CN112870216A - Pharmaceutical composition, preparation and application - Google Patents
Pharmaceutical composition, preparation and application Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
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- 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
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- A61P27/02—Ophthalmic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention belongs to the technical field of biological medicines, and discloses a pharmaceutical composition, a preparation and application thereof. The medicine composition is obtained by test screening; the pharmaceutical composition can be used for preparing eye preparation, has the advantages of small intraocular irritation and comfortable eye drop, and can be used for treating diseases such as inner diseases such as sjogren's syndrome, xerophthalmia, etc., and keratoconjunctival epithelium injury caused by various external diseases (such as postoperative, drug-induced, traumatic, wearing contact lenses, etc.).
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel pharmaceutical composition, a preparation and application.
Background
Dry eye is also called keratoconjunctival xerosis, which is a general term for various diseases caused by abnormal quality or quantity of tear fluid or abnormal dynamics due to any reasons, resulting in the reduction of the stability of tear film and accompanied by ocular discomfort and/or pathological features of ocular surface tissues. Common symptoms include dry eyes, easy tiredness, itching eyes, foreign body sensation, burning sensation, viscous secretion, aversion to wind, photophobia and sensitivity to external stimulation; sometimes, the eyes are too dry, the basic tears are insufficient, and the reflex tears are stimulated to secrete, so that the frequent tears are caused; in more severe cases, the eyes become inflamed, engorged, keratinized, and the corneal epithelium is broken and the filaments are adhered, and this damage may cause keratoconjunctival disorders and affect vision over time. Recent studies have suggested that changes in the ocular surface, immune-based inflammatory responses, apoptosis, changes in sex hormone levels, etc., are factors involved in the development of dry eye.
Disclosure of Invention
Based on the above reasons, the applicant has conducted intensive research on salvianolic acid a on the basis of research on dry eye diseases, and unexpectedly found a novel pharmaceutical composition for treating dry eye diseases and other diseases, wherein the pharmaceutical composition contains salvianolic acid a and sodium hyaluronate as active ingredients.
The invention is realized by the following technical scheme.
A pharmaceutical composition comprises salvianolic acid A and sodium hyaluronate as active ingredients.
Wherein the salvianolic acid A: the weight ratio of the sodium hyaluronate is 1: 1 to 2.
The pharmaceutical composition is prepared into a pharmaceutical preparation by taking the raw materials.
The pharmaceutical preparation comprises eye drops, ophthalmic gel, eye ointment or any one of the pharmaceutically acceptable dosage forms suitable for topical application to the eye, wherein the salvianolic acid A accounts for 0.02-0.2 part by weight per 100 parts by weight of the pharmaceutical preparation.
The pharmaceutical composition comprises poloxamer 407 or tyloxapol, and the addition amount of the poloxamer 407 or tyloxapol is calculated according to the weight ratio of the salvianolic acid A: salvianolic acid A: poloxamer 407 or tyloxapol ═ 1: 0.5 to 2, or 1: 1 to 4.
The eye drops or the eye gel comprise bacteriostatic agents; the bacteriostatic agent is one or more of thimerosal, quaternary ammonium salt, domiphen bromide, Xibitai, chlorobutanol, nipagin, and triciric acid; the dosage of the bacteriostatic agent is expressed by the weight ratio of the bacteriostatic agent to the salvianolic acid A, wherein the ratio of the bacteriostatic agent to the salvianolic acid A is 0.002-0.5: 0.1-1.0.
The eye drops comprise a thickening agent; the thickening agent is any one or more of hydroxypropyl methylcellulose, xanthan gum, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and polycarbophil; the weight ratio of the thickening agent to the salvianolic acid A is 0.1-0.5: 0.1-1.0.
The ophthalmic gel includes a thickening agent; the thickening agent is selected from one or more of carbomer, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, chondroitin sulfate and polycarbophil; the weight ratio of the thickening agent to the salvianolic acid A is 0.5-5.0: 0.1-1.0.
The eye drops or the eye gel comprise a pH regulator, and the pH value is regulated to 5.5-7.0; the pH regulator is any one or more of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid and borax.
The eye drops comprise one or two of sodium chloride and mannitol, and the osmolality of the eye drops is adjusted to 250-350 mOsmol/kg.
Each 100 parts by weight of the eye ointment comprises 8-15 parts by weight of anhydrous lanolin, 2-10 parts by weight of liquid paraffin and 75-95 parts by weight of yellow vaseline.
The application of the pharmaceutical composition in preparing a medicine for treating xerophthalmia.
The application of the pharmaceutical composition in preparing the medicines for treating the internal diseases caused by the xerophthalmia syndrome and the Sjogren-Johnson syndrome of the eyes.
The pharmaceutical composition is applied to the preparation of medicines for treating endogenous diseases such as keratitis, corneal ulcer, conjunctivitis, keratoconjunctivitis, conjunctival hemorrhage, blepharitis, blepharoconjunctivitis, pinkeye, scleritis, panoculitis and the like.
The application of the pharmaceutical composition in preparing medicines for treating diseases such as keratoconjunctival epithelial injury and the like caused by various exogenous diseases (such as postoperative diseases, drug-induced diseases, trauma, contact lens wearing and the like).
The invention aims to disclose an ophthalmic local external medicine for treating xerophthalmia, which has antibacterial and anti-inflammatory effects, good treatment effect, stable property and small toxic and side effects. Also discloses a preparation method of the ophthalmic preparation.
Rabbit animal experiments show that the eye drops, eye gel and eye ointment prepared by using the curcuma zedoary as the pharmacodynamic raw material have good intraocular penetrability and can achieve effective treatment concentration in aqueous humor, cornea, conjunctiva and vitreous body. According to the observation of a rat animal model, the local external-use zedoary turmeric preparation for eyes prepared by the method has small intraocular irritation and is comfortable to be dropped into eyes, and can be used for treating internal diseases such as sicca's syndrome, Stevens-Johnson syndrome, xerophthalmia (dry eye) and the like and corner conjunctival epithelial injury caused by various external diseases such as postoperative diseases, drug resistance, trauma, contact lens wearing and the like.
Detailed Description
The present invention is further illustrated by the following examples.
Examples 1 to 4
TABLE 1 preparation of salvianolic acid A eye drops raw material composition and dosage
According to the technical scheme of the invention, the types of auxiliary materials for preparing the salvianolic acid A eye drops are not limited to the types listed in the table above, and can be selected from the following multiple types:
if a pH regulator is used for regulating the pH value of the finished eye drops to 5.5-7.5; the pH regulator is any one of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid and borax or any combination of the substances.
When the bacteriostatic agent is added, any bacteriostatic agent which is called in pharmaceutics can be used, and the dosage of the bacteriostatic agent is the conventional dosage in pharmaceutics. For example, 0.002% -0.005% of thimerosal; ② quaternary ammonium salts (including benzalkonium chloride and benzalkonium bromide), domiphen bromide, Xibitai and the like, the effective concentration is 0.002% -0.01%; ③ alcohols, 0.3 to 0.6 percent of chlorobutanol is commonly used; the parabens are usually 0.03-0.06 percent of ethylparaben; acids, such as 0.01-0.08% triciric acid. The concentrations of all the substances are volume-weight percent, namely the substances contain grams per hundred milliliters.
When the thickening agent is added, the thickening agent which is commonly used in pharmaceutics, such as any one of hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, polycarbophil, polyvinylpyrrolidone and the like or any combination of the above varieties can be adopted, different polymerization degrees can be adopted, and finally the eye drops reach proper viscosity.
The preparation method comprises swelling prescription amount of sodium hyaluronate with appropriate amount of water for injection for 2-4 hr, adding 50% of cosolvent of prescription water for injection, adding salvianolic acid A, stirring for dissolving, adding poloxamer 407 or tyloxapol, stirring for dissolving, adding pH regulator and osmotic pressure regulator, optionally adding thickener according to prescription, stirring, filtering, adding dissolved sodium hyaluronate, and stirring. Adding bacteriostatic agent, adding water for injection to full dose (or adding water for injection to full dose without adding bacteriostatic agent), filtering, and packaging. And adjusting the pH value of the finished eye drops to 5.5-7.0 by using a pH regulator.
Examples 5 to 8
TABLE 2 preparation of Salvianolic acid A ophthalmic gel raw Material Components and amounts
According to the technical scheme of the invention, the types of auxiliary materials for preparing the salvianolic acid A ophthalmic gel are not limited to the types listed in the table above, and can be selected from the following various types:
wherein, if the bacteriostatic agent needs to be added, the variety selection and the dosage of the bacteriostatic agent are the same as those of the embodiment 1 to 4.
The thickening agent is selected from one or any combination of carbomer, hydroxypropyl methylcellulose, sodium hyaluronate, polyvinyl alcohol, polycarbophil, polyvinylpyrrolidone, carboxymethyl cellulose and chondroitin sulfate; the dosage ratio of the thickening agent to the salvianolic acid A is 0.1-1 g to 0.02-0.1 g.
Adjusting the pH value of the finished eye drops to 5.5-7.0 by using a pH regulator; the pH regulator is any one of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid and borax or any combination of the substances.
The preparation method comprises swelling prescription amount of sodium hyaluronate with appropriate amount of water for injection for 2-4 hr, adding 50% of cosolvent of prescription water for injection, adding salvianolic acid A, stirring for dissolving, adding poloxamer 407 or tyloxapol, stirring for dissolving, adding pH regulator and osmotic pressure regulator, optionally adding thickener according to prescription, stirring, filtering, adding dissolved sodium hyaluronate, and stirring. Adding bacteriostatic agent, adding water for injection to full dose (or adding water for injection to full dose without adding bacteriostatic agent), filtering, and packaging under sterile condition.
Examples 9 to 11
TABLE 3 preparation of Salvianolic acid A eye ointment raw Material Components and amounts
The preparation method comprises preparing eye ointment by conventional method. The production method comprises the steps of taking a proper amount of water for injection to swell prescription amount of sodium hyaluronate for 2-4 hours, adding the total amount of salvianolic acid A after 50% of prescription water for injection cosolvent is used, stirring and dissolving, adding poloxamer 407 or tyloxapol, stirring and dissolving, adding a proper amount of sterilized and cooled liquid paraffin, grinding into fine paste, sieving by a 200-mesh sieve, gradually adding a sterile and filtered mixture of lanolin and yellow vaseline, and uniformly mixing to obtain the product. The preparation apparatus and the packaging container are sterilized.
The following tests measured the content of salvianolic acid A and related substances (sodium hyaluronate has high stability)
Experimental example 1 stability test of salvianolic acid A eye drops
1. And (3) illumination test: the 0.05 percent salvianolic acid A eye drops without adding the bacteriostatic agent prepared by the method of the embodiment 2 of the invention are placed under the condition of external package of a Novelia (NOVELIA) eye medicine bottle, and the sample is placed under the condition of 4500lx +/-500 lx strong light irradiation, and the relevant indexes are sampled and measured on days 0, 5 and 10. The results show that the product is stable under the illumination condition on the 10 th day.
TABLE 4 illumination test results
2, high-temperature test: the 0.05 percent salvianolic acid A eye drops without adding the bacteriostatic agent, which are prepared by the method of the embodiment 2 of the invention, are placed in an environment at 60 ℃ under the condition of external package of a Novelia (NOVELIA) eye medicine bottle, and the indexes of pH value, content and the like are inspected by sampling at 0, 5 and 10 days, and the result shows that when the sample at the high temperature of 60 ℃ is compared with the sample at 0d, each index has no obvious change, and the quality of the sample is indicated to be stable at the temperature of 60 ℃.
TABLE 5 high temperature test results
3. And (3) accelerated test: 0.05 percent of salvianolic acid A eye drops which are prepared by the method of the embodiment 2 and are not added with bacteriostatic agent are placed in a constant temperature and humidity box under the condition of external package of a Novelia (NOVELIA) eye medicine bottle, placed under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 25 +/-5 percent, sampled at the 1 st, the 2 nd, the 3 rd and the 6 th months according to the quality standard draft respectively, and then the determination is carried out according to the quality standard draft. The results are shown in Table 6.
TABLE 6 accelerated test results
4. And (3) long-term test: 0.05 percent of salvianolic acid A eye drops which are prepared by the method of the embodiment 2 and are not added with bacteriostatic agent are placed in a constant temperature and humidity box under the condition of external package of a Novelia (NOVELIA) eye medicine bottle, placed under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 40 +/-5 percent, sampled at 3 rd, 6 th, 9 th and 12 th months according to time and determined according to a quality standard draft. The results of the measurement were compared with the results of the measurement at 0 month, and the results are shown in Table 7.
TABLE 7 Long-term test results
The results show that: the characters are not changed, and visible foreign matters meet the regulations; in the related substance examination, the content of the related substance has no obvious increasing trend, no other impurities appear, the content measurement and pH value examination results have no obvious change, and the salvianolic acid A eye drops grow aseptically after being examined aseptically, which shows that the salvianolic acid A eye drops provided by the invention have good stability. The other products of the invention were tested in the same way and the results of the tests with the same trend were obtained, which are not listed any more depending on the space.
Experimental example 2 eye irritation test of Salvianolic acid A eye drops of the present invention
Rabbit eye irritation test Using 0.1% Salvianolic acid A eye drops prepared according to the method of example 4 of the present invention
6 healthy New Zealand rabbits, female and male, were selected for the test. Adopting a self-contrast method of the left and right eyes of the same body, and administering salvianolic acid A eye drops (administration concentration of 0.1mg/ml) at the left side, wherein the administration volume is 100 mul, 50 mul/drop and 2 drops in total; an equal volume of 0.9% sodium chloride injection was given to the right for control, 5 times daily for 28 consecutive days. Before each 1 administration, about 1 hour after 8, 15 and 22 days of the last administration, and 1, 2, 4, 24, 48 and 72 hours after 28 days of the last administration, observing local reaction conditions of eyes of all animals and recording scores of abnormal conditions and eye reactions in detail, wherein the scoring result shows that 6/6 animals have no obvious irritation on the cornea and iris of the left eye and the right eye, and the scores of irritation reactions are 0; the micro hyperemia of iris blood vessels appears in the left eye and the right eye of part of animals, but the score values are small and are 1. Calculating to obtain the values of the right eye irritation responses of the rabbits at all observation time points within the range of 0-0.067; the scores of the left eye and the right eye are both in the nonirritant range of 0-3 points; before every 1 administration, 1 hour after 8, 15 and 22 days of the last administration, and 1, 2, 4, 24, 48 and 72 hours after 28 days of the last administration, the two eyes of the animals are subjected to fluorescein staining examination, the examination result shows that no obvious abnormal change is seen in the two eyes of the rabbits, and the slit lamp examination and the photographing are carried out on the two eyes of the rabbits before the first administration, 8, 15 and 22 days of the administration and 72 hours after 28 days of the last administration, and the examination result shows that no obvious abnormal change is seen in the two eyes of the rabbits.
The results show that the salvianolic acid A eye drops prepared by the invention can be continuously dropped for multiple times (the administration concentration is 0.1mg/ml of the original solution) for 28 days, and do not cause irritation reaction to rabbit eyes. The other products of the invention were tested in the same way and the same results were obtained, which are not listed any more depending on the space.
Experimental example 3 evaluation of curative effect of salvianolic acid A eye drops for treating rabbit xerophthalmia caused by local atropine dripping
The method of using 1% atropine sulfate for local dripping is adopted to induce a rabbit dry eye model, and normal saline is used as a contrast, and the treatment and improvement effects of the 0.05% salvianolic acid A eye drops prepared by the method in the embodiment 2 of the invention on the rabbit dry eye model eye are observed. 20 common-grade New Zealand rabbits (40 eyes) are respectively female and male, 1% atropine sulfate eye drops are dropped into both eyes, 1% atropine sulfate eye drops are dropped into the eyes at 8, 12, 16 and 20 days, respectively, and 1-2 drops are dropped each time to induce rabbit dry eye model eyes. Randomly selecting 10 rabbits, treating with 0.05% salvianolic acid A eye drop, 3 times per day, 2 drops per time, and continuously using for 14 days as experimental group; the control group was prepared by using normal saline 2 times a day, 2 drops each time, for 10 additional rabbits. The animals in the experimental group and the control group are administered with 2.5 g.L per day in both eyes-1The eye drop containing chloramphenicol can be used for anti-infective treatment 1 time per day, 2 drops per time, and continuously for 14 days. The results of the study are as followsThe following:
1. after the animals in the eye observation and treatment group are given the salvianolic acid A eye drops, the symptoms of congestion and edema of the eyes of the experimental group are relieved compared with the model eyes in the control group, and the animals with conjunctival secretion in the rabbit eyes of the experimental group have fewer animals and the degree is relieved.
2. Compared with the cornea fluorescein staining score before the atropine is dripped for molding, the cornea fluorescein staining score of each observation time point after the control group is dripped with the atropine is obviously increased (P is less than 0.01) compared with the cornea fluorescein staining score before the dripping with the atropine; the time points after the dropping of the medicine in the experimental group have no statistical difference (P is more than 0.05) compared with the time points before the dropping of the medicine. Compared with the control group, the experimental group is obviously lower than the control group (P is less than 0.01) at other observation time points except for the 14 th day before and after the dropping. See table 8.
TABLE 8 fluorescein staining scores (n-10) before and after molding and after dropping of the drug for the experimental and control groups
Note: p < 0.05, P < 0.01, compared to the composition before molding; compared with the control group, the delta P is less than 0.01.
The Schirmer test showed a significant reduction (P < 0.01) in the Schirmer I test values at time points after the control group was dosed compared to the control group before the dosing. The time points after the dropping of the medicine in the experimental group have no statistical difference (P is more than 0.05) compared with the time points before the dropping of the medicine. Compared with the control group, the experimental group is obviously higher than the control group (P is less than 0.01) at other observation time points except for the 1 st and 14 th days before and after the dropping.
TABLE 9 changes in the wet length of the filter paper from the Schirmer I test before and after administration of salvianolic acid A ophthalmic solutions (n ═ 10)
Note: p < 0.05, P < 0.01, compared to the composition before molding; compared with the control group, the delta P is less than 0.01.
Experimental results show that the salvianolic acid A eye drops have a certain curative effect on the treatment of the rabbit xerophthalmia of the atropine dripped locally, can inhibit the appearance of the rabbit xerophthalmia induced by the atropine eye drops, promote the secretion of the tears of the rabbits, obviously increase the secretion amount, and are expected to become a novel ophthalmic preparation applied to clinic.
The other products of the invention were tested in the same way and the same results were obtained, which are not listed any more depending on the space.
Claims (15)
1. A pharmaceutical composition characterized in that the active ingredients of the pharmaceutical composition comprise: salvianolic acid A and sodium hyaluronate.
2. The pharmaceutical composition of claim 1, wherein the ratio of salvianolic acid A: the weight ratio of the sodium hyaluronate is 1: 1 to 2.
3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is prepared as a raw material into a pharmaceutical preparation.
4. A pharmaceutical composition according to claim 3, wherein the pharmaceutical formulation comprises eye drops, ophthalmic gel, eye ointment or any pharmaceutically acceptable form suitable for topical ocular administration.
5. The drug of claim 1 or 2, wherein the pharmaceutical composition comprises poloxamer 407 or tyloxapol, and the weight ratio of the added amount of poloxamer 407 or tyloxapol to salvianolic acid A is as follows: salvianolic acid A: poloxamer 407 or tyloxapol ═ 1: 0.5 to 2, or 1: 1 to 4.
6. The pharmaceutical composition of claim 4, wherein the ophthalmic solution or gel comprises a bacteriostatic agent; the bacteriostatic agent is one or more of thimerosal, quaternary ammonium salt, domiphen bromide, Xibitai, chlorobutanol, nipagin, and triciric acid; the weight ratio of the bacteriostatic agent to the salvianolic acid A is as follows: the bacteriostatic agent is salvianolic acid A0.002-0.5: 0.1-1.0.
7. The pharmaceutical composition of claim 4, wherein the ophthalmic solution comprises a thickening agent; the thickening agent is any one or more of hydroxypropyl methylcellulose, xanthan gum, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and polycarbophil; the weight ratio of the thickener to the salvianolic acid A is 0.1-0.5: 0.1-1.0.
8. The pharmaceutical composition of claim 4, wherein the ophthalmic gel comprises a thickening agent; the thickening agent is selected from one or more of carbomer, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, chondroitin sulfate and polycarbophil; the weight ratio of the used amount of the thickening agent to the salvianolic acid A is 0.5-5.0: 0.1-1.0.
9. The pharmaceutical composition of claim 4, wherein the eye drops or the eye gel comprises a pH regulator, wherein the pH value is regulated to 5.5-7.0; the pH regulator is any one or more of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid and borax.
10. The pharmaceutical composition as claimed in claim 4, wherein the eye drop comprises one or both of sodium chloride and mannitol, and the osmolality of the eye drop is adjusted to 250-350 mOsmol/kg.
11. The pharmaceutical composition according to claim 4, wherein the eye ointment comprises 8 to 15 parts by weight of anhydrous lanolin, 2 to 10 parts by weight of liquid paraffin, and 75 to 95 parts by weight of yellow vaseline, per 100 parts by weight of the eye ointment.
12. Use of a pharmaceutical composition according to any one of claims 1-11 for the manufacture of a medicament for the treatment of dry eye.
13. Use of a pharmaceutical composition according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of ocular dryness syndrome, ocular stess-johnson syndrome and other intrinsic disorders.
14. Use of a pharmaceutical composition according to any one of claims 1-11 for the manufacture of a medicament for the treatment of an endogenous disorder such as keratitis, corneal ulcer, conjunctivitis, keratoconjunctivitis, conjunctival hemorrhage, blepharitis, blepharoconjunctivitis, pinkeye, scleritis, or bulbar conjunctivitis.
15. Use of a pharmaceutical composition according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of disorders associated with disorders of the conjunctival epithelium of the cornea caused by various extrinsic conditions (e.g. post-operative, pharmaceutical, trauma, contact lens wear, etc.).
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CN110200956A (en) * | 2019-07-17 | 2019-09-06 | 吴广森 | A kind of ophthalmic external use medicine compositions |
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