WO2017166888A1 - Goutte ophtalmique et procédé de préparation et application correspondants - Google Patents

Goutte ophtalmique et procédé de préparation et application correspondants Download PDF

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Publication number
WO2017166888A1
WO2017166888A1 PCT/CN2017/000180 CN2017000180W WO2017166888A1 WO 2017166888 A1 WO2017166888 A1 WO 2017166888A1 CN 2017000180 W CN2017000180 W CN 2017000180W WO 2017166888 A1 WO2017166888 A1 WO 2017166888A1
Authority
WO
WIPO (PCT)
Prior art keywords
eye drops
eye
tromethamine
biphenyl acetate
ester
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.)
Ceased
Application number
PCT/CN2017/000180
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English (en)
Chinese (zh)
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GUANGDONG ZHONGKE DRUG R&D Ltd
Original Assignee
GUANGDONG ZHONGKE DRUG R&D Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by GUANGDONG ZHONGKE DRUG R&D Ltd filed Critical GUANGDONG ZHONGKE DRUG R&D Ltd
Publication of WO2017166888A1 publication Critical patent/WO2017166888A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/185—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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K47/08—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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • the invention relates to an eye drop prepared by using biphenyl acetate and the application thereof, and the preparation method of the biphenyl acetate tromethamine eye drop is illustrated as an example.
  • Biphenylacetic acid as an anti-inflammatory analgesic drug was marketed in Japan, Italy and other countries in 1993. It is used for analgesic and anti-inflammatory effects such as osteoarthritis, frozen shoulder, tenosynovitis, periorbital inflammation, muscle pain and soft tissue injury, and after alleviating trauma. Swelling pain.
  • biphenylacetic acid is insoluble in water, it can only be used as a topical drug, which seriously affects the promotion and use of the drug.
  • Japan there was a biphenyl ethyl acetate injection emulsion (insoluble in water) for clinical analgesia.
  • biphenylacetate tromethamine salt (hereinafter, aniline fenbutanol is substituted for benzacetamide tromethamine salt) has better water solubility and safety than other salts, and is suitable for preparation into an injection solution.
  • anhydrous sodium carbonate is used as a solubilizer to promote the dissolution of nigroprofen; and the pH of the anilinoprofen eye drops is maintained at about 7.5, maintaining the relative stability of the flexiphene, and the effect on the cornea is mild and non-irritating.
  • the addition of the surfactant poloxamer 407 can prolong the retention time of the drug in the cornea and improve the bioavailability of the drug; the sodium chloride is added to adjust the osmotic pressure so that the osmotic pressure is consistent with the intraocular pressure; and a small amount is added.
  • Disodium edetate is used as a metal ion chelating agent; since aniline is incompatible with benzalkonium chloride, hydroxyethyl ester is used as a preservative, and the application range of hydroxyphenylethyl ester is just at pH 7-9.
  • the antibacterial efficacy test verified its inhibition The effect of the bacteria; the influencing factors test showed that the product is relatively stable to high temperature and illumination; by examining the effects of different packaging materials on the stability of aniline fentanyl eye drops, the results show that the compatibility of phenamifofen eye drops with different packaging materials They are all better, so the polypropylene packaging eye drops bottle, which is the common packaging material for general eye drops, is selected as the inner packaging material of this product.
  • the above research results show that the above-mentioned formulated nigroprofen eye drops are relatively stable.
  • the eye drops prepared by the present invention have an active ingredient of nigroprofen (biphenylacetate tromethamine). Its chemical formula is:
  • the molecular formula is C 18 H 23 NO 5 and the molecular weight is 333.14.
  • anhydrous sodium carbonate as a solubilizer promotes the dissolution of nigroprofen and maintains the pH of the flexionoside eye drops at around 7.5, maintaining the relative stability of the flexiphene, and acting mildly on the cornea without irritation.
  • Adding the surfactant poloxamer 407 can prolong the retention time of the drug in the cornea, and improve the bioavailability of the drug; adding sodium chloride to adjust the osmotic pressure, so that the osmotic pressure is consistent with the intraocular pressure; and adding a small amount Disodium edetate is used as a metal ion chelating agent; since aniline is incompatible with benzalkonium chloride, hydroxyethyl ester is used as a preservative to ensure the sterility requirements of aniline fentanyl eye drops in accordance with the national pharmacopoeia.
  • the prescription mainly contains nigroprofen, poloxamer 407, hydroxyethyl ester, sodium chloride, anhydrous sodium carbonate, disodium edetate and other raw materials; in the selection of raw materials Sodium chloride and anhydrous sodium carbonate are all injection-grade aseptic auxiliary materials.
  • Poloxamer 407, disodium edetate and hydroxyphenylethyl ester are selected as pharmaceutical excipients with national approval number; Liquid Production process using the production process of internationally accepted sterilization filtration, under production conditions of GMP, one hundred clean production zone, production of aniline to ensure good quality drops ketoprofen.
  • the specification is determined according to the pharmacodynamic concentration screening test of aniline fentanyl eye drops, and the effective concentration is determined to be 0.1%.
  • 1 mg of aniline is contained per 1 ml of phenamifofen eye drops, and reference is made to the similar drug that has been marketed in Japan.
  • the specification of Lofin Eye Drops is 5ml: 5mg, so we tentatively set the product size to 5ml: 5mg.
  • other salts of biphenylacetic acid, sodium salt, ammonium salt, potassium salt, diethylamine, guanamine salt, etc. are used, and the pH value and the selection of the bacteriostatic agent are the same. It is also possible to dissolve the biphenyl acetic acid in a certain concentration of sodium carbonate solution, and the pH and the bacteriostatic agent are selected in the same manner. Hydroxyphenyl ethyl ester can be used
  • Dissolve anhydrous sodium carbonate with a small amount of water for injection add a prescribed amount of nigroprofen, and stir to completely dissolve.
  • Dissolve the hydroxyethyl ester with a small amount of water for injection and boil it to dissolve completely.
  • Dissolve poloxamer 407 with 50% of the prescribed amount of water for injection, add dissolved sodium carbonate and nigroprofen, add sodium chloride and disodium edetate, stir to dissolve, and finally add dissolved Hydroxyphenyl ethyl ester, add water for injection to the full amount, stir evenly.
  • the bacteria were sterilized by filtration through a 0.22 ⁇ m microporous membrane.
  • Eye drops are multi-dose preparations, which cannot be kept sterile during use, and nigrofiprofen itself does not have sufficient antibacterial activity. Therefore, suitable effective bacteriostatic agents should be added to prevent the preparation from being stored and used during normal use. Microbial contamination and reproduction that may occur can cause the drug to deteriorate and cause harm to the user.
  • the bacteriostatic agent added to the eye drops is not only required to be effective, but also requires rapid action to achieve bacteriostatic action in the interval between two uses of the patient.
  • Foreign eye drops are most commonly used in quaternary ammonium salts. We first use benzalkonium chloride to add eye drops. The solution immediately turbid and replaced with benzalkonium bromide. The same result indicates that quaternary ammonium salts and aniline are used. Fen is not compatible. Then we chose hydroxyphenyl esters, which are effective at pH 7 ⁇ 9. The eye drops we prepared are just within this pH range.
  • Conjunctival hyperemia referring to the conjunctiva and bulbar conjunctiva: normal blood vessel 0 points; blood vessels Congestion was bright red 1 point; blood vessel congestion was dark red, blood vessels were difficult to distinguish 2 points; diffuse hyperemia was purple red 3 points.
  • B. Conjunctival edema no 0 points; slight edema (including nictitating membrane) 1 point; obvious edema, with partial eyelid valgus 2 points; edema to the eyelid nearly half closed 3 points; edema to the eyelids mostly closed 4 points.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une goutte opthalmique préparée à l'aide d'un biphénylacétate ou d'un acide biphénylacétique. Une étude technique a montré que le niveau de pH doit être contrôlé dans une plage spécifique. Un ester d'hydroxybenzoate est sélectionné en tant qu'agent antimicrobien. L'invention est stable et améliore un effet anti-inflammatoire local.
PCT/CN2017/000180 2016-03-30 2017-02-17 Goutte ophtalmique et procédé de préparation et application correspondants Ceased WO2017166888A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610207600.4A CN105769758B (zh) 2016-03-30 2016-03-30 一种联苯乙酸盐滴眼液及其制备方法与应用
CN201610207600.4 2016-03-30

Publications (1)

Publication Number Publication Date
WO2017166888A1 true WO2017166888A1 (fr) 2017-10-05

Family

ID=56395710

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/000180 Ceased WO2017166888A1 (fr) 2016-03-30 2017-02-17 Goutte ophtalmique et procédé de préparation et application correspondants

Country Status (2)

Country Link
CN (1) CN105769758B (fr)
WO (1) WO2017166888A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116350580A (zh) * 2023-02-21 2023-06-30 广州大光制药有限公司 一种单剂量苯胺洛芬滴眼液及其制备方法
CN120093686A (zh) * 2025-03-26 2025-06-06 武汉五景药业有限公司 珍珠明目滴眼液及其制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105769758B (zh) * 2016-03-30 2018-08-14 广东中科药物研究有限公司 一种联苯乙酸盐滴眼液及其制备方法与应用
CN106983718B (zh) * 2016-08-12 2019-01-11 广东中科药物研究有限公司 一种联苯乙酸或其氨丁三醇盐注射液的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102885803A (zh) * 2011-12-29 2013-01-23 广东中科药物研究有限公司 联苯乙酸氨丁三醇盐在制备治疗眼部炎症反应药物中的应用
CN105769758A (zh) * 2016-03-30 2016-07-20 广东中科药物研究有限公司 一种联苯乙酸盐滴眼液及其制备方法与应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102885803A (zh) * 2011-12-29 2013-01-23 广东中科药物研究有限公司 联苯乙酸氨丁三醇盐在制备治疗眼部炎症反应药物中的应用
CN105769758A (zh) * 2016-03-30 2016-07-20 广东中科药物研究有限公司 一种联苯乙酸盐滴眼液及其制备方法与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG, SHILEI ET AL.: "Preservative for Ophthalmic Preparation", FOOD AND DRUG, vol. 12, no. 09, 31 December 2010 (2010-12-31), pages 343 - 346, ISSN: 1672-979X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116350580A (zh) * 2023-02-21 2023-06-30 广州大光制药有限公司 一种单剂量苯胺洛芬滴眼液及其制备方法
CN120093686A (zh) * 2025-03-26 2025-06-06 武汉五景药业有限公司 珍珠明目滴眼液及其制备方法

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CN105769758B (zh) 2018-08-14
CN105769758A (zh) 2016-07-20

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