CN111588693A - Cromolyn sodium eye drops and preparation method thereof - Google Patents
Cromolyn sodium eye drops and preparation method thereof Download PDFInfo
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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
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- 239000003889 eye drop Substances 0.000 title claims abstract description 71
- 229940012356 eye drops Drugs 0.000 title claims abstract description 59
- 229960000265 cromoglicic acid Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 title description 43
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 21
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract description 18
- 229940124274 edetate disodium Drugs 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 13
- 150000003751 zinc Chemical class 0.000 claims abstract description 13
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 claims abstract 9
- 238000001914 filtration Methods 0.000 claims description 14
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 13
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical group [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 13
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 11
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000004806 packaging method and process Methods 0.000 claims description 6
- 239000002033 PVDF binder Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229940023490 ophthalmic product Drugs 0.000 claims description 5
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000009924 canning Methods 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 235000010338 boric acid Nutrition 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 2
- 229960001763 zinc sulfate Drugs 0.000 claims description 2
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 2
- 239000002997 ophthalmic solution Substances 0.000 claims 7
- 229940054534 ophthalmic solution Drugs 0.000 claims 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 16
- 230000003204 osmotic effect Effects 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 9
- 230000008961 swelling Effects 0.000 abstract description 9
- 208000003251 Pruritus Diseases 0.000 abstract description 7
- 230000002829 reductive effect Effects 0.000 abstract description 5
- 244000005700 microbiome Species 0.000 abstract description 4
- 206010067484 Adverse reaction Diseases 0.000 abstract description 3
- 230000006838 adverse reaction Effects 0.000 abstract description 3
- 230000001133 acceleration Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 23
- 210000001508 eye Anatomy 0.000 description 7
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 6
- 208000002205 allergic conjunctivitis Diseases 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 230000007794 irritation Effects 0.000 description 5
- 210000005252 bulbus oculi Anatomy 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 208000024998 atopic conjunctivitis Diseases 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003630 histaminocyte Anatomy 0.000 description 3
- 206010023332 keratitis Diseases 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 201000005539 vernal conjunctivitis Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 201000007717 corneal ulcer Diseases 0.000 description 1
- 229940109248 cromoglycate Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002740 effect on eyes Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 150000005204 hydroxybenzenes Chemical class 0.000 description 1
- 239000000815 hypotonic solution Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BIYQNLJPABKADF-UHFFFAOYSA-M sodium;2-[2-amino-3-(4-bromobenzoyl)phenyl]acetate;hydrate Chemical compound O.[Na+].NC1=C(CC([O-])=O)C=CC=C1C(=O)C1=CC=C(Br)C=C1 BIYQNLJPABKADF-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940071127 thioglycolate Drugs 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 230000009959 type I hypersensitivity Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic 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
- A61K31/352—Heterocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
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
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
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
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
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
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
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)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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Patent Citations (4)
| 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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