CN111450054B - Ophthalmic preparation containing caffeic acid ester, preparation method and application - Google Patents
Ophthalmic preparation containing caffeic acid ester, preparation method and application Download PDFInfo
- Publication number
- CN111450054B CN111450054B CN202010360205.6A CN202010360205A CN111450054B CN 111450054 B CN111450054 B CN 111450054B CN 202010360205 A CN202010360205 A CN 202010360205A CN 111450054 B CN111450054 B CN 111450054B
- Authority
- CN
- China
- Prior art keywords
- acid ester
- caffeic acid
- water
- extract
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- SWUARLUWKZWEBQ-VQHVLOKHSA-N phenethyl caffeate Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-VQHVLOKHSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000284 extract Substances 0.000 claims abstract description 32
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 25
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 42
- 239000004471 Glycine Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 18
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 229940116229 borneol Drugs 0.000 claims description 18
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 claims description 18
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims description 18
- 208000002177 Cataract Diseases 0.000 claims description 13
- 239000000654 additive Substances 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 11
- 239000000872 buffer Substances 0.000 claims description 10
- 239000003755 preservative agent Substances 0.000 claims description 10
- 230000002335 preservative effect Effects 0.000 claims description 10
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 8
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002604 borneol group Chemical group 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000007865 diluting Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000004806 packaging method and process Methods 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000004952 Polyamide Substances 0.000 claims description 2
- 230000002421 anti-septic effect Effects 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
- 239000004327 boric acid Substances 0.000 claims description 2
- 239000006172 buffering agent Substances 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims description 2
- 239000012982 microporous membrane Substances 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 3
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000003889 eye drop Substances 0.000 description 26
- 229940012356 eye drops Drugs 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 241001013934 Erigeron breviscapus Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 6
- 230000007794 irritation Effects 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- DJSISFGPUUYILV-UHFFFAOYSA-N UNPD161792 Natural products O1C(C(O)=O)C(O)C(O)C(O)C1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-UHFFFAOYSA-N 0.000 description 5
- NPLTVGMLNDMOQE-UHFFFAOYSA-N carthamidin Natural products C1=CC(O)=CC=C1C1OC2=CC(O)=C(O)C(O)=C2C(=O)C1 NPLTVGMLNDMOQE-UHFFFAOYSA-N 0.000 description 5
- DJSISFGPUUYILV-ZFORQUDYSA-N scutellarin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-ZFORQUDYSA-N 0.000 description 5
- 229930190376 scutellarin Natural products 0.000 description 5
- 239000003480 eluent Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 3
- 210000000744 eyelid Anatomy 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960001471 sodium selenite Drugs 0.000 description 3
- 239000011781 sodium selenite Substances 0.000 description 3
- 235000015921 sodium selenite Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000208838 Asteraceae Species 0.000 description 2
- 241000132521 Erigeron Species 0.000 description 2
- 206010024214 Lenticular opacities Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000000546 chi-square test Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- CWVRJTMFETXNAD-GMZLATJGSA-N 5-Caffeoyl quinic acid Natural products O[C@H]1C[C@](O)(C[C@H](OC(=O)C=Cc2ccc(O)c(O)c2)[C@@H]1O)C(=O)O CWVRJTMFETXNAD-GMZLATJGSA-N 0.000 description 1
- 241001289295 Asarum sieboldii Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- PZIRUHCJZBGLDY-UHFFFAOYSA-N Caffeoylquinic acid Natural products CC(CCC(=O)C(C)C1C(=O)CC2C3CC(O)C4CC(O)CCC4(C)C3CCC12C)C(=O)O PZIRUHCJZBGLDY-UHFFFAOYSA-N 0.000 description 1
- 206010051559 Corneal defect Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229960002028 atropine sulfate Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- CWVRJTMFETXNAD-NXLLHMKUSA-N trans-5-O-caffeoyl-D-quinic acid Chemical compound O[C@H]1[C@H](O)C[C@](O)(C(O)=O)C[C@H]1OC(=O)\C=C\C1=CC=C(O)C(O)=C1 CWVRJTMFETXNAD-NXLLHMKUSA-N 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an ophthalmic preparation containing caffeic acid ester, which comprises caffeic acid ester extracts and pharmaceutic adjuvants, wherein the other components are water, and conventional preparation of the ophthalmic preparation by using single caffeic acid ester cannot obviously improve the eye function.
Description
Technical Field
The invention relates to an ophthalmic preparation containing caffeic acid ester and a preparation method thereof, belonging to the field of biomedicine.
Technical Field
Herba Erigerontis is a plant of erigeron of Compositae, and is also called herba Erigerontis, herba erigerontis, or herba Erigerontis, and can be used as Chinese herbal medicine. Herba Erigerontis has effects of dispelling cold, relieving exterior syndrome, dispelling pathogenic wind, removing dampness, activating collaterals and relieving pain.
The caffeic acid esters component, especially the caffeoylquinic acid component contained in erigeron breviscapus, has various biological activities: antioxidant activity, anti-inflammatory activity, antimicrobial activity, hepatocyte protection, platelet aggregation inhibition, and some invention patents also relate to the medical use of caffeic acid esters.
The caffeic acid esters component is used as a main component of erigeron breviscapus of erigeron of Compositae, and has high content, and the content of total caffeic acid esters is higher than that of scutellarin in most batch of erigeron breviscapus. Scutellarin has been prepared into single medicines, such as scutellarin tablets, scutellarin for injection, scutellarin injection and the like. The caffeic acid ester component in herba Erigerontis exists in herba Erigerontis injection, herba Erigerontis dripping pill, herba Erigerontis capsule, herba Erigerontis soft capsule, herba Erigerontis mixture, etc. However, the caffeic acid ester in erigeron breviscapus is not used as a separate patent medicine or a health-care product.
However, no caffeic acid ester extract eye drops are available in China at present, the related technical reasons are numerous, one of the technical reasons is that when the existing caffeic acid ester is used alone, the eye drops cannot play an obvious eye protection function, and the eye drops can play a medicinal value only by being matched with other auxiliary materials.
Disclosure of Invention
In order to solve the technical problems, the inventor provides an ophthalmic preparation containing caffeic acid ester, wherein the ophthalmic preparation is prepared from caffeic acid ester extract, pharmaceutic adjuvant and water, and the weight percentage of the caffeic acid ester extract is 0.1-40%.
The caffeic acid ester is the caffeic acid ester extract extracted from erigeron breviscapus, and the extraction process of the caffeic acid ester can refer to the related content of Chinese patent ZL 201410764764.8.
Further preferably, the ophthalmic preparation is eye drops, gels, ophthalmic liposomes and clathrate eye drops.
The invention provides an ophthalmic preparation containing caffeic acid ester, which comprises the following components:
caffeic acid ester extract 0.1-20%
0.1 to 5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
appropriate amount of pH regulator and buffer
0.001-1% of preservative
0.1 to 10 percent of additive
The balance of water, and the pH value is 5-7.
Further, the ophthalmic preparation is
Caffeic acid ester extract 1-15%
0.1 to 5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
appropriate amount of pH regulator and buffer
0.005% of preservative
0.2 to 3 percent of additive
The balance of water, and the pH value is 5.5-6.5.
Preferably, the first and second electrodes are formed of a metal,
5 to 15 percent of caffeic acid ester extract,
1 to 5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
appropriate amount of pH regulator and buffer
0.01 to 1 percent of preservative
0.5 to 1.5 percent of additive
The balance of water, and the pH value is 5.5-6.5.
The pH regulator is KOH, NaOH or other alkaline solution, and the corresponding buffering agent is Na2HPO4And NaH2PO4Boric acid and borax. The weight is preferably 0.1 to 15%.
The preservative is selected from one or more of benzalkonium chloride, phenethyl alcohol, sorbic acid and parabens.
The additive is borneol.
Preferably 0.1-1% of preservative, 0.2-3% of additive and the balance of water, and the pH value is 5.5-6.5. More preferably 0.1-1% of preservative, 0.5-1.5% of additive and the balance of water, and the pH value is 5.5-6.5.
The caffeic acid ester extract belongs to a mixture, the caffeic acid ester extract with the content is soluble within the pH value range of the invention, the content of the caffeic acid ester extract is within 20 percent by weight after a proper amount of glycine is added, the caffeic acid ester extract in the ophthalmic preparation is completely dissolved and quickly dissolved, and the solution is stable and does not precipitate after being placed.
Further, the extraction process of the caffeic acid ester extract is preferably as follows:
taking 800g of erigeron breviscapus, adding water or 0-45 percent of erigeron breviscapus, decocting for at least two times, merging decoction, filtering, and concentrating the filtrate under reduced pressure to obtain clear paste with the relative density of 1.15-1.25(75 ℃). Diluting the fluid extract with 3 times of water, adding 5% sodium hydroxide solution to adjust pH to 7.5-8.5, filtering, adding 10% sulfuric acid solution to adjust pH to 2-3, filtering to obtain filtrate and precipitate; taking filtrate, passing through a polyamide column, carrying out gradient elution, eluting with at least 2 times of water, discarding water eluent, eluting with 20-90% ethanol, collecting ethanol eluent when the ethanol eluent is eluted with 40% ethanol and eluent eluted with 70% ethanol, recovering ethanol, concentrating to obtain clear paste with the relative density of 1.10-1.20 at 70 ℃, adding an alkali solution, adjusting the pH to 7-10, extracting with ethyl acetate for at least 1-3 times, taking an alkali water layer, adjusting the pH to 2-3 with a sulfuric acid or hydrochloric acid solution, extracting with ethyl acetate for 2 times, collecting an ethyl acetate extracting solution, recovering the ethyl acetate solution under reduced pressure, adding water into the remaining thick paste, boiling, concentrating to obtain the clear paste with the relative density of 1.20-1.30 at 45 ℃, and obtaining the caffeic acid ester extract.
The main drug effect component of the invention is the mixture of caffeic acid ester and glycine, and experiments prove that the caffeic acid ester component is a strong oxidant, retina is a tissue with very active metabolism, a large amount of oxygen is needed, tissue damage can be caused by insufficient oxygen or free radical generation, blindness is finally caused, and the caffeic acid ester component can play a role in repairing and preventing symptoms from further worsening. The technical solution of the present invention is not expected to produce the technical effects and functions which are not obvious from the prior art and the known technology, and the technical solution of the present invention is not expected to be combined by the prior art and the technical solution of the present invention is not expected to provide any motivation for developing the ophthalmic preparation of caffeic acid esters extracted from asarum sieboldii through the prior art, so that the technology and the product of the present invention have prominent substantive features and significant progress compared with the similar products on the market, which is the novelty and creativity of the technical solution of the present invention.
The present invention further provides a method for preparing the ophthalmic preparation containing caffeic acid ester, which comprises the following steps:
1) weighing corresponding components according to the prescription;
2) diluting the pH regulator with a small amount of water to obtain a solution; grinding Borneolum Syntheticum in water to dissolve, adding antiseptic, additive, pH regulator and buffer, adjusting pH to 5-7, adding the rest water to corresponding scale, mixing, filtering with microporous membrane, and packaging.
The invention provides application of the ophthalmic preparation containing caffeic acid ester in preparing medicaments for treating retinal diseases, in particular glaucoma and cataract diseases.
Research section
1. Caffeic acid ester and glycine ophthalmic preparation has cataract improving effect.
The traditional Chinese medicine composition eye drop preparation provided by the invention has a drug effect experiment on rat cataract caused by sodium selenite
60 rats with 12d birth are selected, and the weight of the rats is 18-20g, and the rats are half female and half male.
Rats were randomly divided into 5 groups (blank control, model control, positive drug control, eye drop group prepared in experimental example 1 (glycine and borneol were removed in example), eye drop group prepared in experimental example 2 (borneol was not contained in example 1)), and were injected intraperitoneally with 0.05% sodium selenite solution 0.01L/kg for molding, and blank group was injected intraperitoneally with an equal amount of physiological saline solution. The drug formulation was started to be applied to the mice by eye drop treatment when the eyes of the mice were opened after 3 days, and the blank control and the model group were both given physiological saline,
the positive control group used medicinal preparation is commercially available BAINING preparation with concentration of 0.5% at 9:00, 11:00, 15:00 daily
Eye drops, 1 drop/eye/time, were administered for 14 d. The ratio of the plaque to the pupil was compared by instilling a 1% atropine sulfate solution in the eyes of the mice for mydriasis before, at the 2 nd, and at the 15 th days after the eyes were opened, and observing the lenticular opacity of the eyes in a dark room using a hand-held slit lamp.
Table 1 effect of eye drops on the incidence of opacity of rat lenses.
P <0.01, Chi-Square Test, compared to the model control group.
The caffeic acid ester concentration is increased (30 percent and 40 percent) independently, and no glycine is added, so that the therapeutic effect of cataract model mice is not different.
TABLE 2 Effect of eye drops on the ratio of cataract rat plaque to pupillary area (x- + -s)
P <0.01, compared to model control, Chi-Square Test.
As can be seen from tables 1 and 2, the eye drops prepared in Experimental example 2 effectively (p < 0.05) reduced the phase of the cataract rat lens opacity on day 15; experimental example 2 the plaque nucleus area was effectively reduced (p < 0.05) on day 15 of treatment.
In the rat cataract model experiment caused by sodium selenite, the eye drops in the experimental example 2 can effectively inhibit the formation and development process of cataract, but the experimental example 1 can hardly play the role of treating cataract.
It is noted that in the experimental group and the control group, some rats showed eye irritation.
Early tests found that caffeic acid ester solutions within 0.01% -40% do not produce toxicity to ocular cell osmotic pressure and environmental conditions.
2. The inventors therefore further evaluated the effect of borneol:
subject: healthy adult white rabbits, 10, were kept in the laboratory environment for at least 3 days prior to the experiment. Both eyes of the experimental animals were examined 24 hours before the start of the experiment, and animals with study irritation symptoms, corneal defects, and mustard damage could not be used for the experiment.
The experimental animals and the experimental animal rooms conform to the corresponding national regulations, and the conventional feed and drinking water are not limited.
The experimental steps are as follows:
the lower eyelid of the right study of the rabbit is pulled open, the eye drops are dropped (or smeared) into the conjunctival sac, the upper eyelid and the lower eyelid are passively closed for 1s, and the study on the other side is not processed to be used as a qualification control. The eyes are not washed 24 hours after dropping the eye drops. For 15 days. (Scoring Standard slight)
TABLE 3 Ocular irritation response grading
Note: when the cornea, iris and conjunctiva are 0, it is judged to be non-irritant.
According to the above test, 10 rabbits were compared with own left eye, and the prescription used in example 1 was that 1 rabbit with microstimulation was added to the borneol group, while 4 rabbits with slight irritation and 4 irritations were observed to the non-borneol group. Therefore, the potential irritation analysis of the caffeic acid ester eye drops can be effectively reduced by adding the borneol.
Further, the above-mentioned test was repeated to measure the concentration of borneol, and it was found that the content of borneol was adjusted based on the formulation of example 1, and that borneol could exert its irritation-reducing function at a concentration of 0.1-10%, and that if it is too high, the stability of the solution would be changed, and the effect thereof was the best at a concentration of 1.2%.
4. Stability study
The stability research of 6 months (standing at room temperature) is carried out by adopting a detection method of pharmacopoeia, and the stability of the eye drop disclosed by the invention is better than that of the conventional eye drop without adding borneol and glycine.
TABLE 4 stability comparison
Therefore, the prescription has better stability compared with the parallel prescription.
Has the advantages that:
the invention provides an ophthalmic preparation containing caffeic acid ester, which has the tendency of improving cataract of a rat model by combining with glycine in a synergistic manner, and meanwhile, borneol is added into the preparation, so that the preparation can keep the solution clear and transparent within 6 months, has the advantages of good content and impurity stability, small irritation and the like, and is suitable for eye protection and improvement application of cataract.
Detailed Description
The invention is further described in the following examples, which are not intended to limit the scope of the invention.
Example 1
1000g eye drops
Caffeic acid ester extract 20%
2 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
0.05 percent of benzalkonium chloride
1.2 percent of borneol
Na2HPO4And NaH2PO4Appropriate amount of buffer
The balance being water, pH 6.5.
The preparation method comprises the following steps: weighing 200g of caffeic acid ester (provided by Yunnan biological grain pharmaceutical industry and prepared by related patent applications), 20g of glycine, KOH as a pH regulator, 0.5g of preservative and 12g of borneol, mixing, adding water for dissolving, adjusting the pH to 6.5, finally adding the residual water, filtering by using a 0.22 mu m microporous filter membrane, performing aseptic subpackaging, filling into an eye drop bottle, and packaging.
Example 2
1000g eye drops
Caffeic acid ester extract 15%
1.5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
0.05 percent of benzalkonium chloride
1.2 percent of borneol
Na2HPO4And NaH2PO4Appropriate amount of buffer
The balance being water, pH 6.5.
Preparation method example 1.
Example 3
1000g eye drops
Caffeic acid ester extract 10%
1 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
Benzalkonium chloride 0.03%
1.2 percent of borneol
Na2HPO4And NaH2PO4Appropriate amount of buffer
The balance of water, and the pH value is about 6.
Preparation method example 1.
Example 4
1000g eye drops
Caffeic acid ester extract 5%
1 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
Benzalkonium chloride 0.02%
1.2 percent of borneol
The balance of water, and the pH value is about 5.5-6.
Preparation method example 1.
Example 5
1000g eye drops
Caffeic acid ester extract 3%
1 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
Benzalkonium chloride 0.02%
1.2 percent of borneol
The balance of water, and the pH value is about 6.
Preparation method example 1.
Example 6
1000g eye drops
Caffeic acid ester extract 1%
1 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
proper amount of KOH
0.05 percent of benzalkonium chloride
1.2 percent of borneol
The balance being water, pH 5.5.
Preparation method example 1.
The above-mentioned embodiments only express a few embodiments of the present invention, and the description is specific and detailed, but it should not be understood as the limitation of the patent scope of the present invention, it should be noted that, for those skilled in the art, many variations and modifications can be made without departing from the concept of the present invention, and these all fall into the protection scope of the present invention, therefore, the protection scope of the present invention is subject to the appended claims.
Claims (7)
1. An ophthalmic preparation containing caffeic acid ester is characterized by being prepared from caffeic acid ester extract, glycine, pharmaceutic adjuvants and water, and the ophthalmic preparation consists of the following components:
0.1-20% of caffeic acid ester extract;
0.1 to 5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
appropriate amount of pH regulator and buffer
0.001-1% of preservative, wherein the preservative is selected from one or more of benzalkonium chloride, phenethyl alcohol, sorbic acid and parabens;
0.1-10% of additive, wherein the additive is borneol;
the balance of water, and the pH value is 5-7.
2. The caffeate-containing ophthalmic preparation of claim 1, wherein the caffeate extract is prepared by the following steps:
decocting herba Erigerontis in water for at least two times, mixing decoctions, filtering, and concentrating the filtrate into fluid extract; adjusting pH of the fluid extract until it is dissolved, filtering, adding sulfuric acid or hydrochloric acid solution into the filtrate to adjust pH to 1-5, and filtering to obtain filtrate and precipitate;
collecting filtrate, passing through polyamide column, eluting with water, discarding water eluate, gradient eluting with 20-90% ethanol, collecting ethanol eluate, recovering ethanol, concentrating into fluid extract, extracting with organic solvent with water solubility of 80g/L or less at 20 deg.C, collecting organic solvent extractive solution, and recovering organic solvent to obtain fluid extract as caffeic acid ester extract.
3. The ophthalmic preparation containing caffeic acid ester according to any one of claims 1-2, wherein the weight percentage of caffeic acid ester extract contained in the ophthalmic preparation is 0.1-15%.
4. The ophthalmic formulation containing caffeate of claim 3, wherein the ophthalmic formulation consists of:
caffeic acid ester extract 5-15%
1 to 5 percent of glycine
The pharmaceutic adjuvant comprises a mixture of a pharmaceutically acceptable excipient,
appropriate amount of pH regulator and buffer
0.01 to 1 percent of preservative
0.5 to 1.5 percent of additive
The balance of water, and the pH value is 5.5-6.5.
5. The ophthalmic formulation of claim 4, wherein the pH adjusting agent is KOH or NaOH and the corresponding buffering agent is Na2HPO4And NaH2PO4Boric acid and/or borax.
6. A method of preparing an ophthalmic formulation containing caffeate according to claim 1, comprising the steps of:
1) weighing corresponding components according to the prescription;
2) diluting pH regulator with small amount of water to obtain solution, grinding Borneolum Syntheticum with water to dissolve, adding water into caffeic acid ester extract, glycine, antiseptic, additive, pH regulator and buffer to obtain solution, adjusting pH to 5-7, adding the rest water to corresponding scale, mixing, filtering with microporous membrane, and packaging.
7. Use of an ophthalmic formulation comprising caffeate according to claim 1 in the preparation of a medicament for the treatment of cataracts.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010360205.6A CN111450054B (en) | 2020-04-30 | 2020-04-30 | Ophthalmic preparation containing caffeic acid ester, preparation method and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010360205.6A CN111450054B (en) | 2020-04-30 | 2020-04-30 | Ophthalmic preparation containing caffeic acid ester, preparation method and application |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111450054A CN111450054A (en) | 2020-07-28 |
CN111450054B true CN111450054B (en) | 2021-11-19 |
Family
ID=71670570
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010360205.6A Active CN111450054B (en) | 2020-04-30 | 2020-04-30 | Ophthalmic preparation containing caffeic acid ester, preparation method and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111450054B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112618504B (en) * | 2020-11-19 | 2022-08-16 | 云南生物谷药业股份有限公司 | Medicinal composition containing erigeron breviscapus extract and borneol and preparation method thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101491532A (en) * | 2008-01-21 | 2009-07-29 | 昆明振华制药厂有限公司 | Erigeron breviscapus eye-preparation and preparation method thereof |
CN104473919A (en) * | 2014-04-21 | 2015-04-01 | 林艳和 | Process for extracting caffeate from erigeron breviscapus |
-
2020
- 2020-04-30 CN CN202010360205.6A patent/CN111450054B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101491532A (en) * | 2008-01-21 | 2009-07-29 | 昆明振华制药厂有限公司 | Erigeron breviscapus eye-preparation and preparation method thereof |
CN104473919A (en) * | 2014-04-21 | 2015-04-01 | 林艳和 | Process for extracting caffeate from erigeron breviscapus |
Non-Patent Citations (1)
Title |
---|
灯盏细辛提取物对高眼压大鼠视网膜神经节细胞的保护作用;杨建华 付敏;《中国中医眼科杂志》;20130430;第96-99页 * |
Also Published As
Publication number | Publication date |
---|---|
CN111450054A (en) | 2020-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10406189B2 (en) | Methods and compositions for treating and preventing signs or symptoms of eye disease | |
JP2021505650A (en) | Ophthalmic drug preparations and their use | |
CN104490861A (en) | Sustained-release nepafenac eye-drops preparation | |
CN103040888A (en) | Ophthalmologic external preparation, as well as preparation method and application thereof | |
CN102362924B (en) | Medicinal composition for treating ophthalmic diseases and preparation method thereof | |
CN104225265A (en) | Traditional Chinese medicine composition for alleviating asthenopia | |
CN111450054B (en) | Ophthalmic preparation containing caffeic acid ester, preparation method and application | |
CN103301146A (en) | Traditional Chinese medicine monomer combination capable of resisting oxidation and improving eyeground blood circulation | |
CN102920722A (en) | Ophthalmic preparation for treating fundus diseases | |
EP2182963B1 (en) | Herbal composition on the basis of extracts of foeniculum vulgare, murraya koenigii and triphala | |
CN107320446A (en) | A kind of forsythin eye drops and preparation method thereof | |
CN113786380A (en) | Pilocarpine nitrate ophthalmic gel and preparation method thereof | |
CN111437252B (en) | Ophthalmic preparation containing erigeron breviscapus extract, preparation method and application | |
CN114796395A (en) | Traditional Chinese medicine eye drops and application thereof | |
CN116407496B (en) | Eye drops containing artemisinin prodrug and preparation method thereof | |
CN105983006A (en) | Composition for relieving visual fatigue and preparation method of composition | |
CN102688227A (en) | Borneol-containing salvianolic acid A composition ophthalmic preparation and preparation method thereof | |
CN112007066B (en) | Capsella bursa-pastoris extract and preparation method and application thereof | |
CN107714709A (en) | Otoginsenoside and its salt are preparing the purposes in treating cataract medicine | |
TWI749568B (en) | Ophthalmic compositions and medical uses thereof in treatment of myopia | |
TWI830221B (en) | Method for relieving dry eye syndrome | |
CN110876746B (en) | Ginkgo diterpene lactone eye preparation and preparation method and application thereof | |
CN111450044B (en) | Ophthalmic preparation containing scutellarin, preparation method and application thereof | |
CN108524448A (en) | A kind of euphadienol anti-cataract eye-drops preparations and its preparation method and application | |
CN101804057A (en) | Chuagxiongzine ophthalmic preparation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |