CN104491876A - Sodium hyaluronate-containing epinastine eye drops and preparation method thereof - Google Patents
Sodium hyaluronate-containing epinastine eye drops and preparation method thereof Download PDFInfo
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- 239000003889 eye drop Substances 0.000 title claims abstract description 39
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 title claims abstract description 14
- 229940012356 eye drops Drugs 0.000 title abstract description 24
- 229920002385 Sodium hyaluronate Polymers 0.000 title abstract description 12
- 229940010747 sodium hyaluronate Drugs 0.000 title abstract description 12
- 229960003449 epinastine Drugs 0.000 title 1
- 229960002548 epinastine hydrochloride Drugs 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000008215 water for injection Substances 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000337 buffer salt Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
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- 230000002421 anti-septic effect Effects 0.000 claims 2
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- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
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- 239000003814 drug Substances 0.000 abstract description 15
- 208000002205 allergic conjunctivitis Diseases 0.000 description 12
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229960001631 carbomer Drugs 0.000 description 3
- 239000002562 thickening agent Substances 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010052140 Eye pruritus Diseases 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
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- 229940112573 elestat Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
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- 230000014759 maintenance of location Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
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- 230000002335 preservative effect Effects 0.000 description 2
- 230000001932 seasonal effect Effects 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010018258 Giant papillary conjunctivitis Diseases 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 206010069664 atopic keratoconjunctivitis Diseases 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
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- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
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- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
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- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种含玻璃酸钠的盐酸依匹斯汀滴眼液及其制备方法。该滴眼液中，盐酸依匹斯汀的含量为0.05-0.5％，玻璃酸钠的含量为0.01-0.5％，pH值控制在4.0-7.5。本发明选用玻璃酸钠可延长药物在眼部的滞留时间，并提高生物利用度。The invention relates to an epinastine hydrochloride eye drop containing sodium hyaluronate and a preparation method thereof. In the eye drops, the content of epinastine hydrochloride is 0.05-0.5%, the content of sodium hyaluronate is 0.01-0.5%, and the pH value is controlled at 4.0-7.5. The sodium hyaluronate selected in the present invention can prolong the residence time of the medicine in the eyes and improve the bioavailability.
Description
技术领域technical field
本发明涉及一种含玻璃酸钠的盐酸依匹斯汀滴眼液及其制备方法The invention relates to an epinastine hydrochloride eye drop containing sodium hyaluronate and a preparation method thereof
背景技术Background technique
过敏性结膜炎是一类常见的眼表过敏性疾病，其主要是由I型及IV型变态反应引起。该病最主要的症状是眼痒，常伴有结膜充血、水肿和乳头、滤泡增生等体征。根据临床表现、病程及预后差异，过敏性结膜炎可分为5种类型：季节性过敏性结膜炎、常年性过敏性结膜炎、春季角结膜炎、巨乳头性结膜炎和特应性角结膜炎。其患病率约为总人口的20％，我国过敏性结膜炎好发于中青年，以常年性过敏性结膜炎和季节性过敏性结膜炎为主要类型。临床上用于过敏性结膜炎的常用药物有：(1)抗组胺类；(2)肥大细胞稳定剂；(3)双效药物；(4)非甾体抗炎药；(5)糖皮质激素类；(6)免疫抑制剂。Allergic conjunctivitis is a common ocular surface allergic disease, which is mainly caused by type I and type IV allergies. The main symptom of the disease is eye itching, often accompanied by conjunctival hyperemia, edema, nipple, follicular hyperplasia and other signs. Allergic conjunctivitis can be divided into 5 types according to clinical manifestations, course of disease and prognosis: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis and atopic keratoconjunctivitis inflammation. Its prevalence rate is about 20% of the total population. In my country, allergic conjunctivitis occurs in young and middle-aged people, with perennial allergic conjunctivitis and seasonal allergic conjunctivitis as the main types. Commonly used drugs clinically for allergic conjunctivitis include: (1) antihistamines; (2) mast cell stabilizers; (3) dual-effect drugs; (4) non-steroidal anti-inflammatory drugs; Corticosteroids; (6) Immunosuppressants.
盐酸依匹斯汀(Epinastine hydrochloride)为第二代抗组胺药，具有选择性抑制外周H1受体的作用，无中枢镇静作用和抗胆碱作用。临床多用于治疗过敏性鼻炎、湿疹、荨麻疹、皮炎、皮肤瘙痒症、银屑病、过敏性支气管哮喘等。其临床疗效和副作用方面要优于苯海拉明、非那根、扑尔敏、西替利嗪等其他抗过敏药物。盐酸依匹斯汀用于过敏性结膜炎，在改善眼痒和结膜充血方面疗效甚好，且不会增加眼表损害和干眼症的危险。Epinastine hydrochloride is a second-generation antihistamine that selectively inhibits peripheral H1 receptors without central sedative and anticholinergic effects. It is mostly used clinically to treat allergic rhinitis, eczema, urticaria, dermatitis, pruritus, psoriasis, allergic bronchial asthma, etc. Its clinical efficacy and side effects are superior to other antiallergic drugs such as diphenhydramine, phenergan, chlorpheniramine, and cetirizine. Epinastine hydrochloride is used for allergic conjunctivitis, and it is very effective in improving ocular itching and conjunctival hyperemia without increasing the risk of ocular surface damage and dry eye syndrome.
盐酸依匹斯汀滴眼液(商品名：Elestat)由美国Allergan公司研制开发，于2004年在国外上市，用于治疗过敏性结膜炎。但是该滴眼液用药后由于受泪液稀释、鼻泪管排泄等导致药液外溢流失，眼部的生物利用度较低，作用的时间也极为短暂。为了延长滴眼液的作用时间，提高生物利用度，改善治疗效果，可在普通的滴眼液制剂处方中加入增粘剂，增加滴眼液的黏度，延长药物在眼部的滞留时间，从而提高药物的生物利用度。制剂中常用的增粘剂有例如卡波姆、泊洛沙姆、羟丙甲纤维等。但是在这些辅料中：卡波姆凝胶遇盐类电解质黏度会下降，且卡波姆可造成视力模糊；泊洛沙姆对温度敏感而不稳定；羟丙甲纤维素等合成高分子聚合物，其溶液属于牛顿流体，眨眼时有疼痛感。因此，以上这些增粘剂大多不适于配制滴眼液。Epinastine Hydrochloride Eye Drops (trade name: Elestat) was developed by Allergan Corporation of the United States and was launched abroad in 2004 for the treatment of allergic conjunctivitis. However, the eye drops have low bioavailability and a very short duration of action due to lacrimal dilution and nasolacrimal duct drainage. In order to prolong the action time of eye drops, increase the bioavailability and improve the therapeutic effect, a thickener can be added to the prescription of ordinary eye drops to increase the viscosity of the eye drops and prolong the residence time of the drug in the eyes, thereby Improve the bioavailability of drugs. Viscosifiers commonly used in formulations include, for example, carbomer, poloxamer, hypromellose, and the like. However, among these excipients: the viscosity of carbomer gel will decrease when it encounters salt electrolytes, and carbomer can cause blurred vision; poloxamer is sensitive to temperature and unstable; synthetic polymers such as hypromellose , its solution belongs to Newtonian fluid, and there is pain when blinking. Therefore, most of these thickeners are not suitable for the preparation of eye drops.
综上所述，本领域迫切需要开发一种可以延缓药液外溢流失，延长药物滞留时间的盐酸依匹斯汀滴眼液。In summary, there is an urgent need in this field to develop an epinastine hydrochloride eye drop that can delay the spillage of the drug solution and prolong the retention time of the drug.
发明内容Contents of the invention
针对上述问题，申请人做了大量的研究，最终发现在盐酸依匹斯汀滴眼液中加入玻璃酸钠可解决上述问题。玻璃酸又称透明质酸，是一种广泛存在于机体各组织中的粘多糖，具有良好的生物相容性、增粘作用、生物粘附以及铺展润湿能力。此外，玻璃酸钠与盐酸依匹斯汀带有相反电荷，可形成离子对从而促进药物在眼部的滞留。In response to the above problems, the applicant has done a lot of research and finally found that adding sodium hyaluronate to epinastine hydrochloride eye drops can solve the above problems. Hyaluronic acid, also known as hyaluronic acid, is a mucopolysaccharide widely present in various tissues of the body. It has good biocompatibility, thickening effect, bioadhesion, and spreading and wetting capabilities. In addition, sodium hyaluronate and epinastine hydrochloride have opposite charges, which can form ion pairs to promote drug retention in the eye.
本发明的目的是提供一种含有玻璃酸钠的盐酸依匹斯汀滴眼液，它能增加滴眼液的黏度，延长药物在眼部的滞留时间，从而提高药物在眼部的生物利用度。The object of the present invention is to provide a kind of epinastine hydrochloride eye drop containing sodium hyaluronate, it can increase the viscosity of eye drop, prolong the residence time of medicine in eye, thereby improve the bioavailability of medicine in eye .
本发明所述滴眼液由药物活性成分、增粘剂、抗氧剂、等渗调节剂、pH调节剂、缓冲盐、防腐剂及注射用水组成。The eye drop of the invention is composed of pharmaceutical active ingredients, thickening agent, antioxidant, isotonic regulator, pH regulator, buffer salt, preservative and water for injection.
本发明所述滴眼液中各组分重量百分含量为：In the eye drops of the present invention, the weight percentages of each component are:
本发明所述玻璃酸钠的相对分子质量Mr＝10万-400万。The relative molecular mass of the sodium hyaluronate in the present invention is Mr=100,000-4,000,000.
本发明所述缓冲盐为醋酸-醋酸钠缓冲液或柠檬酸-柠檬酸钠缓冲液。The buffer salt of the present invention is acetic acid-sodium acetate buffer or citric acid-sodium citrate buffer.
本发明所述等渗调节剂为氯化钠和葡萄糖中的一种或几种。The isotonic regulator of the present invention is one or more of sodium chloride and glucose.
本发明所述适量的pH调节剂使滴眼液pH至4.0-7.5。The appropriate amount of pH regulator in the present invention makes the pH of the eye drops to 4.0-7.5.
本发明所述防腐剂选自苯扎氯铵、苯扎溴铵、羟苯甲酯、羟苯乙酯或羟苯丙酯中的一种或几种。The preservative in the present invention is selected from one or more of benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben or propylparaben.
本发明所述pH调节剂选自氢氧化钠和盐酸中的一种或几种。The pH regulator in the present invention is selected from one or more of sodium hydroxide and hydrochloric acid.
本发明所述滴眼液的制备方法，步骤包括：在注射用水中加入盐酸依匹斯汀、缓冲盐、等渗调节剂、EDTA-2Na溶解后，再加入溶胀完全的玻璃酸钠溶液，搅拌均匀后加入pH调节剂，过滤灌装。The preparation method of eye drops of the present invention, the step comprises: after adding epinastine hydrochloride, buffer salt, isotonic regulator, EDTA-2Na in water for injection to dissolve, then add the fully swellable sodium hyaluronate solution, stir After uniformity, add a pH regulator, filter and fill.
本发明所述滴眼液的用法用量：每侧一次1滴，一日2次。The usage and dosage of the eye drops of the present invention: 1 drop on each side, 2 times a day.
本发明所述滴眼液的特点在于：黏度增加可防止药液外溢流失，使药物长时间滞留病灶区，从而提高药物的生物利用度。The eye drops of the present invention are characterized in that the increase in viscosity can prevent the spillage and loss of the liquid medicine, so that the medicine stays in the lesion area for a long time, thereby improving the bioavailability of the medicine.
具体实施方式Detailed ways
下文将结合实例对本发明做详细说明，但这些具体例并不用于限定本发明。The present invention will be described in detail below in conjunction with examples, but these specific examples are not intended to limit the present invention.
实施例1盐酸依匹斯汀滴眼液的制备The preparation of embodiment 1 epinastine hydrochloride eye drops
100mL注射用水中包含：100mL water for injection contains:
制备方法：在注射用水中加入盐酸依匹斯汀、磷酸二氢钠、氯化钠、乙二胺四乙酸二钠、苯扎氯铵溶解后，再加入溶胀完全的玻璃酸钠溶液，搅拌均匀后加入酸或碱调节pH至7.0，过滤灌装。Preparation method: Add epinastine hydrochloride, sodium dihydrogen phosphate, sodium chloride, edetate disodium, and benzalkonium chloride into water for injection to dissolve, then add fully swollen sodium hyaluronate solution, and stir evenly Then add acid or alkali to adjust the pH to 7.0, filter and fill.
实施例2盐酸依匹斯汀滴眼液的制备The preparation of embodiment 2 epinastine hydrochloride eye drops
100mL注射用水中包含：100mL water for injection contains:
制备方法：同实施例1的制备方法Preparation method: with the preparation method of embodiment 1
实施例3盐酸依匹斯汀滴眼液的制备The preparation of embodiment 3 epinastine hydrochloride eye drops
100mL注射用水中包含：100mL water for injection contains:
制备方法：同实施例1的制备方法Preparation method: with the preparation method of embodiment 1
实施例4盐酸依匹斯汀滴眼液黏度的测定The mensuration of the viscosity of embodiment 4 epinastine hydrochloride eye drops
分别测定实施例1、实施例2和实施例3滴眼液的黏度。结果如表1所示：Measure the viscosity of embodiment 1, embodiment 2 and embodiment 3 eye drops respectively. The results are shown in Table 1:
表1盐酸依匹斯汀滴眼液的黏度The viscosity of table 1 epinastine hydrochloride eye drops
实施例5兔眼泪液药物动力学实验Embodiment 5 Rabbit tears pharmacokinetic experiment
样品：sample:
1)对照组：盐酸依匹斯汀滴眼液上市制剂(商品名：Elestat)；试验组：实施例1、实施例2、实施例31) Control group: epinastine hydrochloride eye drops listed preparation (trade name: Elestat); test group: embodiment 1, embodiment 2, embodiment 3
2)实验方法：健康新西兰白兔，雌性，体重1.5-2.0kg，随机分为4组，每组3只。分别在兔眼结膜囊内滴加滴眼液50μL。滴眼后于15、30、60、90、120、180、240、360min将毛细管置于眼睑内，吸取泪液10μL，置于塑料离心管中，加入90μL甲醇涡旋2min，10000rpm离心10min，取上清液20μ1进样HPLC分析，计算盐酸依匹斯汀的泪液浓度。统计矩法计算的药动学参数药时曲线下面积(AUC)以及平均滞留时间(MRT)，数据如表2所示：2) Experimental method: Healthy New Zealand white rabbits, female, weighing 1.5-2.0 kg, were randomly divided into 4 groups, with 3 rabbits in each group. Add 50 μL of eye drops to the conjunctival sac of the rabbits. Put the capillary in the eyelid at 15, 30, 60, 90, 120, 180, 240, and 360 minutes after eye drops, absorb 10 μL of tear fluid, put it in a plastic centrifuge tube, add 90 μL of methanol to vortex for 2 minutes, centrifuge at 10,000 rpm for 10 minutes, and take the 20 μl of supernatant was injected into HPLC for analysis, and the tear concentration of epinastine hydrochloride was calculated. The pharmacokinetic parameters area under the drug-time curve (AUC) and mean residence time (MRT) calculated by the statistical moment method, the data are shown in Table 2:
表2盐酸依匹斯汀滴眼液在兔泪液中的药动学参数The pharmacokinetic parameters of table 2 epinastine hydrochloride eye drops in rabbit tears
结果显示，所有试验组与对照组相比AUC及MRT均有显著性差异(P＜0.05)，且试验组中实施例1、实施例2、实施例3的AUC分别为对照组AUC的3.2倍、6.1倍、6.4倍。这表明玻璃酸钠的加入可延长药物在泪液中的滞留时间，从而提高药物在眼部的生物利用度。The results showed that all test groups had significant differences in AUC and MRT compared with the control group (P<0.05), and the AUCs of Example 1, Example 2, and Example 3 in the test group were 3.2 times that of the control group's AUC respectively. , 6.1 times, 6.4 times. This shows that the addition of sodium hyaluronate can prolong the residence time of drugs in tears, thereby improving the bioavailability of drugs in the eye.
Claims (8)
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