WO2018205961A1 - 一种用于治疗干眼的滴眼液 - Google Patents

一种用于治疗干眼的滴眼液 Download PDF

Info

Publication number
WO2018205961A1
WO2018205961A1 PCT/CN2018/086240 CN2018086240W WO2018205961A1 WO 2018205961 A1 WO2018205961 A1 WO 2018205961A1 CN 2018086240 W CN2018086240 W CN 2018086240W WO 2018205961 A1 WO2018205961 A1 WO 2018205961A1
Authority
WO
WIPO (PCT)
Prior art keywords
sodium
eye
potassium
acid
solution according
Prior art date
Application number
PCT/CN2018/086240
Other languages
English (en)
French (fr)
Inventor
刘祖国
张晓博
林祥
Original Assignee
厦门大学
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 厦门大学 filed Critical 厦门大学
Priority to US16/623,320 priority Critical patent/US20200171066A1/en
Priority to ES18798346T priority patent/ES2899597T3/es
Priority to EP18798346.5A priority patent/EP3636252B1/en
Publication of WO2018205961A1 publication Critical patent/WO2018205961A1/zh

Links

Images

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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K47/16—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
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the invention belongs to the technical field of dry eye treatment, and in particular relates to an eye drop for treating dry eye.
  • Dry eye is a common and frequently-occurring disease in ophthalmology clinics.
  • the prevalence of dry eye in women under 50 years old is 5.7%, and the prevalence rate increases to 9.8% after over 75 years old, and female dry eyes Symptoms are more pronounced than men.
  • the higher the level of education the higher the prevalence rate.
  • the prevalence of dry eye in men aged 50-54 is 3.9%.
  • the age is over 80, the prevalence increases. 7.67%, it is estimated that by 2030, the number of male dry eye patients in the United States will reach 2.79 million.
  • Dry eyes can cause dry eyes, foreign body sensation, visual fatigue, decreased vision, etc. Serious dry eyes can cause significant loss of vision and even blindness. Dry eye patients are affected by daily activities such as reading, working, using computers, watching TV, and driving. It can be said that dry eye seriously affects human work efficiency and quality of life, and has become a social problem that modern people have to face and urgently need to solve.
  • the pathogenesis of dry eye is related to inflammation, apoptosis, neuromodulation abnormalities, and sex hormone disorders.
  • the importance of inflammation in the pathogenesis of dry eye has been well documented in recent years.
  • TNF-a, IL-1 ⁇ , MMP-9 and other inflammatory factors are associated with ocular surface epithelial damage in dry eye patients.
  • Inflammation of the ocular surface and lacrimal gland in patients with dry eye is primarily associated with massive infiltration and activation of CD4 + T lymphocytes. Decreased goblet cells and squamous metaplasia were positively correlated with CD4 + T cell infiltration and IFN- ⁇ expression in dry eye patients.
  • the inflammatory factors secreted by CD4 + T cells play an important role in the development of dry eye.
  • the up-regulation of Th1 cytokine IFN- ⁇ in dry eye ocular surface leads to a large number of apoptosis of conjunctival epithelial cells; IFN- ⁇ /IL- Upregulation of 13 resulted in a decrease in the density of conjunctival goblet cells; up-regulation of the Th17 cytokine IL-17A resulted in damage to the corneal barrier function.
  • the expression of inflammatory markers such as HLA class II, ICAM-1, and CCR5 in the conjunctival epithelium of patients with dry eye is significantly increased.
  • Lam et al recently confirmed that the expression of inflammatory chemokines IL-8, MIP-1 ⁇ and RANTES in tears of various dry eye patients is up-regulated; CD11b + and CD11c + antigen presenting cells are involved in the inflammatory process of dry eye ocular surface; T cells play an important role in the pathogenesis of dry eye.
  • CD4 + , CD25 + T cells and CD8 + T cells can inhibit the proliferation of pathological CD4 + T lymphocytes in dry eye.
  • NK/NKT cells can aggravate corneal barrier function by promoting dry eye Th-17 response; clinical studies have shown that administration of anti-inflammatory drugs such as corticosteroids, immunosuppressive cyclosporine and FK506 local eye can effectively alleviate symptoms of dry eye And signs.
  • cyclosporine A After 6 months of topical treatment with cyclosporine A, the expression of inflammation-related markers (such as IL-1, TNF- ⁇ , etc.) decreased significantly. After 3 months of treatment with 0.05% cyclosporine A, the ocular surface symptoms and signs were significantly reduced, and the inflammatory factors of IL-4, IL-5, IL-17A, TNFa and IFN- ⁇ in tears were significantly decreased. Local treatment with cyclosporine A can effectively inhibit the infiltration of dry eye conjunctiva CD4 + T cells and apoptosis of conjunctival epithelial cells and goblet cell loss. Patients with Sjogren's syndrome use 0.03% tacrolimus to improve tear film stability and maintain normal ocular surface condition.
  • inflammation-related markers such as IL-1, TNF- ⁇ , etc.
  • FK506 local eye can inhibit the activation of mouse NF- ⁇ B signaling pathway and reduce the ocular surface signs of dry eye.
  • 0.02% tacrolimus local eye can significantly increase the amount of tear secretion in the dry eye model of the puppy.
  • cyclosporine A and FK506 are highly lipophilic and hardly soluble in water, and are mostly made into various vegetable oil eye drops at home and abroad. These oily eye drops are intensively irritated to the eyes, and the patient is usually intolerant. Occasionally, allergies occur, and the drug immediately precipitates in the tears, making the intraocular bioavailability low.
  • microemulsions, micelles, liposomes, poly- ⁇ -caprolactone nanoparticles, chitosan nanoparticles and the like In order to improve the ophthalmic bioavailability of the two drugs, it has been studied to prepare microemulsions, micelles, liposomes, poly- ⁇ -caprolactone nanoparticles, chitosan nanoparticles and the like.
  • the above process can effectively increase the drug loading of poorly soluble drugs or water insoluble drugs.
  • the emulsification technique can reduce the irritation of the local application, and because the dispersion of the emulsion droplets is large, the absorption of the medicine is fast, and the bioavailability can be effectively improved. Even so, the congenital deficiency of fat-soluble eye drops is still not completely overcome at present. More than 1 billion people around the world suffer from dry eye and have a huge need for dry eye treatment. Therefore, it is extremely urgent to screen for new ocular surface immunosuppression of dry eye, especially for water-
  • An eye drop for treating dry eye having a pH of 5.0 to 7.0, and its active ingredient is 5-hydroxy-1-beta-D-furanosyl-1H-imidazole-5-carboxamide (aka: imidazole Bin), specifically the following weight percentage components:
  • the balance is water.
  • the pH adjusting agent is sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, acetic acid, sodium acetate, citric acid, lemon.
  • At least one of sodium, tartaric acid, sodium tartrate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, hydrochloric acid and phosphoric acid the purpose of which is to make the pH of the eye drops and tears
  • the pH is equal or close to reduce the irritation of the eye drops, and the drug is stabilized and the drug effect is improved.
  • the isotonic agent is sodium chloride, potassium chloride, boric acid, borax, sodium sulfate, potassium sulfate, sodium nitrate, potassium nitrate, sodium acetate, mannitol, glycerin, propylene glycol or At least one of glucose.
  • the function of the isotonic agent is to make the osmotic pressure of the eye drops equal or close to the osmotic pressure of the tear liquid, so as to reduce the irritation of the eye drops and improve the drug effect.
  • the bacteriostatic agent is benzalkonium chloride, benzalkonium bromide, chlorhexidine acetate, glucose chlorhexidine, chlorobutanol, phenoxyethanol, methylparaben At least one of hydroxyethyl ester and hydroxypropyl propyl ester.
  • the proper amount of the bacteriostatic agent can make the eye drops not easily infected by bacteria, thereby ensuring the safety of the product.
  • the stabilizer is sodium sulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium nitrite, sodium thiosulfate, ascorbic acid, thiourea, ascorbyl stearate, dibutyl cresol, half At least at least one of cystine, tocopherol acetate, dichloroisocyanate, disodium edetate, sodium calcium edetate, dimercaptopropanol, glycerin, mannitol, and butylated hydroxyanisole One.
  • the role of the stabilizer is to increase the stability of the eye drops and improve the efficacy.
  • the tackifier is sodium hyaluronate, sodium carboxymethylcellulose, grade a cellulose, polyethylene glycol, polyvinyl alcohol, carbomer and povidone At least one.
  • the role of the tackifier is to increase the viscosity of the eye drops, prolong the retention time of the drug on the ocular surface, and increase the effective drug concentration.
  • the solubilizing agent is at least one of polysorbate, polyoxyethylene castor oil glyceryl ether, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, and poloxamer.
  • solubilizers The role of solubilizers is to increase the solubility of the drug.
  • the topical treatment of the eye drops of the invention can protect the corneal epithelial barrier function of the dry eye mouse, restore the number of conjunctival goblet cells, and have better anti-inflammatory and immunosuppressive effects.
  • Fig. 1 is a graph showing the results of fluorescent staining of corneal OGD according to Example 10 of the present invention.
  • Fig. 2 is a graph showing the results of PAS staining of conjunctival goblet cells according to Example 10 of the present invention.
  • Fig. 3 is a graph showing the results of staining of conjunctival CD4 + T cells according to Example 10 of the present invention.
  • FIG. 4 is a diagram showing the results of Real-Time PCR according to Embodiment 10 of the present invention.
  • the above liquid is filtered through a 0.45 ⁇ m microporous membrane filter once, and then filtered twice through a 0.22 ⁇ m microporous membrane.
  • the above prepared chemical solution is filtered once through a 0.45 ⁇ m microporous membrane and then filtered once through a 0.22 ⁇ m microporous membrane.
  • the filtered drug solution is sterilized by autoclaving at 121 ° C for 8 minutes and cooled.
  • the above liquid is filtered through a 0.45 ⁇ m microporous membrane filter once, and then filtered twice through a 0.22 ⁇ m microporous membrane.
  • the above prepared chemical solution is filtered once through a 0.45 ⁇ m microporous membrane membrane, and then filtered once through a 0.22 ⁇ m microporous membrane;
  • the filtered drug solution is sterilized by autoclaving at 121 ° C for 8 minutes and cooled.
  • the above drug solution was filtered through a 0.45 ⁇ m microporous membrane filter once, and then filtered twice through a 0.22 ⁇ m microporous membrane.
  • step 3 Weigh accurately 1.00 g of imidazolium and add to the mixed solution obtained in step 2.
  • the dissolution process can be heated appropriately, stirred and dissolved, and cooled to room temperature if heated.
  • the drug solution was filtered through a 0.45 ⁇ m micropore filter and filtered twice through a 0.22 ⁇ m microporous membrane.
  • step 3 Weigh accurately 1.00 g of imidazolium and add to the mixed solution obtained in step 2.
  • the dissolution process can be heated appropriately, stirred and dissolved, and cooled to room temperature if heated.
  • the drug solution was filtered through a 0.45 ⁇ m microporous membrane filter once, and then filtered twice through a 0.22 ⁇ m microporous membrane.
  • the solution obtained in the step 2 is added dropwise to the solution obtained in the step 2, and the dissolved sodium hyaluronate solution is slowly added, stirred and uniformly mixed, and then made up to 1000 mL with water for injection to obtain a drug solution.
  • the drug solution was filtered through a 0.45 ⁇ m micropore filter and filtered twice through a 0.22 ⁇ m microporous membrane.
  • the prescriptions are all taken as 1000 mL.
  • the formulation ratio can be increased by referring to the proportion of the prescription.
  • Eye-pointing method Eye-eye treatment using the above-mentioned eye drops, 4 times a day, and both eyes.
  • PAS staining Paraffin specimens of mouse whole eyeball (conjunctival sac) were cut into 5um slices and stained with periodic acid-Schiff (PAS) reagent to observe the morphology and quantity of conjunctival goblet cells.
  • Stage 1 Pre-denaturation cycle number: 195 ° C, 30 sec.
  • Stage 2 number of PCR reaction cycles: 4095 ° C, 5 sec. 60 ° C, 34 sec.
  • PAS staining of conjunctival goblet cells showed a significant increase in the number of conjunctival goblet cells in the 0.1% imidazoribin group compared with the dry eye group.
  • the results showed that: 0.1% medrizine local eye treatment can significantly restore the number of goblet cells and ensure the amount of mucin secretion. (as shown in picture 2)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth 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)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种用于治疗干眼的滴眼液，pH为5.0～7.0，有如下重量百分比的组分组成：有效成分5-羟基-1-beta-D-呋喃糖基-1H-咪唑-5-羧酰胺0.05～0.1％、pH值调节剂适量、等渗剂0.01～3％、抑菌剂0.003～0.5％、稳定剂0.001～0.5％、增粘剂0.01～0.5％、增溶剂2～5％，余量为水。本发明的滴眼液可保护干眼小鼠角膜上皮屏障功能，恢复结膜杯状细胞数量，并有较好的抗炎及免疫抑制效果。

Description

一种用于治疗干眼的滴眼液 技术领域
本发明属于干眼治疗技术领域，具体涉及一种用于治疗干眼的滴眼液。
背景技术
干眼是眼科门诊常见病与多发病。据Schaumberg等在美国进行的大样本干眼流行病学调查显示：50岁以下的女性干眼患病率为5.7％，而超过75岁后患病率升高到9.8％，且女性的干眼症状较男性更为明显，随着教育程度越高，患病率越高；同样的，年龄在50-54岁的男性干眼患病率为3.9％，超过80岁则患病率升高到7.67％，估计到2030年全美男性干眼患者将达到279万人。而在我国，从石常宏等进行的流行病学调查结果来看，在纳入的31124例患者中，干眼患病率为67.9％，女性(72.7％)高于男性(62.8％)，但小于25岁的研究对象男性干眼患病率高于女性。小于25岁年龄组干眼患病率为54.3％，25～45岁年龄组干眼患病率为65.9％，大于45岁年龄组干眼患病率为79.1％。随着科技的发展，大量高科技产品在年轻一代中得到广泛的普及，如手机、平板电脑等，大大增加了年轻人的用眼负担，加上周围环境的恶化及生活压力的增加，干眼的患病率逐年提高，并出现明显的年轻化。干眼可引起眼睛干涩感、异物感、视疲劳、视力下降等；严重干眼，可导致视力明显下降，甚至失明。干眼患者在日常活动中，如读书、工作、使用计算机、看电视、驾驶等行为都会受到影响。可以说，干眼严重地影响着人类的工作效率和生活质量，已成为现代人不得不面临和迫切需要解决的社会问题。
干眼的发病机制与炎症、细胞凋亡、神经调节异常、性激素失调等有关。炎症在干眼发病机制中的重要性在近年研究中已得到充分证明。TNF-a，IL-1β、MMP-9等炎症因子与干眼患者眼表上皮细胞损害有关。干眼症患者眼表和泪腺的炎症主要与CD4 +T淋巴细胞的大量浸润和激活相关。干眼患者结膜杯状细胞减少及鳞状上皮化生与CD4 +T细胞浸润程度及IFN-γ表达量呈正相关。CD4 +T细胞分泌的炎症因子在干眼发生发展中起着重要的作用，如：干眼眼表Th1细胞因子IFN-γ的上调导致了结膜上皮细胞的大量凋亡；IFN-γ/IL-13比例上调导致了结膜杯状细胞密度的下降；Th17细胞因子IL-17A的上调导致了角膜屏障功能的损害。临床上干眼患者结膜上皮HLA class II、ICAM-1、CCR5等炎症标志物的表达显著增加。Lam等最近还证实各类干眼 患者中泪液的炎症趋化因子IL-8，MIP-1α和RANTES表达上调；CD11b +与CD11c +抗原提呈细胞均参与了干眼眼表炎症过程；调节性T细胞在干眼发病中起着重要的作用。CD4 +、CD25 +T细胞与CD8 +T细胞可抑制干眼病理性CD4 +T淋巴细胞的增值。NK/NKT细胞可通过促进干眼Th-17反应而恶化角膜屏障功能；临床研究证明给予抗炎症治疗，如皮质类固醇激素、免疫抑制剂环孢霉素及FK506局部点眼可以有效缓解干眼的症状和体征。
2013年，中华医学会眼科学分会角膜病学组达成了干眼临床诊疗专家共识，在干眼的定义、流行病学及危险因素、分类、检查和诊断、治疗等方面建立了规范。对于中重度干眼，建议糖皮质激素、非甾体类抗炎药及免疫抑制剂治疗。其中，免疫抑制治疗是干眼治疗的关键之一。目前，临床上常用的免疫抑制剂主要是0.05％环孢霉素A滴眼液(Cyclosporin)及0.05％他克莫司滴眼液(FK506)，两种药物在临床应用中均显示出较好的疗效。经过环孢霉素A局部治疗6个月后，炎症相关标志物(如IL-1、TNF-α等)表达均显著下降。0.05％环孢素A治疗3个月后，患者眼表症状和体征显著减轻，泪液中IL-4、IL-5、IL-17A、TNFa、IFN-γ的炎症因子显著降低。环孢霉素A局部治疗可有效抑制干眼结膜CD4 +T细胞的浸润与结膜上皮细胞凋亡、杯状细胞丢失。干燥综合征患者使用0.03％他克莫司点眼能够提高泪膜稳定性，维持正常眼表状态。动物实验表明，0.025％的FK506局部点眼能抑制小鼠NF-κB信号通路激活，减轻干眼的眼表体征。0.02％他克莫司局部点眼能显著提高干眼模型的小狗的泪液分泌量。然而，环孢霉素A及FK506亲脂性强，在水中几乎不溶，国内外大多将其制成各种植物油滴眼液。这些油性滴眼剂滴入眼后，对眼睛有强刺激性，患者通常不能耐受，偶有过敏现象发生，且药物遇泪液立即析出，使得眼内生物利用度很低。为了提高两种药物的眼用生物利用度，已有研究将其制备成微乳、胶束、脂质体、聚ε己内酯纳米粒、壳聚糖纳米粒等。以上工艺可有效地增加难溶性药物或水不溶性药物的载药量。尤其是乳化技术，可以减少局部应用的刺激性，且由于乳滴的分散度大，药物吸收快，生物利用度可有效提高。即便如此，与水溶性药物相比，脂溶性滴眼液的先天不足在目前仍无法完全克服。全球约有10多亿人口经受着干眼的困扰，有着巨大的干眼病治疗需求，因此，筛选干眼新型眼表免疫抑制，尤其是水溶性较好的眼用免疫抑制剂极为紧迫。
发明内容
本发明的目的在于克服现有技术缺陷，提供一种用于治疗干眼的滴眼液。
本发明的技术方案如下：
一种用于治疗干眼的滴眼液，pH为5.0～7.0，其有效成分为5-羟基-1-beta-D-呋喃糖基-1H-咪唑-5-羧酰胺(又名：咪唑立宾)，具体有如下重量百分比的组分：
5-羟基-1-beta-D-呋喃糖基-1H-咪唑-5-羧酰胺 0.05～0.1％
pH值调节剂适量
等渗剂 0.01～3％
抑菌剂 0.003～0.5％
稳定剂 0.001～0.5％
增粘剂 0.01～0.5％
增溶剂 2～5％
余量为水。
在本发明的一个优选实施方案中，所述pH值调节剂为磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、硼酸、硼砂、醋酸、醋酸钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、盐酸和磷酸中的至少一种，其目的是使滴眼液的酸碱度与泪液的酸碱度相等或接近，以减少滴眼液的刺激性，并使药物稳定，药效提高。
在本发明的一个优选实施方案中，所述等渗剂为氯化钠、氯化钾、硼酸、硼砂、硫酸钠、硫酸钾、硝酸钠、硝酸钾、醋酸钠、甘露醇、甘油、丙二醇或葡萄糖中的至少一种。等渗剂的作用是为了使滴眼液的渗透压与泪液的渗透压相等或接近，以减轻滴眼液的刺激性，提高药效。
在本发明的一个优选实施方案中，所述抑菌剂为苯扎氯铵、苯扎溴铵、醋酸氯己定、葡萄糖氯己定、三氯叔丁醇、苯氧乙醇、羟苯甲酯、羟苯乙酯和羟苯丙酯中的至少一种。适量抑菌剂可以使得所述滴眼液不易被细菌感染，保证了产品的安全。
在本发明的一个优选实施方案中，所述稳定剂为亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、亚硝酸钠、硫代硫酸钠、抗坏血酸、硫脲、抗坏血酸硬脂酸酯、二丁基甲酚、半胱氨酸、生育酚乙酸酯、二氯异氰、乙二胺四乙酸二钠、乙二胺四乙酸钙钠、二巯基丙醇、甘油、甘露醇和丁基化羟基苯甲醚中的至少一种。稳定剂的作用是为了增加滴眼液的稳定性，提高药效。
在本发明的一个优选实施方案中，所述增粘剂为玻璃酸钠、羧甲基纤维素钠、甲级纤维素、聚乙二醇、聚乙烯醇、卡波姆和聚维酮中的至少一种。增粘剂的作用是为 了增加滴眼液的粘稠度，延长药物在眼表的存留时间，提高有效药物浓度。
在本发明的一个优选实施方案中，所述增溶剂为聚山梨酯类、聚氧乙烯蓖麻油甘油醚、聚氧乙烯脂肪酸酯类、聚氧乙烯脂肪醇醚类和泊洛沙姆中的至少一种。增溶剂的作用是为了增加药物的溶解度。
本发明的有益效果：本发明的滴眼液的局部治疗可保护干眼小鼠角膜上皮屏障功能，恢复结膜杯状细胞数量，并有较好的抗炎及免疫抑制效果。
附图说明
图1为本发明实施例10的角膜OGD荧光染色结果图。
图2为本发明实施例10的结膜杯状细胞PAS染色结果图。
图3为本发明实施例10的结膜CD4 +T细胞染色结果图。
图4为本发明实施例10的Real-Time PCR结果图。
具体实施方式
以下通过具体实施方式结合附图对本发明的技术方案进行进一步的说明和描述。
实施例1
配方：
咪唑立宾 1.00g
苯扎氯铵 0.03g
氯化钠 8.30g
0.1mol/L盐酸 30mL
注射用水 定容至1000mL
制备工艺：
1、精密称取1.00g咪唑立宾、苯扎氯铵0.03g、氯化钠8.30g、0.1mol/L盐酸30mL，加200mL注射用水溶解，搅拌均匀后，用注射用水定容至1000mL，得药液。
2、将上述溶液经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤2次。
3、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例2
配方：
咪唑立宾 1.00g
醋酸氯己定 0.05g
磷酸二氢钠 7.20g
磷酸氢二钠 0.95g
氯化钠 4.79g
注射用水 定容至1000mL
制备工艺：
1、精密称取1.00g咪唑立宾，加入300mL注射用水使之溶解，得溶液①备用。
2、精密称取醋酸氯己定0.05g，、7.20g磷酸二氢钠、0.95g磷酸氢二钠、4.79g氯化钠，加200mL注射用水溶解后，将其进行搅拌混合均匀，得溶液②备用。
3、将溶液①和溶液②进行混合，搅拌均匀后，用注射用水定容至1000mL，得药液。
4、将上述药液经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤2次。
5、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例3
配方：
咪唑立宾 1.00g
苯扎溴铵 0.03g
磷酸二氢钠 6.40g
磷酸氢二钠 1.89g
氯化钠 4.72g
乙二胺四乙酸二钠 0.10g
注射用水 定容至1000mL
制备工艺：
1、精密称取1.00g咪唑立宾、0.03g苯扎溴铵、6.40g磷酸二氢钠、1.89g磷酸氢二钠、4.72g氯化钠、0.10g乙二胺四乙酸二钠，加200mL注射用水溶解，搅拌均匀 后，用注射用水定容至1000mL，得药液。
2、将上述配制的药液，经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤1次。
3、过滤后的药液，采用热压灭菌法，于121℃下灭菌8分钟，冷却。
4、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例4
配方：
咪唑立宾 1.00g
葡萄糖氯己定 0.10g
硼酸 19.10g
甘油 13.00g
注射用水 定容至1000mL
制备工艺：
1、精密称取1.00g咪唑立宾、0.10g葡萄糖氯己定、19.10g硼酸、13.00g甘油，加200mL注射用水溶解，将其进行搅拌混合，用注射用水定容至1000mL，得药液。
2、将上述药液经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤2次。
3、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例5
配方：
咪唑立宾 1.00g
苯扎氯铵 0.03g
磷酸二氢钠 7.20g
磷酸氢二钠 0.95g
甘油 14.00g
乙二胺四乙酸二钠 0.10g
注射用水 定容至1000mL
制备工艺：
1、精密称取1.00g咪唑立宾、0.03g苯扎氯铵、7.20g磷酸二氢钠、0.95g磷酸氢二钠、14.0g甘油、0.10g乙二胺四乙酸二钠，加200mL注射用水溶解，将其进行搅拌混合，用注射用水定容至1000mL，得药液。
2、将上述配制的药液，经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤1次；
3、过滤后的药液，采用热压灭菌法，于121℃下灭菌8分钟，冷却。
4、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例6
配方：
咪唑立宾 1.00g
苯扎氯铵 0.03g
磷酸二氢钠 7.20g
磷酸氢二钠 0.95g
氯化钠 4.79g
乙二胺四乙酸二钠 0.10g
玻璃酸钠 0.10g
注射用水 定容至1000mL
制备工艺：
1、精密称取0.10g玻璃酸钠，加200mL注射用水，溶胀、放置、过夜，并于每1h进行搅拌5min。
2、精密称取1.00g咪唑立宾、0.03g苯扎氯铵、7.20g磷酸二氢钠、0.95g磷酸氢二钠、4.79g氯化钠、0.10g乙二胺四乙酸二钠，加200mL注射用水溶解，将其进行搅拌，混合均匀后，加入步骤1所得玻璃酸钠溶液，搅拌混合，然后用注射用水定容至1000mL，得药液。
3、将上述药液经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤2次。
4、药液检验合格后，在A级环境下，灌装5.0mL上述药液至5mL单剂量包装塑料容器中，封口，即得成品。
实施例7
配方：
咪唑立宾 1.00g
苯扎氯铵 0.03g
磷酸二氢钠 6.40g
磷酸氢二钠 1.90g
氯化钠 4.70g
乙二胺四乙酸二钠 0.10g
玻璃酸钠 0.10g
注射用水 定容至1000mL
制备工艺：
1、精密称取0.10g玻璃酸钠，加入200mL注射用水，放置溶胀12h，并每1h搅拌5min。
2、精密称取0.03g苯扎氯铵和0.10g乙二胺四乙酸二钠，加入300mL注射用水，搅拌溶解均匀，然后精密称取6.40g磷酸二氢钠、1.90g磷酸氢二钠和氯化钠4.70g加入到上述所得溶液中，搅拌均匀。
3、精密称取1.00g咪唑立宾，加入到步骤2所得混合溶液中，溶解过程可适当加热，搅拌溶解，若加热需冷却至室温。
4、将步骤3所得溶液加入到步骤1所得已溶解的玻璃酸钠溶液中，搅拌混合均匀，然后用注射用水定容至1000mL，得药液。
5、将药液经0.45μm微孔滤膜过滤一次，再经0.22μm微孔滤膜过滤两次。
6、药液检验合格后，在A级环境下，灌装药液5.0mL至5mL已灭菌单剂量包装塑料瓶中，封口，即得成品。
实施例8
配方：
咪唑立宾 1.00g
苯扎溴铵 5.00g
磷酸二氢钠 6.40g
磷酸氢二钠 1.90g
氯化钠 4.70g
亚硫酸钠 5.00g
玻璃酸钠 0.10g
注射用水 定容至1000mL
制备工艺：
1、精密称取0.10g玻璃酸钠，加入200mL注射用水，放置溶胀12h，并每1h搅拌5min。
2、精密称取5.00g苯扎溴铵和5.00g亚硫酸钠，加入500mL注射用水，搅拌溶解均匀，然后精密称取6.40g磷酸二氢钠、1.90g磷酸氢二钠和氯化钠4.70g加入到上述所得溶液中，搅拌均匀。
3、精密称取1.00g咪唑立宾，加入到步骤2所得混合溶液中，溶解过程可适当加热，搅拌溶解，若加热需冷却至室温。
4、将步骤3所得溶液加入到步骤1所得已溶解的玻璃酸钠溶液中，搅拌混合均匀，然后用注射用水定容至1000mL，得药液。
5、将药液经0.45μm微孔滤膜过滤1次，再经0.22μm微孔滤膜过滤2次。
6、药液检验合格后，在A级环境下，灌装药液5.0mL至5mL已灭菌单剂量包装塑料瓶中，封口，即得成品。
实施例9
配方：
咪唑立宾 1.00g
苯扎氯铵 0.03g
磷酸二氢钠 6.40g
磷酸氢二钠 1.90g
氯化钠 4.70g
乙二胺四乙酸二钠 0.10g
玻璃酸钠 0.10g
聚山梨酯80 30mL
注射用水 定容至1000mL
制备工艺：
1、精密称取0.10g玻璃酸钠，加入200mL注射用水，放置溶胀12h，并每1h搅拌5min。
2、精密称取6.40g磷酸二氢钠、1.90g磷酸氢二钠加入300mL注射用水中，搅拌均匀。
3、精密称取1.00g咪唑立宾和氯化钠4.70g置乳钵中研细，加入30mL聚山梨酯80充分研匀。将精密称取的0.03g苯扎氯铵和0.10g乙二胺四乙酸二钠溶于300mL注射用水中，加热搅拌，保持水温70～80℃，再把乳钵中的咪唑立宾等完全转入到上述水溶液中，边加边充分搅拌，再加注射用水300mL，待冷却至室温后应澄清。
4、将步骤2所得溶液滴加到步骤2所得溶液中，再缓慢加入已溶解的玻璃酸钠溶液，搅拌混合均匀，然后用注射用水定容至1000mL，得药液。
5、将药液经0.45μm微孔滤膜过滤一次，再经0.22μm微孔滤膜过滤两次。
6、在A级生产环境下，灌装药液5.0mL至5mL已灭菌单剂量包装塑料瓶中，封口，即得滴眼液成品。
以上实施例中处方均以1000mL为例，实际工业生产中可参考处方比例相应增加配制量。
实施例10眼部疗效评价
0.1％咪唑立宾滴眼液对干眼小鼠的治疗作用
实验方法：
1建立小鼠干眼模型：10-12周龄的雌性C57BL/6小鼠皮下注射东莨菪碱0.5mg/0.2mL，每天4次，并饲养于干燥环境内5天(RH＝30±3；T＝23-25℃)；正常对照组饲养于正常环境中(RH：60％-80％；T：23-25℃)。
2咪唑立宾滴眼液制备：干眼治疗组采用实施例1的操作方法制备0.1％咪唑立宾滴眼液。
点眼方式：使用上述滴眼液进行点眼治疗，每天4次，点双眼。
评价指标与操作方法：
1角膜OGD荧光染色：处死小鼠，用移液枪将0.5μl Oregongreen-dextran(OGD)滴入小鼠下结膜囊内，手动瞬目，1分钟后用1mL生理盐水冲洗结膜囊，活体荧光显微镜下观察并拍摄角膜上皮荧光染色情况。
2结膜杯状细胞PAS染色：小鼠全眼球(含结膜囊)石蜡标本切成5um薄片，利用过碘酸-希夫(PAS)试剂染色，观察结膜杯状细胞形态和数量。
3结膜CD4 +T细胞染色：冰冻切片用丙酮在-20℃下固定10分钟，0.2％Triton-X的PBS破膜10分钟，0.3％H 2O 2消除内源性过氧化物酶。用20％正常的山羊血清阻滞45 分钟。一抗CD4常温下孵育1小时。在充分洗(涤)后，用生物素(酰)化的第二抗体孵育30分钟。最后应用Vectastain Elite ABC试剂盒显色并染核。
4 Real-Time PCR：
按下列组分配制PCR反应液：
DEPC+结膜RNA 12
40u RNA酶抑制剂(可不加) 0.5
5×Reaction Buffer 4
10mM dNTPs 2
Random Primer 1
RT酶 1
Total 20
三步法PCR扩增标准程序：
Stage 1：预变性循环数：195℃，30sec.
Stage 2：PCR反应循环数：4095℃，5sec.60℃，34sec.
Stage 3：溶解曲线
运用相对Ct法分析基因的相对表达量，具体采用以下公式计算得出，即目标基因相对表达量＝2 -ΔΔCt；其中，-ΔΔCt＝-(ΔCt，q-ΔCt，cb)，ΔCt，q＝Ct，x-Ct，r，ΔCt，cb＝Ct，cb-Ct，r，这里的r＝参照基因，Cb＝校准值，X＝目标基因；循环阈值(C)通过初级信号(荧光)来确定。
实验结果与结论：
1 角膜OGD荧光染色结果显示，与干眼组相比，0.1％咪唑立宾治疗组角膜点状染色数量明显减少，未见片状染色。结果说明：0.1％咪唑立宾局部点眼治疗可显著减轻角膜上皮损伤，具有保护角膜上皮屏障的效果。(如图1所示)
2 结膜杯状细胞PAS染色结果显示，与干眼组相比，0.1％咪唑立宾治疗组结膜杯状细胞数量显著增加。结果说明：0.1％咪唑立宾局部点眼治疗可显著恢复杯状细胞数量，保证黏蛋白分泌量。(如图2所示)
3 结膜CD4 +T细胞染色结果显示，与干眼组相比，0.1％咪唑立宾治疗组棕黄色细 胞比例明显减少。对两组的CD4 +T细胞数进行统计学分析显示，其差异具有统计学意义。结果说明：0.1％咪唑立宾局部点眼治疗可显著减轻结膜CD4 +T细胞浸润，具有明显的抗炎效果。(如图3所示)
4 Real-Time PCR结果显示，与干眼组相比，0.1％咪唑立宾治疗组结膜炎症因子TNF-α、IL-1β、IFN-γ和IL-13表达明显减少，差异具有统计学意义。结果说明：0.1％咪唑立宾局部点眼治疗具有较好的抗炎及免疫抑制作用。(如图4所示)
以上所述，仅为本发明的较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。

Claims (7)

  1. 一种用于治疗干眼的滴眼液，其特征在于：pH为5.0～7.0，其有效成分为5-羟基-1-beta-D-呋喃糖基-1H-咪唑-5-羧酰胺，包括有如下组份及重量百分比：
    5-羟基-1-beta-D-呋喃糖基-1H-咪唑-5-羧酰胺0.05～0.1％
    pH值调节剂适量
    等渗剂0.01～3％
    抑菌剂0.003～0.5％
    稳定剂0.001～0.5％
    增粘剂0.01～0.5％
    增溶剂2～5％
    余量为水。
  2. 如权利要求1所述的滴眼液，其特征在于：所述pH值调节剂为磷酸二氢钠、磷酸氢二钠、磷酸二氢钾、磷酸氢二钾、硼酸、硼砂、醋酸、醋酸钠、柠檬酸、柠檬酸钠、酒石酸、酒石酸钠、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、氢氧化钠、氢氧化钾、盐酸和磷酸中的至少一种。
  3. 如权利要求1所述的滴眼液，其特征在于：所述等渗剂为氯化钠、氯化钾、硼酸、硼砂、硫酸钠、硫酸钾、硝酸钠、硝酸钾、醋酸钠、甘露醇、甘油、丙二醇或葡萄糖中的至少一种。
  4. 如权利要求1所述的滴眼液，其特征在于：所述抑菌剂为苯扎氯铵、苯扎溴铵、醋酸氯己定、葡萄糖氯己定、三氯叔丁醇、苯氧乙醇、羟苯甲酯、羟苯乙酯和羟苯丙酯中的至少一种。
  5. 如权利要求1所述的滴眼液，其特征在于：所述稳定剂为亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、亚硝酸钠、硫代硫酸钠、抗坏血酸、硫脲、抗坏血酸硬脂酸酯、二丁基甲酚、半胱氨酸、生育酚乙酸酯、二氯异氰、乙二胺四乙酸二钠、乙二胺四乙酸钙钠、二巯基丙醇、甘油、甘露醇和丁基化羟基苯甲醚中的至少一种。
  6. 如权利要求1所述的滴眼液，其特征在于：所述增粘剂为玻璃酸钠、羧甲基纤维素钠、甲级纤维素、聚乙二醇、聚乙烯醇、卡波姆和聚维酮中的至少一种。
  7. 如权利要求1所述的滴眼液，其特征在于：所述增溶剂为聚山梨酯类、聚氧乙烯蓖麻油甘油醚、聚氧乙烯脂肪酸酯类、聚氧乙烯脂肪醇醚类和泊洛沙姆中的至少一种。
PCT/CN2018/086240 2017-05-11 2018-05-10 一种用于治疗干眼的滴眼液 WO2018205961A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US16/623,320 US20200171066A1 (en) 2017-05-11 2018-05-10 Eye drop for treating dry eye
ES18798346T ES2899597T3 (es) 2017-05-11 2018-05-10 Colirio para tratar el ojo seco
EP18798346.5A EP3636252B1 (en) 2017-05-11 2018-05-10 Eye drop for treating eye dryness

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710331802.4 2017-05-11
CN201710331802.4A CN107049938B (zh) 2017-05-11 2017-05-11 一种用于治疗干眼的滴眼液

Publications (1)

Publication Number Publication Date
WO2018205961A1 true WO2018205961A1 (zh) 2018-11-15

Family

ID=59596191

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/086240 WO2018205961A1 (zh) 2017-05-11 2018-05-10 一种用于治疗干眼的滴眼液

Country Status (5)

Country Link
US (1) US20200171066A1 (zh)
EP (1) EP3636252B1 (zh)
CN (1) CN107049938B (zh)
ES (1) ES2899597T3 (zh)
WO (1) WO2018205961A1 (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107049938B (zh) * 2017-05-11 2021-01-05 艾迈德(厦门)生物科技有限公司 一种用于治疗干眼的滴眼液
CN112516080B (zh) * 2018-01-23 2023-09-19 盛元医药广州有限公司 一种眼用药物组合物及其制备方法和应用
CN109568486B (zh) * 2018-12-06 2021-06-01 中山大学中山眼科中心 一种具有治疗结膜炎功效的组合物及其制备方法
CN109864993B (zh) * 2019-03-08 2021-02-19 中国农业科学院兰州兽医研究所 一种咪唑立宾在制备预防口蹄疫病毒感染的药物中的应用
CN112220749B (zh) * 2020-10-28 2022-11-29 厦门上佳源生物科技有限公司 咪唑立宾以及包含咪唑立宾的组合物的用途
CN115089548B (zh) * 2022-07-19 2023-08-08 河南省人民医院 一种无菌他克莫司溶液型滴眼液及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07215881A (ja) * 1994-02-03 1995-08-15 Asahi Chem Ind Co Ltd シェーグレン症候群治療剤
CN101528217A (zh) * 2006-10-18 2009-09-09 博士伦公司 包含二甘氨酸的眼用组合物
CN107049938A (zh) * 2017-05-11 2017-08-18 厦门大学 一种用于治疗干眼的滴眼液

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103110575B (zh) * 2013-03-07 2014-11-05 宁夏康亚药业有限公司 一种美洛昔康滴眼液及其制备方法和应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07215881A (ja) * 1994-02-03 1995-08-15 Asahi Chem Ind Co Ltd シェーグレン症候群治療剤
CN101528217A (zh) * 2006-10-18 2009-09-09 博士伦公司 包含二甘氨酸的眼用组合物
CN107049938A (zh) * 2017-05-11 2017-08-18 厦门大学 一种用于治疗干眼的滴眼液

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3636252A4 *
XIAOBO ZHANG ET AL.: "Topical Application of Mizoribine Suppresses CD4+ T- cell - Mediated Pathogenesis in Murine Dry Eye", INVEST OPHTHALMOL VIS SCI., vol. 58, no. 14, 31 December 2017 (2017-12-31), pages 6056 - 6064, XP055612188, ISSN: 1552-5783 *

Also Published As

Publication number Publication date
ES2899597T3 (es) 2022-03-14
CN107049938A (zh) 2017-08-18
EP3636252A4 (en) 2021-01-06
EP3636252A1 (en) 2020-04-15
EP3636252B1 (en) 2021-11-03
CN107049938B (zh) 2021-01-05
US20200171066A1 (en) 2020-06-04

Similar Documents

Publication Publication Date Title
WO2018205961A1 (zh) 一种用于治疗干眼的滴眼液
EP1744759B1 (en) Use of loteprednol etabonate for the treatment of dry eye
US20110294897A1 (en) Treating Xerophthalmia With Compounds Increasing Meibomian Gland Secretion
US11413323B2 (en) Ophthalmic composition for treatment of dry eye disease
JP7465453B2 (ja) ４－（７－ヒドロキシ－２－イソプロピル－４－オキソ－４ｈ－キナゾリン－３－イル）－ベンゾニトリルの製剤
Chen et al. Hydrogel eye drops as a non-invasive drug carrier for topical enhanced Adalimumab permeation and highly efficient uveitis treatment
WO2023024126A1 (zh) 一种含伏立康唑的眼用凝胶剂及其制备方法与应用
CN102085175B (zh) 一种眼用凝胶剂及其制备方法
CN102512467A (zh) 一种三七总皂苷的眼用制剂及其制备方法
CN102008488A (zh) 一种曲安奈德眼用制剂及其制备方法
MX2012006081A (es) Metodo para determinar selectivamente un agente que es util para el tratamiento de ojo seco y/o lesion de la cornea y la conjuntiva y una composicion farmceutica obtenida por el metodo.
CN105963319A (zh) 一种饱和氢气盐水洗液及其制备方法和应用
CN112220749B (zh) 咪唑立宾以及包含咪唑立宾的组合物的用途
CN113318121B (zh) 一种用于治疗糖尿病性视网膜病变的药物及其制备方法
CN107854470A (zh) 阿卡他定组合物、其制备方法和用途
US20230158045A1 (en) Pharmaceutical compositions of mycophenolic acid and/or betamethasone for the treatment of ocular disorders
CN102018656A (zh) 含有效成分拉坦前列素的眼用凝胶剂及其制备方法
CN114524951A (zh) 一种聚多巴胺药物递送载体及其应用
WO2023098537A1 (zh) 丙谷二肽的新用途和包含丙谷二肽的眼用组合物
TW202202168A (zh) 用於改善玻璃體混濁的組成物及其應用
JP2024095674A (ja) ４－（７－ヒドロキシ－２－イソプロピル－４－オキソ－４ｈ－キナゾリン－３－イル）－ベンゾニトリルの製剤
CN116474105A (zh) 一种预防、缓解或治疗眼部疾病的药物组合物、制备方法及其应用
JP2011219412A (ja) 緑内障の視野改善治療薬
Sunder et al. will, T.(Department of Ophthalmology, University of Louisville, School of Medi-cine, Louisville, KY.). Invest. Ophth. 12: 45-51, 1973.
JP2016222563A (ja) 網膜色素変性処置用眼科用組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18798346

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018798346

Country of ref document: EP

Effective date: 20191211