CN111588693A - Cromolyn sodium eye drops and preparation method thereof - Google Patents

Cromolyn sodium eye drops and preparation method thereof Download PDF

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CN111588693A
CN111588693A CN202010560727.0A CN202010560727A CN111588693A CN 111588693 A CN111588693 A CN 111588693A CN 202010560727 A CN202010560727 A CN 202010560727A CN 111588693 A CN111588693 A CN 111588693A
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eye drops
sodium
cromolyn sodium
preparation
regulator
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CN111588693B (en
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罗灼辉
王学文
余小兵
苏焕东
欧佩欣
杨勋
刘洋
陈光毅
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Lakerspharma Co ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183Amino acids, e.g. glycine, EDTA or aspartame
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/08Antiallergic agents

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Abstract

The invention discloses a cromolyn sodium eye drop and a preparation method thereof. The sodium cromoglicate eye drops provided by the invention contain sodium cromoglicate, edetate disodium, bacteriostatic agent, zinc salt, isotonic regulator and pH regulator, can effectively guarantee the bacteriostatic effect of the product while reducing the usage amount of the bacteriostatic agent, improves the use safety of patients, can be packaged in multiple doses, can be repeatedly used for multiple times, and cannot be infected by environmental microorganisms; in addition, the product is added with proper amount of Zn2+The pruritus and red swelling possibly induced in the clinical use process are reduced; the cromolyn sodium eye drops prepared by the method are clear and transparent, the osmotic pressure ratio is 0.9-1.1, the pH value is 5.0-7.0, adverse reactions and potential risks caused by osmotic pressure and clarity of products are avoided, the products can be durably stable within 6 months of acceleration, no impurity growth and no new impurity increase are generated, and the cromolyn sodium eye drops are safe, effective and controllable in quality.

Description

Cromolyn sodium eye drops and preparation method thereof
Technical Field
The invention belongs to the field of pharmacy. More particularly, relates to a cromolyn sodium eye drop and a preparation method thereof.
Background
Cromolyn sodium, also known as cromolyn disodium, is an antiallergic drug and can be used for treating allergic asthma, allergic rhinitis or ulcerative colitis. Can stabilize mastocyte membrane, inhibit mast cell lysis and degranulation, and prevent release of allergic medium in antigen-antibody reaction. The cromolyn sodium eye drop is used for treating allergic conjunctivitis, vernal conjunctivitis and vernal keratitis. Local eye drops can only effectively alleviate the degranulation reaction of mast cells in type I hypersensitivity, thereby slowing down the activation and aggregation of subsequent eosinophils, neutrophils and monocytes.
The prior sodium cromoglicate eye drops basically use bacteriostatic agents to achieve a certain antiseptic effect, the bacteriostatic agents used in the prior multi-dose sodium cromoglicate eye drops on the market are all of nipagin type, and usually a mixture of hydroxybenzene esters is needed to be used, the dosage is up to 0.1-0.3% to achieve the effective antiseptic effect, but the bacteriostatic agent components can directly influence the components of eye tears, change the microenvironment on the surface of eyeballs, damage the original tightly connected epithelial cell structure, cause corneal epithelial desquamation, defect and epithelial erosion in severe cases, can cause corneal ulcer, even corneal dissolution, perforation and blindness, and correspondingly increase the potential risk after the use of patients, for example, CN201510697341.3 discloses a bromfenac sodium hydrate thermosensitive in-situ gel eye drops, which solves the problems of short retention time in eyes and low bioavailability of the traditional eye drops, however, the effective antibacterial and antiseptic effect can be achieved only by adding 0.01-1% of the bacteriostatic agent, and the potential risk of the patient after the bacteriostatic agent is used is correspondingly increased due to the increase of the dosage of the bacteriostatic agent. In contrast, patent CN200910073614.1 discloses a single-dose sodium cromoglycate eye drop containing no bacteriostatic agent, wherein the single dose reduces irritation to eyes because no bacteriostatic agent is added, but the single-dose eye drop has high production cost and high market price, and is not suitable for wide popularization and application. In addition, the existing multi-dose sodium cromoglycate eye drop product composition is hypotonic, has large stimulation effect on eyes, has obvious stabbing pain and scorching feel after use, is relatively poor in clarity of products of the sodium cromoglycate eye drops sold in China, brings a lot of uncertainty for clinical use, and can induce eye itching and red swelling after being used by part of patients at present.
Therefore, the development of sodium cromoglycate eye drops which have low bacteriostatic agent content, isotonicity, stable product, good clarity and small side effect and can be prepared into a multi-dose form is urgently needed.
Disclosure of Invention
The invention aims to provide the cromolyn sodium eye drops which have low bacteriostatic agent content, are isotonic and have good product clarity and can be prepared into a multi-dose form, and the preparation method thereof. The sodium cromoglycate eye drops provided by the invention have low bacteriostatic agent content, and the use safety of patients is improved; by combining the low-dose bacteriostatic agent with the edetate disodium, the bacteriostatic effect of benzalkonium chloride or benzalkonium bromide is improved, the bacteriostatic effect of the product can be effectively guaranteed, and fungi, gram-positive bacteria and gram-negative bacteria can be inhibited, so that the canning form can be multi-dose packaging, repeated use can be realized, the bacteriostatic effect of the product and the sterile risk of multi-dose use are guaranteed, and the defect of high production cost of single-dose eye drops is avoided; in addition, the product is added with proper amount of Zn2+Promoting the contraction of capillary vessels, relieving the local congestion of eyeballs and reducing the pruritus and red swelling possibly induced in the clinical use process; and according to the inventionThe cromolyn sodium eye drops prepared by the method are clear and transparent, the osmotic pressure ratio is 0.9-1.1, the cromolyn sodium eye drops are equivalent to the osmotic pressure of tears, adverse reactions and potential risks caused by the osmotic pressure and clarity of products are avoided, the pH value is 5.0-7.0, the cromolyn sodium eye drops are close to the pH value of the tears, the products can be durably stable within 6 months of acceleration, all impurities are not increased, new impurities are not generated, and the cromolyn sodium eye drops are safe, effective and controllable in quality.
Therefore, the primary object of the present invention is to provide a cromolyn sodium eye drop.
Another object of the present invention is to provide an ophthalmic product comprising the above-mentioned cromolyn sodium eye drops.
Still another object of the present invention is to provide a method for producing the above-mentioned eye drops.
In order to achieve the purpose, the invention is realized by the following scheme:
the invention provides a cromolyn sodium eye drop, which comprises cromolyn sodium, edetate disodium, a bacteriostatic agent, zinc salt, an isotonic regulator and a pH regulator;
wherein the bacteriostatic agent is benzalkonium chloride or benzalkonium bromide; the zinc salt is zinc chloride or zinc sulfate; the isotonic regulator is one or more of sodium chloride, sodium sulfate, boric acid and borax.
In the sodium cromoglycate eye drops, the edetate disodium serving as a stabilizer of the product can chelate metal impurities in the raw material sodium cromoglycate firstly, and in addition, the sodium cromoglycate is Cromoglic acid-Na and Cromoglic acid-Na+In aqueous solution, Na+Can be captured by water molecule to release cromolyn, which has low solubility in water to form turbidity, and a specific amount of edetate disodium is preferably added to supplement Na in water solution+Thereby reducing the risk of product clarity degradation.
Benzalkonium chloride or benzalkonium bromide is used as bacteriostatic agent in the product, has inhibitory effect on fungi, gram-positive bacteria and gram-negative bacteria, and is a broad-spectrum and high-efficiency bacteriostatic agent. The invention unexpectedly discovers that the combination of edetate disodium and benzalkonium chloride or benzalkonium bromide can greatly improve the bacteriostatic action of the obtained eye drops, effectively ensure the bacteriostatic effect of products and improve the use safety of patients, and the eye drops can be prepared into a multi-dose packaging form to realize repeated use, thereby avoiding the defect of high production cost of single-dose eye drops.
In addition, specific zinc salt is added into the eye drops, so that capillary vessel contraction is promoted, local congestion of eyeballs is relieved, and pruritus and swelling possibly induced in the clinical use process are reduced in the process that the sodium cromoglycate eye drops are used for treating allergic conjunctivitis, vernal conjunctivitis and vernal keratitis.
The sodium cromoglycate eye drops obtained by adding the specific dosage of the isoosmotic adjusting agent are isoosmotic, the osmotic pressure ratio is about 0.9-1.1, the product and tears have similar osmotic pressure, the irritation in clinical use is reduced, the curative effect is improved, and the irritation of the product to eyes due to low osmosis is avoided.
Preferably, the eye drops comprise the following components in percentage by weight: the weight percentage of each component is as follows: 2-4% of cromolyn sodium, 0.01-0.2% of edetate disodium, 0.01-0.03% of bacteriostatic agent, 0.01-0.02% of zinc salt, 0.01-0.03% of benzalkonium chloride and 0.5-1.3% of isotonic regulator, wherein the pH regulator is adjusted to be 5.0-7.0, and the balance is water for injection.
According to the invention, the edetate disodium with a specific dosage is reasonably compounded with the bacteriostatic agent with a low addition amount, so that the bacteriostatic effect of the low-concentration benzalkonium chloride or benzalkonium bromide used alone can be obviously enhanced, and the bacteriostatic effect is obviously improved, and meanwhile, the use safety of patients is improved because the bacteriostatic agent has low concentration and small irritation.
Further preferably, the weight percentage of the cromolyn sodium in the eye drops is 2% or 4%; the weight percentage of the isotonic regulator in the eye drops is 0.7-1.2%.
As a preferred embodiment, the pH adjusting agent is hydrochloric acid or sodium hydroxide. By adjusting the pH value of the product to 5.0-7.0, the pH value of the product is close to that of tears, so that the use safety and comfort are improved, and the irritation is small.
The invention also claims an ophthalmic product containing the eye drops.
The ophthalmic product also comprises pharmaceutically acceptable auxiliary materials.
The invention also provides a preparation method of the eye drops, which comprises the steps of taking cromolyn sodium, edetate disodium, an isotonic regulator and zinc salt, adding water for injection to dissolve, filtering for the first time, adding a bacteriostatic agent, stirring for dissolving, regulating pH, adding the rest of water for injection, filtering for the second time, and canning to obtain the eye drops.
Preferably, the first filtration is through a 0.45 μm PVDF microporous membrane filtration.
Preferably, the second filtration is through a 0.22 μm PVDF microporous membrane filtration.
Further preferably, the second filtration is through at least two layers of 0.22 μm PVDF microporous filter membrane filtration.
The eye drops prepared by the method can be packaged into single dose package or multi-dose package. Based on the efficient bacteriostatic performance of the eye drops, the eye drops can be repeatedly used for many times without causing microbial pollution through multi-dose packaging, and the high cost caused by using single-dose packaging to reduce the use of bacteriostatic agents in the existing market is avoided.
Compared with the prior art, the invention has the beneficial effects that:
(1) the cromolyn sodium eye drops prepared by the method have high clarity, are isotonic, have osmotic pressure ratio of 0.9-1.1 and pH of 5.0-7.0, avoid adverse reaction and potential risk caused by osmotic pressure and clarity problems of products, can be durably stable after being accelerated for 6 months, do not increase all impurities, do not increase newly added impurities, and are safe, effective and controllable in quality.
(2) According to the invention, the edetate disodium with a specific dosage is reasonably compounded with the bacteriostatic agent with a low addition amount, so that the bacteriostatic and bactericidal effects of the benzalkonium chloride or benzalkonium bromide with a low concentration which is used independently can be obviously enhanced, the potential risks brought by the bacteriostatic agent with a high concentration are reduced, and the use safety of patients is improved. Based on the efficient bacteriostatic performance of the eye drops, the eye drops can be packaged in multiple doses, so that the microbial pollution can not be caused in the process of repeated use, the bacteriostatic effect of the eye drops and the sterile risk of multiple doses during use are guaranteed, and the high cost caused by single dose packaging for reducing the use of bacteriostatic agents in the existing market is avoided.
(3) The sodium cromoglycate eye drops are added with the zinc salt with specific dosage and specific type, so that in the process of treating allergic conjunctivitis, vernal conjunctivitis and vernal keratitis, the sodium cromoglycate eye drops promote capillary vessel contraction, relieve local congestion of eyeballs and reduce pruritus and red swelling possibly induced in the clinical use process.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 different proportions of edetate disodium, benzalkonium chloride or benzalkonium bromide have bacteriostatic effects
1. 100g of edetate disodium and benzalkonium chloride or benzalkonium bromide aqueous solution are prepared, and the bacteriostatic effect is shown in Table 1:
TABLE 1
Figure BDA0002546193530000041
Figure BDA0002546193530000051
Figure BDA0002546193530000061
The results in table 1 show that by reasonably compounding edetate disodium and benzalkonium chloride or benzalkonium bromide with low addition amount, the bacteriostatic effect of low-concentration benzalkonium chloride or benzalkonium bromide alone can be remarkably enhanced, and particularly, the growth inhibition effect on gram-negative bacteria pseudomonas aeruginosa and fungi candida albicans is particularly enhanced, so that the multidose eye drops prepared by the method are not easily polluted by microorganisms in the process of opening and closing packages for multiple times after being repeatedly used, the bacteriostatic effect of the product and the sterile risk of multidose use are guaranteed, and the high cost caused by using single-dose package eye drops in the existing market can be effectively avoided.
EXAMPLE 2 different proportions of cromolyn sodium eye drops
1. 1000g of eye drops are prepared, and the dosage of each component in each eye drop is shown in the following table 2:
TABLE 2
Figure BDA0002546193530000062
2. Preparation method
Dissolving sodium cromoglycate, disodium edetate, an isotonic regulator and zinc salt in water for injection, filtering for the first time, adding a bacteriostatic agent, stirring for dissolving, regulating the pH to 5.0-7.0 by using hydrochloric acid or sodium hydroxide, adding the rest of water for injection, filtering for the second time, and canning to obtain the injection.
3. The performance results of the sodium cromoglycate eye drops prepared in different ratios in experimental groups 1-8 are shown in table 3:
TABLE 3
Figure BDA0002546193530000063
Figure BDA0002546193530000071
Experimental results show that the 10 sodium cromoglycate eye drops are colorless, transparent and clear, have osmotic pressure ratio of about 0.9-1.1 and pH value of 5.0-7.0, are prepared into multi-dose packages, can be repeatedly used within one month, are not polluted by microorganisms in the process of repeated use, and have lower consumption of bacteriostatic agents, so that the potential risk of patients after use is reduced, and any allergy and pruritus are caused. And the method can be enduringly and stably accelerated for 6 months, all impurities are not increased, and no newly added impurities are generated, so that the method is safe and effective, and the quality is controllable. In addition, 1 test subject with the use allergy history (itching and swelling of eyes after use) of the sodium cromoglycate eye drops is invited to carry out trial experiments, and the result proves that the test subject does not have any symptoms of itching and swelling of eyes after using the eye drops of the experimental groups 1-8.
Comparative example
1. 1000g of eye drops were prepared, and the amounts of the components in each eye drop are shown in Table 4:
TABLE 4
Figure BDA0002546193530000081
2. The preparation method is the same as that of example 2
3. The performance results of the sodium cromoglycate eye drops with different proportions in comparison groups 1-4 are shown in table 5:
TABLE 5
Figure BDA0002546193530000082
The results of the comparative experiments show that the sodium cromoglycate eye drops prepared by the comparative groups 2-4 are not colorless and clear in the solution under the examination of the [ clarity and color of the solution ], the osmotic pressure ratio of the products of the comparative groups 2-3 is lower, the products are hypotonic solutions, and when 20 bottles of the comparative group 2 are randomly taken to examine visible foreign matters, 2 bottles of the products generate smog-like particles during rotation, which is supposed to be related to the formation of almost water-insoluble cromoglycate. The comparison groups 2 and 4 were prepared in multi-dose packages without adding edetate disodium, and after 15 days of repeated use (once in the morning and at night), the thioglycolate fluid medium reacted positively under the sterile examination, warning the product of the risk of fungal infection, while the other comparison groups did not detect microorganisms.
In addition, 10 SD rats were used in the test, and 1 of 5 SD rats showed redness and swelling after 7 days of continuous use of the eye drops of comparative group 1, while 5 SD rats showed no redness and swelling after 7 days of continuous use of the eye drops of experimental group 5. The invention shows that the phenomenon of discomfort of eyes caused by part of individuals to the sodium cromoglycate eye drops can be effectively avoided by adding the zinc salt into the eye drops.
The above examples only represent some embodiments of the present invention, and the description thereof is more specific and detailed, but not to be construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. An eye drop of cromolyn sodium is characterized by comprising cromolyn sodium, edetate disodium, bacteriostat, zinc salt, isotonic regulator and pH regulator;
wherein the bacteriostatic agent is benzalkonium chloride or benzalkonium bromide; the zinc salt is zinc chloride or zinc sulfate; the isotonic regulator is one or more of sodium chloride, sodium sulfate, boric acid or borax.
2. The eye drops according to claim 1, wherein the weight percentages of the components are as follows: 2-4% of cromolyn sodium, 0.01-0.2% of edetate disodium, 0.01-0.03% of bacteriostatic agent, 0.01-0.02% of zinc salt, 0.01-0.03% of benzalkonium chloride and 0.5-1.3% of isotonic regulator, wherein the pH regulator is adjusted to be 5.0-7.0, and the balance is water for injection.
3. An ophthalmic solution according to claim 2, wherein the pH adjusting agent is hydrochloric acid or sodium hydroxide.
4. An ophthalmic product comprising the ophthalmic solution according to any one of claims 1 to 3.
5. The ophthalmic product of claim 4, further comprising a pharmaceutically acceptable excipient.
6. A process for preparing an eye drop as claimed in any one of claims 1 to 3, wherein the preparation process comprises dissolving cromolyn sodium, disodium edetate, isotonic regulator and zinc salt in water for injection, filtering, adding bacteriostatic agent, stirring for dissolving, regulating pH, adding water for injection, filtering again, and packaging.
7. A process for the preparation of ophthalmic solutions according to claim 6, wherein the first filtration is a filtration through a 0.45 μm PVDF microporous membrane.
8. A process for the preparation of ophthalmic solutions according to claim 6, wherein the second filtration is a filtration through a 0.22 μm VDF millipore membrane.
9. The process for the preparation of ophthalmic solutions according to claim 8, wherein the second filtration is carried out through at least two 0.22 μm PVDF microporous filter membranes.
10. A process for the preparation of ophthalmic solutions according to claim 6, wherein the canning of the ophthalmic solution obtained is carried out in single-dose or multi-dose packs.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1416824A (en) * 2002-11-12 2003-05-14 武汉天天明药业有限责任公司 Medicament for preventing and treating myopia and asthenopia
JP2005247802A (en) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd Eye drops
CN101185645A (en) * 2007-11-21 2008-05-28 吉林大学 Cromoglyn sodium gel eyedrop and preparation method
CN102697713A (en) * 2012-06-14 2012-10-03 浙江尖峰药业有限公司 Sodium hyaluronate eye drops and a preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1416824A (en) * 2002-11-12 2003-05-14 武汉天天明药业有限责任公司 Medicament for preventing and treating myopia and asthenopia
JP2005247802A (en) * 2004-03-08 2005-09-15 Zeria Pharmaceut Co Ltd Eye drops
CN101185645A (en) * 2007-11-21 2008-05-28 吉林大学 Cromoglyn sodium gel eyedrop and preparation method
CN102697713A (en) * 2012-06-14 2012-10-03 浙江尖峰药业有限公司 Sodium hyaluronate eye drops and a preparation method thereof

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Application publication date: 20200828

Assignee: Chengdu Ruier Pharmaceutical Technology Co.,Ltd.

Assignor: LAKERSPHARMA Co.,Ltd.

Contract record no.: X2023980046791

Denomination of invention: A sodium cromolyte eye drop and its preparation method

Granted publication date: 20220805

License type: Common License

Record date: 20231110

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