
Preferably, the eye drops are eye drops.
The main excellent technical effects of the invention comprise:
the invention develops the alcaftadine eye drops which have small irritation to eye administration and high compliance to eye administration of patients, and have excellent illumination, high temperature and high temperature stability, thereby having excellent storage and transportation stability and effectively ensuring the medication safety of the alcaftadine eye drops. In addition, the alcaftadine eye drops have excellent treatment effect on eye diseases such as choroidal neovascularization and the like.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally performed under conventional conditions.
Example 1 Acetadine eyedrops
The prescription of the alcaftadine eye drops of example 1 is shown in table 1:
TABLE 1 prescription composition of the acatadine eye drops (Specification: 2.5 mg/ml)
| Components | Amount of the composition |
| Acatadine | 2.5g |
| Glycerol | 3.0g |
| Poloxamer 188 | 4.0g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 1.5g |
| Mannitol | 2.0g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium chloride | 2.0g |
| EDTA-2Na | 0.1g |
| Adding water for injection to | 1000ml |
The preparation method of the alcaftadine eye drops in the embodiment 1 is as follows:
the preparation method comprises the steps of stirring, mixing and dissolving 85% of prescription dose of water for injection, prescription dose of glycerol, prescription dose of poloxamer 188 and prescription dose of polyvinyl alcohol, adding tartaric acid and disodium hydrogen phosphate, stirring and dissolving, adding alcaftadine, stirring and dissolving, adding mannitol, sodium chloride and EDTA-2Na, stirring and dissolving, adding water for injection to the dosage volume, filtering through 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain alcaftadine eye drops, and subpackaging in transparent PET bottles, wherein the specification of alcaftadine is 2.5mg/ml.
Comparative example 1 Acetadine eye drops
The prescription of the alcaftadine eye drops of comparative example 1 is shown in table 2:
TABLE 2 prescription composition of alcaftadine eye drops (specification: 2.5 mg/ml)
The preparation method of the alcaftadine eye drops of comparative example 1 is as follows:
stirring, mixing and dissolving 85% of injection water, glycerol and poloxamer 188 according to the prescription amount, adding tartaric acid according to the prescription amount and disodium hydrogen phosphate according to the prescription amount, stirring and dissolving, adding alcaftadine according to the prescription amount, stirring and dissolving, adding mannitol according to the prescription amount, sodium chloride according to the prescription amount and EDTA-2Na according to the prescription amount, stirring and dissolving, adding injection water to the dosage volume, filtering through 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain the alcaftadine eye drops, and subpackaging in transparent PET bottles, wherein the specification of alcaftadine is 2.5mg/ml.
Comparative example 2 Acetadine eye drops
The prescription of the alcaftadine eye drops of comparative example 2 is shown in table 3:
TABLE 3 prescription composition of the acatadine eye drops (Specification: 2.5 mg/ml)
| Components | Dosage of |
| Acatadine | 2.5g |
| Glycerol | 3.0g |
| Poloxamer 188 | 4.0g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 1.5g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium chloride | 2.0g |
| EDTA-2Na | 0.1g |
| Adding water for injection to | 1000ml |
The preparation method of the alcaftadine eye drops of the comparative example 2 is as follows:
mixing and dissolving 85% of prescription dose of water for injection, glycerol, poloxamer 188 and polyvinyl alcohol, stirring and dissolving, adding tartaric acid and disodium hydrogen phosphate, stirring and dissolving, adding alcaftadine, stirring and dissolving, adding sodium chloride and EDTA-2Na, stirring and dissolving, adding water for injection to the volume of the prescription, filtering by 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain the alcaftadine eye drops, and subpackaging in transparent PET bottles, wherein the specification of the alcaftadine is 2.5mg/ml.
Comparative example 3 Acetadine eye drops
The prescription of the alcaftadine eye drops of comparative example 3 is shown in table 4:
TABLE 4 prescription composition of the acatadine eye drops (Specification: 2.5 mg/ml)
The preparation method of the alcaftadine eye drops of the comparative example 3 is as follows:
the preparation method comprises the steps of stirring, mixing and dissolving 85% of prescription dose of water for injection, prescription dose of glycerol, prescription dose of poloxamer 188 and prescription dose of polyvinyl alcohol, adding tartaric acid and disodium hydrogen phosphate, stirring and dissolving, adding alcaftadine, stirring and dissolving, adding mannitol, sodium chloride and EDTA-2Na, stirring and dissolving, adding water for injection to the dosage volume, filtering through 0.45 mu m and 0.22 mu m microporous filter membranes in sequence to obtain alcaftadine eye drops, and subpackaging in transparent PET bottles, wherein the specification of alcaftadine is 2.5mg/ml.
Comparative example 4 Acetadine eye drops
The prescription of the alcaftadine ophthalmic solution of comparative example 4 is shown in table 5:
TABLE 5 prescription composition of the Acetadine eye drops (Specification: 2.5 mg/ml)
| Components | Dosage of |
| Acatadine | 2.5g |
| Glycerol | 3.0g |
| Poloxamer 188 | 4.0g |
| Polyvinyl alcohol | 1.0g |
| Tartaric acid | 0.8g |
| Mannitol | 1.2g |
| Disodium hydrogen phosphate | 0.5g |
| Sodium chloride | 2.0g |
| EDTA-2Na | 0.1g |
| Adding water for injection to | 1000ml |
The preparation method of the alcaftadine eye drops of the comparative example 4 is as follows:
mixing and dissolving 85% of prescription dose of water for injection, prescription dose of glycerol, prescription dose of poloxamer 188 and prescription dose of polyvinyl alcohol by stirring, adding tartaric acid and disodium hydrogen phosphate by stirring, adding alcaftadine by stirring, adding mannitol by stirring, sodium chloride by stirring and EDTA-2Na by stirring, adding injection water to the dosage volume after stirring and dissolving, filtering by microporous filter membranes of 0.45 mu m and 0.22 mu m in sequence to obtain the alcaftadine eye drops, and subpackaging in transparent PET bottles, wherein the specification of the alcaftadine is 2.5mg/ml.
Eye irritation investigation
Healthy white rabbits were randomly divided into 5 groups (n = 10), 1 droplet of the acatadine eye drops prepared in example 1, comparative example 2, comparative example 3 and comparative example 4 was respectively dropped to the left eye of the white rabbit, while 1 droplet of physiological saline was dropped to the right eye of the white rabbit as a control, and dropped 1 time per day for 10 consecutive days, and eye irritation of the acatadine eye drops prepared in example 1, comparative example 2, comparative example 3 and comparative example 4 was examined by sodium fluorescein staining and slit lamp examination at 1h after the first eye drop and 1h after the 10 th eye drop, respectively.
Evaluation items of eye irritation degree and evaluation scores thereof:
cornea: 0 min-no turbidity; 1, scattered or diffuse turbidity, with clear and visible iris; 2-the translucent area is easily distinguished, the iris is blurred; 3 min-a grey-white translucent area appears, the details of the iris are unclear, and the pupil is barely visible; 4 points-cornea is opaque and iris is not recognizable.
Iris: score 0-normal; 1 minute-fold is obviously deepened, hyperemic, swollen, the cornea periphery is slightly hyperemic, pupil still reacts to light; 2 min-hemorrhage/macroscopic necrosis/no response to light (or one of them).
Conjunctival congestion (palpebral conjunctiva and bulbar conjunctiva): score 0-normal blood vessels; 1 minute-blood vessel congestion is bright red; 2 min-blood vessels are deep red in color and are not easily distinguished; 3 points-diffuse hyperemia with purple red color.
Edema: 0 min-edema free; 1 point-mild edema (including eyelids); score 2-marked edema with partial eyelid eversion; score 3-edema to eyelid to semi-closure; 4 min-edema to more than half closure of the eyelids;
secretion: score 0-no secretions; 1 min-small amount of secretion; 2 min-secretions make the eyelids and eyelashes moist or sticky; 3 min-the secretions wet or adhere the entire ocular region.
Evaluation criteria for eye irritation:
the total score of the ocular irritation evaluations and the ocular irritation evaluation criteria corresponding thereto were as follows:
has no irritation: 0-3 (including 0 and not including 3) points;
mild irritation: 3-8 (including 3 and not including 8) points;
moderate irritation: 8-12 (including 8 and not including 12) points;
severe irritation: 12-16 (including 12 and 16).
The higher the overall score for the ocular irritation evaluation, the greater the ocular irritation.
The average total ocular irritation scores of the alcaftadine eye drops prepared in example 1 and comparative examples 1-4 are shown in table 6 below:
TABLE 6 average total ocular irritation score of the alcaftadine ophthalmic solutions prepared in example 1 and comparative examples 1-4
As can be seen from table 6, the alcaftadine eye drops prepared in example 1 were free from ocular irritation, high in safety, and strong in compliance of the patient with eye drop administration.
Stability survey of lighting factors
The acatadine eye drops prepared in example 1 and comparative examples 1 to 4, which were filled in transparent PET bottles, were placed under light conditions (4500lx, 25 ℃) for 0 day, 10 days, and 30 days according to the guidelines of the stability test in Chinese pharmacopoeia formulations, and the acatadine content (%) and impurity content (%) of the acatadine eye drops at different examination time points were measured to examine the light stability of the acatadine eye drops prepared in example 1 and comparative examples 1 to 4.
The results of the light factor examination of the alcaftadine eyedrops of example 1 and comparative examples 1-4 at different examination time points are shown in table 7:
TABLE 7 stability examination of the acatadine eye drops prepared in example 1 and comparative examples 1 to 4 under light conditions (4500 lx,25 ℃ C.)
As seen from table 7, the alcaftadine eye drops prepared in example 1 had excellent light stability and strong light stability.
Accelerated stability review
The alcaftadine eye drops prepared in example 1, which were dispensed in transparent PET bottles, were placed under conditions of 40 ± 2 ℃ temperature and RH75 ± 5% relative humidity for 0 day, 1, 3 and 6 months according to the chinese pharmacopoeia formulation stability test guidelines, and the alcaftadine content (%) and impurity content (%) of the alcaftadine eye drops at different investigation time points were measured to examine the high-temperature and high-humidity accelerated stability of the alcaftadine eye drops prepared in example 1.
The results of the high temperature and high humidity accelerated stability test of the alcaftadine eye drops of example 1 at different test time points are shown in table 8:
TABLE 8 stability test results of the alcaftadine eyedrops prepared in example 1 under accelerated conditions (40. + -. 2 ℃ C., RH 75. + -. 5%)
It is seen from table 8 that the alcaftadine eye drops prepared in example 1 have excellent high-temperature and high-humidity accelerated stability, thus having excellent storage and transportation stability, ensuring the drug quality, and further effectively ensuring the medication safety of the alcaftadine eye drops.
Treatment of ocular diseases
Examination of the treatment of choroidal neovascularization with the alcaftadine eyedrops prepared in example 1
The experimental method comprises the following steps:
constructing a choroidal neovascularization animal model: after mydriasis of healthy blue and green blue rabbits, 20 mu L Matrigel is extracted by an injector and then the needles are inserted from the pars plana of the ciliary body and are penetrated into the vitreous cavity, the needle points are penetrated into the retina, the injection positions are the positions with marrow nerve fibers in the middle and outer 1/3 of the temporal side, the medicine is pushed, the needles are pulled out, the retina has no large-area hemorrhage, and the crystalline lens has no scratch, which is regarded as the success of model building.
Blue-purple blue rabbits, which were successfully used for choroidal neovascularization, were randomly divided into a model group and an alcaftadine group, eye drop administration was started, 1 drop of physiological saline was dropped into the animal eye of the model group as a control, 1 drop of alcaftadine eye drop prepared in example 1 was dropped into the animal eye of the alcaftadine group, 1 drop was dropped into each group daily, after 28 consecutive days and after the full mydriasis of each group of animals, 10% sodium fluorescein (1 ml/kg) was injected through the auricular edge vein, fundus oculi colorography and FFA (fluoroscein fundus angiograph) examination were performed, and the fundus oculi fluorescein leakage area was obtained by analytical treatment, and the results are shown in table 9:
TABLE 9 area of fundus fluorescein leakage after treatment of each group
| Experimental group | Area of fluorescein leakage |
| Model set | 3.95±0.37 |
| Alcaftadine group | 2.23±0.21 * |
Remarking: * Representing p < 0.05 compared to the model group.
As can be seen from table 9, the significant fluorescein leakage area of the model group indicates that the choroidal neovascularization was successfully modeled, and compared with the fluorescein leakage area of the model group, the alcaftadine eye drops prepared in example 1 by eye drop can significantly reduce the fluorescein leakage area of the choroidal neovascularization site, thereby indicating that the alcaftadine eye drops have an excellent inhibitory effect on choroidal neovascularization and can be used for the treatment of choroidal neovascularization.
While the invention has been described in terms of a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention.
Claims (10)
1. An alcaftadine eye drop is characterized by comprising alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water.
2. The alcaftadine eye drops according to claim 1, wherein the alcaftadine is 1-10 parts by weight, preferably 1-5 parts by weight, more preferably 2-3 parts by weight, most preferably 2.5 parts by weight;
1-8 parts by weight of glycerol, preferably 2-4 parts by weight, more preferably 2.5-3.5 parts by weight, most preferably 3.0 parts by weight;
1-8 parts of poloxamer 188, preferably 3-5 parts, more preferably 3.5-4.5 parts, and most preferably 4.0 parts;
the polyvinyl alcohol is 0.1 to 3.0 parts by weight, preferably 0.5 to 1.5 parts by weight, more preferably 0.8 to 1.2 parts by weight, most preferably 1.0 part by weight;
0.5-5 parts by weight of tartaric acid, preferably 1-2 parts by weight, more preferably 1.3-1.7 parts by weight, and most preferably 1.5 parts by weight;
1-3 parts by weight of mannitol, preferably 1.5-2.5 parts by weight, more preferably 1.8-2.2 parts by weight, most preferably 2.0 parts by weight;
the disodium hydrogen phosphate is 0.1 to 1.2 parts by weight, preferably 0.2 to 0.8 parts by weight, more preferably 0.3 to 0.7 parts by weight, most preferably 0.5 parts by weight;
the sodium chloride is 1 to 3 parts by weight, preferably 1.5 to 2.5 parts by weight, more preferably 1.8 to 2.2 parts by weight, most preferably 2.0 parts by weight;
the EDTA-2Na is 0.05 to 0.3 part by weight, preferably 0.05 to 0.15 part by weight, more preferably 0.08 to 0.12 part by weight, and most preferably 0.1 part by weight; and
the amount of the water is 900 to 1100 parts by weight, preferably 950 to 1050 parts by weight, more preferably 980 to 1020 parts by weight, still more preferably 990 to 1010 parts by weight, most preferably 1000 parts by weight.
3. The alcaftadine ophthalmic solution of claim 1, wherein said alcaftadine ophthalmic solution comprises:
4. The alcaftadine ophthalmic solution of claim 1, wherein said alcaftadine ophthalmic solution comprises:
5. the alcaftadine ophthalmic solution of claim 1, wherein said alcaftadine ophthalmic solution comprises:
6. The alcaftadine ophthalmic solution of claim 1, wherein said alcaftadine ophthalmic solution comprises:
7. A method of preparing an ophthalmic solution of alcaftadine of claim 1, comprising the steps of:
mixing alcaftadine, glycerol, poloxamer 188, polyvinyl alcohol, tartaric acid, mannitol, disodium hydrogen phosphate, sodium chloride, EDTA-2Na and water to obtain the alcaftadine eye drops.
8. A kit comprising the alcaftadine eyedrops of claim 1 and a container.
9. Use of the alcaftadine eye drops according to claim 1 for the preparation of a medicament for the prophylaxis and/or treatment of ocular diseases.
10. The use according to claim 9, wherein the ocular disease is selected from the group consisting of: itch, choroidal neovascularization complications, or a combination thereof.
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Non-Patent Citations (1)
| Title |
|---|
| 张加;董江萍;: "2010年美国FDA批准过敏性结膜炎治疗药物阿卡他定(Alcaftadine)滴眼液上市", 药物评价研究, no. 01, pages 71 - 72 * |
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