技术领域technical field
本发明涉及生物医药技术领域，具体涉及一种治疗干眼和/或角膜和结膜损伤，特别是根据DEWS Report(2007)干眼严重度为3以上的干眼和/或角膜和结膜损伤的药物组合物。The invention relates to the technical field of biomedicine, in particular to a drug for treating dry eye and/or corneal and conjunctival damage, especially dry eye and/or corneal and conjunctival damage according to DEWS Report (2007) dry eye severity of 3 or more combination.
背景技术Background technique
干眼症，又称为干性角膜结膜炎，是泪液和眼表面的一种多因素疾病，该疾病导致的症状有不适、视觉障碍、以及具有对眼表面潜在损害的泪膜不稳定，并伴随有泪膜的渗透性增加以及眼表面的炎症。干眼症被认为是一种泪腺功能单位的障碍，一个泪腺功能单位的完整系统包括：泪腺、眼表面(角膜、结膜、以及睑板腺)、以及眼睑、以及连接它们的感觉和运动神经。这种泪腺功能单位以一种调节的方式控制该泪膜的主要成分并且对环境、内分泌学的、以及皮质的影响做出应答。该单位的功能是保持泪膜的完整性、角膜的透明性、以及投影到视网膜上映像的质量。对泪腺功能单位的任何部分(传入感觉神经、传出自主神经以及运动神经、以及泪液分泌腺)的疾病或损害可以使泪膜不稳定并且导致其本身表现为干眼症的眼表面疾病。Dry eye syndrome, also known as keratoconjunctivitis sicca, is a multifactorial disorder of the tear fluid and ocular surface that causes symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface, and This is accompanied by increased permeability of the tear film and inflammation of the ocular surface. Dry eye is considered a disorder of the lacrimal functional unit, a complete system of the lacrimal gland, ocular surface (cornea, conjunctiva, and meibomian glands), and eyelids, and the sensory and motor nerves connecting them. The lacrimal functional unit controls the major components of the tear film and responds to environmental, endocrinological, and cortical influences in a regulated manner. The function of this unit is to maintain the integrity of the tear film, the transparency of the cornea, and the quality of the image projected onto the retina. Disease or damage to any part of the functional unit of the lacrimal gland (the afferent sensory, efferent autonomic and motor nerves, and the lacrimal gland) can destabilize the tear film and lead to ocular surface disease that manifests itself as dry eye.
根据DEWS Report(2007)(参见“The Definition and Classification of DryEye Disease”(p75 92))，对干眼严重度分为4个水平。对于干眼严重度1和2，存在不少推荐治疗药物。对于干眼严重度3以上、特别是例如角膜和结膜等眼表面损伤，可采用自体血清、糖皮质激素等进行治疗，但糖皮质激素长期使用可能引起眼压升高、白内障等，只限于短期应用来控制干眼的重度发作。According to DEWS Report (2007) (see "The Definition and Classification of DryEye Disease" (p75 92)), the severity of dry eye is divided into 4 levels. For dry eye severity 1 and 2, there are a number of recommended treatments. For dry eye severity 3 and above, especially ocular surface damage such as cornea and conjunctiva, autologous serum and glucocorticoids can be used for treatment, but long-term use of glucocorticoids may cause increased intraocular pressure, cataracts, etc., and it is limited to short-term Used to control severe attacks of dry eye.
神经生长因子(Nerve growth factor，NGF)是20世纪50年代初由Levi-Montalcini在小鼠肉瘤细胞内发现的第一个神经营养因子，是一类由神经元、神经支配的靶组织或胶质细胞产生的能促进中枢和外周神经分化、生长和存活的活性蛋白质。近年来，国内外许多体内及体外的实验研究表明NGF在治疗视觉系统的一些疾病如视网膜色素变性、视神经炎、视挫伤、青光眼等所引起的视神经萎缩以及缺血性视神经病变、视网膜脱离术后视功能差等有较好的疗效。如专利文献US2012102591公开了一种色素性视网膜病的治疗方法，包括在受试者的眼表局部施用含有NGF的制剂使视网膜神经节细胞中NGF的含量上升的步骤；专利文献CN201210008398.4公开了一种神经生长因子眼用凝胶，用于修复眼部神经损伤。但还未见NGF与其他已知的干眼症治疗方法和/或治疗剂(如人工泪液、糖皮质激素、免疫抑制剂、泪腺刺激剂(如雄激素泪液)、自体血清、性激素、中药等，特别是糖皮质激素)组合应用于干眼特别是中重度干眼的治疗的报道。Nerve growth factor (NGF) is the first neurotrophic factor discovered by Levi-Montalcini in mouse sarcoma cells in the early 1950s. It is a kind of target tissue or glia innervated by neurons and nerves. Active protein produced by cells that promotes differentiation, growth, and survival of central and peripheral nerves. In recent years, many in vivo and in vitro experimental studies at home and abroad have shown that NGF is effective in treating some diseases of the visual system such as retinitis pigmentosa, optic neuritis, optic contusion, glaucoma, etc. Poor visual function has better curative effect. For example, patent document US2012102591 discloses a treatment method for pigmentary retinopathy, including the step of locally administering a preparation containing NGF to the ocular surface of a subject to increase the content of NGF in retinal ganglion cells; patent document CN201210008398.4 discloses A nerve growth factor ophthalmic gel used to repair eye nerve damage. However, NGF has not been combined with other known dry eye treatments and/or therapeutic agents (such as artificial tears, glucocorticoids, immunosuppressants, lacrimal gland stimulators (such as androgen tears), autologous serum, sex hormones, traditional Chinese medicine, etc. , especially glucocorticoid) combination is applied to the treatment of dry eye, especially moderate to severe dry eye.
发明内容Contents of the invention
本发明提供了一种用于治疗和/或预防干眼症，特别是中重度干眼的药物组合物，所述的药物组合物包括NGF和糖皮质激素。The present invention provides a pharmaceutical composition for treating and/or preventing dry eye, especially moderate-to-severe dry eye. The pharmaceutical composition includes NGF and glucocorticoid.
优选的，所述的NGF为鼠源NGF或人源NGF，更优选为人源NGF；Preferably, the NGF is mouse NGF or human NGF, more preferably human NGF;
在本发明具体的优选实施例中，所述NGF为人重组NGF。In a specific preferred embodiment of the present invention, the NGF is human recombinant NGF.
优选的，所述的糖皮质激素选自：阿氯米松、倍氯米松、倍他米松、布地奈德、环索奈德、氯倍他索、氯可托龙、去氧可的松、皮质醇、可的伐唑、地夫可特、地泼罗酮、地奈德、地塞米松、二氟泼尼酯、氟氢缩松、氟尼缩松、氟轻松、氟西奈德、氟可龙、氟米龙、氟替卡松、哈西奈德、卤米松、卤泼尼松、氢化可的松、氯替泼诺、甲泼尼松、甲泼尼龙、莫米松、萘非可特、19去甲去氧皮质酮、19去甲孕酮、新霉素、去氟可特、帕拉米松、泼尼卡酯、泼尼松龙、泼尼松、泼尼立定、利美索龙、典必殊、曲安西龙、瑞美松龙和乌倍他索；优选自：地塞米松、倍他米松、泼尼松、泼尼松龙、甲泼尼松和氢化可的松；Preferably, the glucocorticoid is selected from the group consisting of: alclomethasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clocotorone, hexamethasone, corticosteroid Alcohol, Cordizole, Deflazacort, Deprorone, Desonide, Dexamethasone, Difluprednate, Fludrosolone, Flunisolide, Fluocinolone, Fluocinonide, Fluocortol fluorometholone, fluticasone, halcinonide, halometasone, haloprednisone, hydrocortisone, loteprednol, methylprednisone, methylprednisolone, mometasone, nafecort, 19 norprednisone Deoxycorticosterone, 19-norprogesterone, neomycin, defluocort, paramethasone, prednicarbate, prednisolone, prednisone, prednidine, rimexolone, Dianbisu , Triamcinolone, Remethasone and Ubetasol; preferably selected from: Dexamethasone, Betamethasone, Prednisone, Prednisolone, Methylprednisone and Hydrocortisone;
在本发明的一个优选实施例中，所述糖皮质激素为地塞米松；In a preferred embodiment of the present invention, the glucocorticoid is dexamethasone;
优选的，所述的药物组合物中NGF和糖皮质激素的质量比例为1:0.1-100，更优选为1:1-10，进一步优选为1:1-5，如1:1、1:2、1:3、1:4、1:5。Preferably, the mass ratio of NGF and glucocorticoid in the pharmaceutical composition is 1:0.1-100, more preferably 1:1-10, further preferably 1:1-5, such as 1:1, 1:1 2. 1:3, 1:4, 1:5.
在本发明的一个优选实施例中，所述的药物组合物中还包括维生素B；In a preferred embodiment of the present invention, the pharmaceutical composition also includes vitamin B;
优选的，所述的维生素B选自：维生素B1、维生素B2、维生素B6和维生素B12中的一种或多种；更优选的，所述的维生素B为维生素B1；Preferably, the vitamin B is selected from one or more of vitamin B1, vitamin B2, vitamin B6 and vitamin B12; more preferably, the vitamin B is vitamin B1;
优选的，所述的药物组合物中，NGF和维生素B的质量比为10-100:1，更优选为10-50:1，如10:1、20:1、30:1、40:1、50:1。Preferably, in the pharmaceutical composition, the mass ratio of NGF to vitamin B is 10-100:1, more preferably 10-50:1, such as 10:1, 20:1, 30:1, 40:1 , 50:1.
优选的，上述药物组合物可以制备成经局部给药、胃肠道给药或非胃肠道给药的各种制剂；所述的局部给药制剂为经过眼部给药的制剂，如：滴眼剂、注射剂、粉针剂、眼膏剂、乳剂、脂质体、微囊剂、凝胶、植入剂、插入剂、眼用膜剂、包含物滴眼剂及其他可用于眼部给药的剂型；所述的非胃肠道给药制剂为适宜的静脉注射、肌肉注射、皮下注射、骨髓注射、透皮给药、粘膜给药、吸入给药等剂型；Preferably, the above-mentioned pharmaceutical composition can be prepared into various preparations for topical administration, gastrointestinal administration or parenteral administration; the topical administration preparation is a preparation for ophthalmic administration, such as: Eye drops, injections, powder injections, eye ointments, emulsions, liposomes, microcapsules, gels, implants, inserts, ophthalmic films, inclusion eye drops and others can be used for ocular administration The formulation for parenteral administration is suitable for intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosal administration, inhalation administration and other dosage forms;
在本发明的一个优选实施例中，所述的药物组合物为眼部给药的制剂，优选自：滴眼剂、眼膏剂、凝胶、眼用膜剂；In a preferred embodiment of the present invention, the pharmaceutical composition is a preparation for ophthalmic administration, preferably selected from: eye drops, eye ointment, gel, and ophthalmic film;
当用于治疗干眼症的本发明的药物组合物用作一种眼用溶液时，它被提供为任何用于眼用溶液的剂型，例如，一种水性滴眼剂(如水性眼用溶液、水性悬浮眼用溶液、粘稠眼用溶液、增溶的眼用溶液等)、或一种非水性滴眼剂(如非水性眼用溶液和非水性悬浮眼用溶液)。When the pharmaceutical composition of the present invention for treating dry eye is used as an ophthalmic solution, it is provided in any dosage form for an ophthalmic solution, for example, an aqueous eye drop (such as an aqueous ophthalmic solution , aqueous suspension ophthalmic solution, viscous ophthalmic solution, solubilized ophthalmic solution, etc.), or a nonaqueous eye drop (such as nonaqueous ophthalmic solution and nonaqueous ophthalmic solution suspension).
优选的，所述的药物组合物为水性滴眼剂，其中，NGF的含量为10-1000μg/ml，优选为2-500μg/ml，更优选为100-300μg/ml；Preferably, the pharmaceutical composition is an aqueous eye drop, wherein the content of NGF is 10-1000 μg/ml, preferably 2-500 μg/ml, more preferably 100-300 μg/ml;
优选的，所述的药物组合物为水性滴眼剂，其中，糖皮质激素的含量为1-1000μg/ml，优选为100-1000μg/ml，更优选为200-800μg/ml；Preferably, the pharmaceutical composition is an aqueous eye drop, wherein the content of the glucocorticoid is 1-1000 μg/ml, preferably 100-1000 μg/ml, more preferably 200-800 μg/ml;
优选的，所述的药物组合物为水性滴眼剂，所述的药物组合物中还包括维生素B，维生素B的含量为1-100μg/ml，优选为1-50μg/ml，更优选为1-20μg/ml；Preferably, the pharmaceutical composition is aqueous eye drops, and the pharmaceutical composition also includes vitamin B, the content of vitamin B is 1-100 μg/ml, preferably 1-50 μg/ml, more preferably 1 -20μg/ml;
优选的，上述药物组合物中还包括药学上可接受的添加剂；Preferably, the above pharmaceutical composition also includes pharmaceutically acceptable additives;
优选的，所述的添加剂选自：抑菌剂、pH调节剂、渗透压调节剂、增溶剂(稳定剂)、增稠剂和螯合剂等中的一种或多种；Preferably, the additive is selected from: one or more of bacteriostats, pH regulators, osmotic pressure regulators, solubilizers (stabilizers), thickeners and chelating agents;
优选的，所述的抑菌剂包括但不限于：硫柳汞、季铵盐类、杜米芬、洗必泰、三氯叔丁醇、尼泊金类和山梨酸中的一种或多种的组合；优选的，所述的季铵盐类抑菌剂如苯扎氯铵、苯扎溴铵，尼泊金类如羟苯乙酯等；Preferably, the bacteriostatic agent includes but is not limited to: a combination of one or more of thimerosal, quaternary ammonium salts, dumiphene, chlorhexidine, chlorobutanol, paraben and sorbic acid; Preferably, the quaternary ammonium salt antibacterial agent such as benzalkonium chloride, benzalkonium bromide, parabens such as ethylparaben etc.;
优选的，所述的药物组合物中防腐剂含量为0.001-1.0％；Preferably, the preservative content in the pharmaceutical composition is 0.001-1.0%;
优选的，所述pH调节剂包括但不限于：磷酸盐、醋酸盐、枸橼酸及其盐、碳酸盐溶液、氢氧化钠、氢氧化钾、盐酸、硼酸和磷酸等中的一种或多种；Preferably, the pH regulator includes, but is not limited to: one of phosphate, acetate, citric acid and its salts, carbonate solution, sodium hydroxide, potassium hydroxide, hydrochloric acid, boric acid and phosphoric acid, etc. or more;
优选的，所述的药物组合物中pH为5.5-7.5；Preferably, the pH in the pharmaceutical composition is 5.5-7.5;
优选的，所述的渗透压调节剂包括但不限于：糖类(如山梨醇、葡萄糖、甘露醇)、多元醇类(如甘油、聚乙二醇、聚丙二醇)、盐类如氯化钠；Preferably, the osmotic pressure regulator includes but not limited to: sugars (such as sorbitol, glucose, mannitol), polyalcohols (such as glycerin, polyethylene glycol, polypropylene glycol), salts such as sodium chloride ;
优选的，所述的增溶剂包括但不限于：环糊精及其衍生物、水溶性聚合物(如聚乙烯吡咯烷酮)、表面活性剂(如聚山梨醇酯80，商品名：吐温80)；Preferably, the solubilizer includes, but is not limited to: cyclodextrin and its derivatives, water-soluble polymers (such as polyvinylpyrrolidone), surfactants (such as polysorbate 80, trade name: Tween 80) ;
优选的，所述的增稠剂选自：甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素羟乙基纤维素和羟丙基纤维素及其盐类的一种或多种；Preferably, the thickener is selected from one or more of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and salts thereof kind;
优选的，所述的螯合剂包括但不限于：依地酸钠、柠檬酸钠、缩聚磷酸钠。Preferably, the chelating agent includes, but is not limited to: sodium edetate, sodium citrate, and sodium condensed phosphate.
在本发明的一个实施例中，所述药物组合物为眼用凝胶、眼用软膏，其中还包括基质化合物；In one embodiment of the present invention, the pharmaceutical composition is ophthalmic gel, ophthalmic ointment, which also includes a matrix compound;
优选的，所述的软膏基质包括植物油、动物脂肪，和从石油得到的半固体烃类，如：羊毛脂、凡士林、液体石蜡、矿物油等；Preferably, the ointment base includes vegetable oil, animal fat, and semi-solid hydrocarbons obtained from petroleum, such as: lanolin, vaseline, liquid paraffin, mineral oil, etc.;
优选的，所述的凝胶基质化合物为生物相容性良好、可形成凝胶的高分子物质，如：泊洛沙姆、结冷胶、壳聚糖、海藻酸钠、透明质酸钠、羟丙甲纤维素、黄原胶、卡波姆等；Preferably, the gel matrix compound is a polymer substance that has good biocompatibility and can form a gel, such as: poloxamer, gellan gum, chitosan, sodium alginate, sodium hyaluronate, Hypromellose, xanthan gum, carbomer, etc.;
优选的，上述药物组合物的制剂包括普通制剂、控释制剂、靶向制剂等。Preferably, the formulations of the above pharmaceutical composition include common formulations, controlled release formulations, targeted formulations and the like.
本发明还提供一种上述药物组合物在制备治疗和/或预防干眼症和/或角膜和结膜损伤的药物中的应用；The present invention also provides an application of the above pharmaceutical composition in the preparation of medicines for treating and/or preventing dry eye and/or corneal and conjunctival damage;
优选的，所述的干眼症为重度干眼症，特别是根据DEWS Report(2007)干眼严重度为3以上的干眼和/或角膜和结膜损伤；Preferably, the dry eye is severe dry eye, especially dry eye and/or corneal and conjunctival damage according to the DEWS Report (2007) dry eye severity of 3 or more;
所述的应用为减轻或消除单独使用糖皮质激素所产生的副作用；Described application is to reduce or eliminate the side effect produced by using glucocorticoid alone;
优选的，所述的副作用为眼压升高。Preferably, the side effect is increased intraocular pressure.
本发明另一方面还提供一种隐形眼镜，其包含、携带、或连接有上述药物组合物，患者可以通过佩戴该隐形眼镜达到给药治疗的目的。Another aspect of the present invention also provides a contact lens, which contains, carries, or is connected with the above-mentioned pharmaceutical composition, and patients can achieve the purpose of administration and treatment by wearing the contact lens.
本发明提供的药物组合物包括NGF和糖皮质激素，二者具有协同作用，可显著缓解干眼症症状，可用于中重度干眼症，特别是根据DEWS Report(2007)干眼严重度为3以上的干眼和/或角膜和结膜损伤的治疗，本发明的组合物中还可包含维生素B，其治疗效果更好。且本发明提供的药物组合物还可有效改善糖皮质激素引起的眼压升高的不良反应，有利于降低糖皮质激素用于眼部疾病治疗时由于眼压升高进一步引起青光眼的风险。The pharmaceutical composition provided by the present invention includes NGF and glucocorticoid, the two have synergistic effect, can significantly relieve dry eye symptoms, and can be used for moderate to severe dry eye, especially according to DEWS Report (2007) dry eye severity is 3 For the above treatment of dry eye and/or corneal and conjunctival damage, vitamin B may also be included in the composition of the present invention, and its therapeutic effect is better. Moreover, the pharmaceutical composition provided by the invention can effectively improve the adverse reaction of increased intraocular pressure caused by glucocorticoids, and is beneficial to reduce the risk of further glaucoma caused by increased intraocular pressure when glucocorticoids are used for the treatment of eye diseases.
具体实施方式Detailed ways
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Apparently, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.
实施例1滴眼液Embodiment 1 eye drops
按照本领域已知的制备方法制备滴眼液，其主要组分及含量如下：Prepare eye drops according to the preparation method known in the art, and its main component and content are as follows:
实施例2滴眼液Embodiment 2 eye drops
按照本领域已知的制备方法制备滴眼液，其主要组分及含量如下：Prepare eye drops according to the preparation method known in the art, and its main component and content are as follows:
实施例3滴眼液Embodiment 3 eye drops
按照本领域已知的制备方法制备滴眼液，其主要组分及含量如下：Prepare eye drops according to the preparation method known in the art, and its main component and content are as follows:
实施例4滴眼液Embodiment 4 eye drops
实施例5滴眼液Embodiment 5 eye drops
按照本领域已知的制备方法制备滴眼液，其主要组分及含量如下：Prepare eye drops according to the preparation method known in the art, and its main component and content are as follows:
实施例6滴眼液Embodiment 6 eye drops
实施例7滴眼液Embodiment 7 eye drops
按照本领域已知的制备方法制备滴眼液，其主要组分及含量如下：Prepare eye drops according to the preparation method known in the art, and its main component and content are as follows:
实施例8眼用凝胶Embodiment 8 ophthalmic gel
按照本领域已知的制备方法制备眼用凝胶，其主要组分及含量如下：Prepare ophthalmic gel according to the preparation method known in the art, its main component and content are as follows:
实施例9眼用膏剂Embodiment 9 ophthalmic ointment
按照本领域已知的制备方法制备眼用膏剂，其主要组分及含量如下：Prepare ophthalmic ointment according to the preparation method known in the art, its main component and content are as follows:
实施例10眼用膜剂Embodiment 10 eye film
按照本领域已知的制备方法制备眼用膜剂，其主要组分及含量如下：According to the preparation methods known in the art to prepare ophthalmic film, its main components and content are as follows:
实施例11角膜结膜损伤治疗效果Embodiment 11 corneal conjunctiva injury treatment effect
根据DEWS Report(2007)，干眼严重度分类如表1所示(参见“Management andTherapy of Dry Eye Disease”(p163-178)。According to DEWS Report (2007), the severity classification of dry eye is shown in Table 1 (see "Management and Therapy of Dry Eye Disease" (p163-178).
表1干眼严重度分级表Table 1 Grading scale of dry eye severity
*必须有征兆和症状。TBUT：荧光素眼泪分解时间。MGD：睑板腺疾病* Must have signs and symptoms. TBUT: fluorescein tear breakdown time. MGD: meibomian gland disease
这里的“根据DEWS Report(2007)的干眼严重度为3以上的干眼和/或角膜和结膜损伤”指的是对应于根据上述分类的干眼严重度为3以上的干眼，和/或表现出这种干眼的任何征兆和症状的角膜和结膜损伤。Here, "dry eye and/or corneal and conjunctival damage according to DEWS Report (2007) with a dry eye severity of 3 or more" means dry eye corresponding to a dry eye severity of 3 or more according to the above classification, and/ Or corneal and conjunctival damage exhibiting any of the signs and symptoms of such dry eye.
1.实验材料与条件1. Experimental materials and conditions
受试样品：实施例1-7制备的滴眼液；Test sample: the eye drops prepared by embodiment 1-7;
对照样品：生理盐水；Control sample: normal saline;
试验动物：清洁级新西兰兔，无眼部疾病，雌雄各半。Experimental animals: Clean grade New Zealand rabbits, no eye diseases, half male and half male.
2.动物模型建立与实验分组2. Animal model establishment and experimental grouping
取实验动物，通过肌肉注射氯胺酮(10mg/kg)和甲苯噻嗪(4mg/kg)，然后对眼部给予0.4％的奥布卡因(每眼两滴)进行麻醉。将兔子保持横卧放置并向一只眼中滴注临用前制备的0.04ml(0.01ml×4次)正庚醇溶液(正庚醇∶乙醇＝8∶2)，以使正庚醇溶液覆盖角膜和球结膜。然后，迫使该兔子眨眼3次并在第三次眨眼后闭眼2分钟。对两只眼睛均进行上述程序。由此，制作角膜和结膜损伤模型。The experimental animals were taken and anesthetized by intramuscular injection of ketamine (10 mg/kg) and xylazine (4 mg/kg), and then 0.4% oxybucaine (two drops per eye) was given to the eyes. Keep the rabbit in a recumbent position and instill 0.04ml (0.01ml×4 times) of n-heptanol solution (n-heptanol:ethanol=8:2) prepared before use into one eye, so that the n-heptanol solution covers Cornea and bulbar conjunctiva. Then, the rabbit was forced to blink 3 times and close the eyes for 2 minutes after the third blink. The above procedure was performed on both eyes. Thus, corneal and conjunctival injury models were produced.
将造模成功的兔眼，随机平均分为8组：第1组为对照组、第2-8组为受试样品组。每天给药2次，连续给药10天，用药前和用药后分别进行荧光素染色实验，对角膜和结膜的状态进行了观察。The successfully modeled rabbit eyes were randomly divided into 8 groups: the first group was the control group, and the second to eighth groups were the test sample groups. The drug was administered twice a day for 10 consecutive days. The fluorescein staining experiments were carried out before and after the drug, and the states of the cornea and conjunctiva were observed.
荧光素染色实验：将2μl的1％萤光素滴入眼中，2分钟后，通过在发光部具有钴蓝滤光镜(FUJI FILTER BPB45)、在镜头之前具有黄色滤光镜(FUJI FILTER SC52)的数码显微镜(VHX 900，KEYENCE CORPORATION(日本))，对角膜和结膜的染色进行拍照和观察，然后对角膜损伤的程度进行评分。对于评分，将各角膜分为5个区域(中央、上部、颞部、鼻部、下部区域)，各区域的荧光素染色强度以3分满分进行评分，将总分(满分15分)用于评价。无染色时染色强度被评分为0；部分染色为1；约三分之二区域的染色为2；全部染色为3。评分数值越小，相应的样品修复效果越高。Fluorescein staining experiment: 2 μl of 1% luciferin was dropped into the eye, and after 2 minutes, passed through a cobalt blue filter (FUJI FILTER BPB45) in the light-emitting part and a yellow filter (FUJI FILTER SC52) in front of the lens A digital microscope (VHX 900, KEYENCE CORPORATION (Japan)) was used to take pictures and observe the staining of the cornea and conjunctiva, and then score the degree of corneal damage. For scoring, each cornea was divided into 5 regions (central, superior, temporal, nasal, and inferior regions), and the intensity of fluorescein staining in each region was scored on a 3-point scale, and the total score (15 points) was used for Evaluation. Staining intensity was scored as 0 for no staining; 1 for partial staining; 2 for staining in about two-thirds of the area; and 3 for total staining. The smaller the score value, the higher the corresponding sample restoration effect.
角膜的荧光素染色评分结果如表2所示。与对照品相比，受试样品组实验动物的角膜荧光素染色评分显著降低，表明修复效果较好；与NGF、地塞米松单独给药的样品相比，二者联合给药效果更好。The scoring results of corneal fluorescein staining are shown in Table 2. Compared with the control substance, the corneal fluorescein staining score of the experimental animals in the test sample group was significantly reduced, indicating a better repair effect; compared with the samples administered with NGF and dexamethasone alone, the combined administration of the two had a better effect .
表2正庚醇诱发角膜结膜损伤的兔的角膜荧光素染色评分结果Table 2 Corneal fluorescein staining score results of n-heptanol-induced corneal and conjunctival injury in rabbits
实施例12降低眼压效果Embodiment 12 reduces intraocular pressure effect
1.实验材料与条件1. Experimental materials and conditions
受试样品：实施例3、7制备的滴眼液(分别记为滴眼液1和滴眼液2)；Tested sample: the eye drops prepared in Examples 3 and 7 (respectively denoted as eye drops 1 and eye drops 2);
对照样品：生理盐水；Control sample: normal saline;
阳性对照药物：实施例6制备的滴眼液；Positive control drug: the eye drops prepared in Example 6;
试验动物：健康C57BL/6J小鼠。Test animals: healthy C57BL/6J mice.
2.实验动物和分组2. Experimental Animals and Grouping
将实验动物平均随机分组，给药4周后，眼压计检测小鼠眼压。实验结果如表3所示。The experimental animals were randomly divided into groups, and after 4 weeks of administration, the intraocular pressure of the mice was detected with a tonometer. The experimental results are shown in Table 3.
表3眼压检测结果Table 3 Results of intraocular pressure test
由表3结果可知，NGF与糖皮质激素组合使用，特别是NGF、糖皮质激素和维生素B1的组合使用，可有效改善糖皮质激素引起的眼压升高的不良反应，有利于降低糖皮质激素用于眼部疾病治疗时由于眼压升高进一步引起青光眼的风险。It can be seen from the results in Table 3 that the combined use of NGF and glucocorticoids, especially the combined use of NGF, glucocorticoids and vitamin B1, can effectively improve the adverse reaction of glucocorticoid-induced intraocular pressure increase, and is beneficial to reduce the adverse reactions of glucocorticoids. Risk of further glaucoma due to increased intraocular pressure when used in the treatment of eye diseases.
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention within.
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| EP4311554A1 (en)* | 2022-07-29 | 2024-01-31 | Dompé farmaceutici S.p.a. | Combination for use in ophthalmology |
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