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WO2019024433A1 - 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用 - Google Patents

氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用 Download PDF

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WO2019024433A1
WO2019024433A1 PCT/CN2018/000282 CN2018000282W WO2019024433A1 WO 2019024433 A1 WO2019024433 A1 WO 2019024433A1 CN 2018000282 W CN2018000282 W CN 2018000282W WO 2019024433 A1 WO2019024433 A1 WO 2019024433A1
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ophthalmic composition
ophthalmic
intraocular pressure
compound
mononitrate
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French (fr)
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王玉强
孙业伟
张在军
张高小
于沛
易鹏
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Foshan Magpie Pharmaceuticals Co Ltd
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    • 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
    • A61K31/13—Amines
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to an aminoadamantanamine mononitrate compound ophthalmic composition, a preparation thereof and an application thereof.
  • Glaucoma refers to an eye disease in which the intraocular pressure exceeds the limits of the intraocular tissues, especially the optic nerve, and causes optic disc depression, optic atrophy, and visual field defects. If not treated in time, the visual field may be completely lost or even blind. The second leading cause of blindness in the world, about 8.4 million people worldwide are blinded by glaucoma.
  • Normal human intraocular pressure range is 10 ⁇ 21mmHg (Schitz intraocular pressure gauge), intraocular pressure exceeds 24mmHg is pathological state, high intraocular pressure can cause permanent irreversible damage of visual function, high intraocular pressure state continues The longer the time, the more serious the visual impairment.
  • Clinical application of glaucoma treatment drugs are more, are intraocular pressure drugs, including mainly pilocarpine, prostaglandin analogues, ⁇ -adrenergic receptor inhibitors, ⁇ -adrenergic receptor agonists and carbonic anhydrase inhibitors Wait.
  • intraocular pressure drugs including mainly pilocarpine, prostaglandin analogues, ⁇ -adrenergic receptor inhibitors, ⁇ -adrenergic receptor agonists and carbonic anhydrase inhibitors Wait.
  • Pilocarpine Among the various commonly used anti-glaucoma drugs, the oldest drug is pilocarpine. Since 1877, Weber first used it for the treatment of glaucoma. It has been more than 100 years old and its intraocular pressure is better. It is suitable for most glaucoma, but the eye has a large adverse reaction, such as burning eyes, stinging, blurred vision and so on.
  • Prostaglandin analogues It is the most widely used glaucoma treatment drug in clinical practice. It can reduce intraocular pressure by increasing the outflow of aqueous humor through the choroidal sclera or trabeculae. The intraocular pressure is reduced by 25% to 33%, including Latan. Prostaglandins, bimatopros and prostaglandins, common side effects are conjunctival hyperemia, eyelash growth and increased iris pigmentation.
  • Beta-adrenergic receptor inhibitors The main mechanism of action is to reduce the binding of adrenaline and norepinephrine to beta receptors, reduce cAMP levels in ciliary epithelial cells, reduce aqueous humor production, and thus reduce intraocular Pressure, intraocular pressure decreased by 20% to 25%, including timolol, carteolol and levobunolol, adverse reactions are more common in the cardiovascular system and respiratory system.
  • Alpha-adrenergic receptor stimulant The main mechanism of action is to reduce the formation of aqueous humor, reduce the iris venous pressure or increase the outflow of aqueous humor through the uveal iris, and the intraocular pressure decreases by 20% to 25%.
  • the main side effect is conjunctival hyperemia. Allergic reactions and fatigue, such as drowsiness.
  • Carbonic anhydrase inhibitor The main mechanism of action is to reduce the formation of aqueous humor, and the intraocular pressure is reduced by 15% to 20%. There are two ways of administration of eye drops and oral administration. The main side effect is atopic dermatitis/conjunctivitis. , corneal edema, etc.
  • Glaucoma optic nerve damage ultimately leads to loss of vision function, and elevated intraocular pressure is the most common risk factor, but in some patients, normal intraocular pressure is still subject to continuous damage.
  • pathogenesis of glaucomatous optic nerve damage there is evidence that when retinal ganglion cells are exposed to high intraocular pressure, they have a series of associated changes in cell downstream pathways, including mitochondrial dysfunction, proteolytic grade. Linkage reaction, endoplasmic reticulum oxidative stress, etc. Therefore, optic nerve protection therapy is an essential treatment for improving optic nerve damage in glaucoma.
  • Optic neuroprotective treatments include lowering intraocular pressure and the use of neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • optic neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • Glutamate blockers glaucomatous retinal ganglion cell apoptosis studies show that excitatory amino acid receptors (NMDA, AMPA and KA receptors) are present on retinal ganglion cells when cells are ischemic or have high intraocular pressure It can cause hypoxia in ganglion cells, cause depolarization of membranes, increase glutamate release, and reduce uptake, which together lead to the accumulation of extracellular glutamate, which causes extracellular calcium ions under the action of its receptors. Influx causes high calcium load in the cells, resulting in an increase in inducible NO synthase, lipid peroxidase, aggregation of oxygen free radicals, mitochondrial degeneration, and apoptosis of optic ganglion cells.
  • Nitric oxide donor drugs Endogenous cell-derived gas signaling molecule NO plays a regulatory role in various tissues of the human body. NO activates guanylate cyclase in vascular smooth muscle cells, resulting in increased cGMP and vasodilation. Recent studies have shown that low concentrations of NO (pmol or low level of nmol) have protective effects on glaucoma retina, which is characterized by diastolic intraocular smooth muscle, trabecular meshwork, Schlemm tube, thereby reducing aqueous circulation resistance, reducing intraocular pressure; Blood vessels, increase vascular flow, reduce vascular resistance; improve the retinal microcirculation through relaxation of capillaries.
  • the NO donor drug currently in clinical research is latanoprostol, which is one of the most promising glaucoma treatments.
  • latanoprostol which is one of the most promising glaucoma treatments.
  • the average intraocular pressure of 0.024% latanoprostol was significantly higher than 0.005%.
  • Prostaglandins The drug is in clinical phase III research.
  • the simultaneous provision of intraocular pressure reduction and optic nerve protection can provide a better therapeutic effect for glaucoma and benefit patients for a long time.
  • the patent (application number: 201410235747.5) provides an amantadine nitrate compound which combines NMDA receptor antagonism and NO release, and can reduce intraocular pressure and exert optic ganglion cell protection.
  • Patent (Application No.: 20160701329) provides the use of aminoadamantane mononitrate compounds in the preparation of medicaments for the prevention and treatment of diseases, including the use in the preparation of medicaments for the prevention and treatment of glaucoma, by administering orally orally orally.
  • Alkanone mononitrate compounds can significantly reduce intraocular pressure and improve the survival rate of optic ganglion cells.
  • the main disadvantages are as follows: First, glaucoma treatment requires long-term medication, and clinical compliance of injection administration is poor. Second, after injection or oral administration, the drug is distributed throughout the body, and the drug concentration of the target site is low, and it is difficult to achieve the effective concentration. And because of the systemic exposure of the drug, the possibility of drug toxicity is increased. Based on this, we have developed an aminoadamantane mononitrate compound ophthalmic preparation.
  • the present invention provides an ophthalmic composition containing an aminoadamantane mononitrate compound and its use in the preparation of a medicament.
  • the ophthalmic composition not only can sufficiently reduce intraocular pressure, but also has an optic ganglion cell protection effect, and can obtain long-term benefits for glaucoma, as well as patients with elevated intraocular pressure or retinal ganglion cell damage.
  • the present invention provides an ophthalmic composition containing an aminoadamantanamine mononitrate compound, wherein the composition comprises aminoammonium amine mononitrate in a mass to volume ratio of 0.001% to 5.0%.
  • a compound the compound is of the formula (I) or a pharmaceutically acceptable salt thereof:
  • R is hydrogen, a linear or branched alkyl group; and n is 1-6.
  • the alkyl group is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, Cyclopentyl, n-hexyl or cyclohexyl.
  • aminoamantylamine mononitrate compound has the following structural formula:
  • the ophthalmic composition can be formulated as an ophthalmic gel, an ophthalmic solution, and an injectable solution that can also be formulated to be suitable for in or near the eye.
  • the ophthalmic composition can be formulated as an ophthalmic gel or ophthalmic solution. More preferably, the ophthalmic composition can be formulated as an ophthalmic gel.
  • the ophthalmic composition, as an ophthalmic gel may further comprise a gellan gum, a poloxamer 407, a carbomer, a polycarbophil, a hydroxypropyl group having a mass to volume ratio of 0.1% to 10%. Methylcellulose or a combination thereof.
  • the composition may further comprise a sustained release agent.
  • the ophthalmic composition may further comprise one or more pharmaceutically acceptable excipients.
  • the auxiliary material may be a thickener, an isotonicity adjusting agent, a tonicity adjusting agent, a mucoadhesive agent, a preservative, a complexing agent, a buffering agent, and a pH adjusting agent.
  • the ophthalmic compositions can be prepared in a conventional manner for various formulations.
  • the present invention provides the pharmaceutical use of the aminoamantaneamine mononitrate compound ophthalmic composition described above, including the use in the preparation of a medicament, wherein the medicament can be used for the prevention and treatment of glaucoma, And other ophthalmic diseases associated with elevated intraocular pressure or retinal ganglion cell damage.
  • the aminoadamantanamine mononitrate compound ophthalmic composition provided by the present invention preferably an ophthalmic gel preparation, has a longer drug release duration and a longer lasting effect than the eye drops, and the eye coagulation is used.
  • the effect of the gel preparation on lowering the intraocular pressure is significantly stronger than that of the intravenous administration of the drug or the administration of the eye drops.
  • the aminoadamantanamine mononitrate compound ophthalmic composition provided by the invention is used for preparing a medicament, and has the advantages of being convenient for use in an ophthalmic disease patient. Compared with injection or oral preparations, the formulation is more compliant, suitable for glaucoma, and long-term medication for patients with ophthalmic diseases with elevated intraocular pressure or optic nerve cell damage;
  • the ophthalmic composition of the aminoammoniumamine mononitrate compound provided by the present invention avoids the disadvantage of systemic exposure of the drug after injection or oral administration, and increased toxicity.
  • Topical administration increases the drug concentration of the drug target site, the drug has a fast onset, the effective concentration is higher, and the patient benefit/risk ratio is higher.
  • the aminoadamantanamine mononitrate compound composition provided by the invention comprises an eye drop gel agent, and the gel agent is a liquid with good fluidity in vitro, and can be evenly spread after being dropped into the eye, in the eye.
  • the residence time is longer, it is not easy to lose, the higher local effective drug concentration can be maintained, and the bioavailability of the drug is provided.
  • Figure 1 depicts the protective effects of different concentrations of MN-08 eye drops on a transient glaucoma model in New Zealand rabbits.
  • Figure 2 depicts the protective effect of MN-08 gel (0.5%) on a New Zealand rabbit transient glaucoma model.
  • Figure 3 depicts a pharmacodynamic comparison of the protective effects of injections, eye drops, and gels on a New Zealand rabbit transient glaucoma model.
  • Figure 4 illustrates the effect of different pharmaceutical dosage forms on intraocular pressure in a New Zealand rabbit transient glaucoma model.
  • New Zealand rabbits weighing 1.5 to 2 kg were selected as model animals to produce high intraocular pressure models. New Zealand rabbits were placed in a clean animal room for 3 days, and the experiment was started after reaching the required body weight range. First, anesthesia with sodium pentobarbital (3%, 1 ml/kg) until no blink reflex; then, using compound tropicamide eye drops, local anesthesia with oxybuprocaine eye drops, card Bom eye drops prevent dry eyes, levofloxacin eye drops anti-inflammatory, iodine disinfected around the eyes; 0.1ml of 5% hypertonic saline is injected into the vitreous of the eye, using a needle of 33G needle, the injection site is the limbus After 3.5-4mm, the injection depth is 5-7mm; after the needle is withdrawn. The Tonolab intraocular pressure gauge was used to measure the intraocular pressure change 1 min after the injection of hypertonic saline to evaluate whether the model was successfully produced. The intraocular pressure was higher than 70 mmHg,
  • the MN-08 drug powder was weighed separately, and the MN-08 eye drops with a mass to volume ratio of 0.02%, 0.1%, and 0.5% were sequentially prepared by using physiological saline;
  • MN-08 drug powder and gellan gum (Gelzan TM CM) powder were weighed separately, and MN-08 gel solution containing 0.5% MN-08 and 0.6% Gelzan TM CM was prepared with physiological saline;
  • New Zealand rabbits were randomly divided into normal saline group, MN-08 eye drops group (0.02%, 0.1%, 0.5%), MN-08 gel solution group (0.5%), and positive control group (0.005% latanolide). ), 5 to 8 per group.
  • the intraocular pressure (0 min) of New Zealand rabbits before the injection of hypertonic saline was measured as the normal intraocular pressure.
  • the intraocular pressure of each experimental group was measured at the time points of 1 min, 10 min, 30 min, 60 min, 90 min and 180 min after modeling.
  • the average value of the three intraocular pressure measurements at each time point was used as the intraocular pressure at that point, and the effect of the drug on intraocular pressure changes within 3 hours after administration was observed.
  • the changes in intraocular pressure in the transient glaucoma model of New Zealand rabbits after administration of different dosage forms and concentrations of MN-08, latanoprost and saline were as shown in the list in Figure 4, and the transientity of New Zealand rabbits after administration of MN-08 eye drops.
  • the glaucoma model intraocular pressure change line diagram is shown in Figure 1.
  • the intraocular pressure of the New Zealand rabbit transient glaucoma model after MN-08 gel is shown in Figure 2.
  • MN-08 injection, eye gel solution The drug effect comparison is shown in Figure 3.
  • MN-08 injection P ⁇ 0.05
  • MN-08 eye drops P ⁇ 0.05
  • MN-08 gel P ⁇ 0.05
  • MN-08 gel 0.5%)
  • MN-08 eye drops 0.5%)
  • the MN-08 gel has a longer duration of action and more than eye drops at the same concentration. Good antihypertensive effect.

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Abstract

包含质量体积比为0.001%～5%的氨基金刚烷胺单硝酸酯类化合物的眼用组合物，以及该眼用组合物在制备预防和治疗青光眼、眼内压升高或伴有视网膜神经节细胞损伤的眼科疾病药物中的应用。

Description

氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用 技术领域
本发明涉及医药技术领域，具体涉及氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用。
背景技术
青光眼(Glaucoma)是指当眼内压超过眼内组织特别是视神经所能承受的限度，并引起视盘凹陷、视神经萎缩及视野缺损的眼病，如不及时治疗，视野可全部丧失甚至失明，是全世界致盲的第二位主要原因，全球约840万人因青光眼而致盲。正常人的眼内压范围为10～21mmHg(Schitz眼内压计)，眼内压超过24mmHg则为病理状态，高眼内压可以导致视功能永久性的不可逆的损伤，高眼内压状态持续时间愈久，视功能损害也愈严重。
青光眼眼内压升高的原因是房水循环的动态平衡受到破坏，少数由于房水分泌过多，但其发病机制尚不完全明确，因此，青光眼的临床治疗仍主要基于降低眼内压，以减少高眼内压状态下的视功能损伤。目前，临床上应用的降低眼内压的方法主要包括药物治疗、激光手术或切开青光眼手术(单独或联合应用)。除非有禁忌症，药物治疗仍是最常用的降眼内压的干预措施。
临床应用青光眼治疗药物较多，均为降眼内压药物，其中，主要包括毛果芸香碱、前列腺素类似物、β-肾上腺素受体抑制剂、α-肾上腺素受体兴奋剂和碳酸酐酶抑制剂等。
毛果芸香碱：在临床各种常用的抗青光眼药物中，最古老的药物是毛果芸香碱，自1877年Weber首先将其用于青光眼的治疗，至今已有100多年的历史，其降眼内压效果较好，对大多数青光眼均适用，但眼部不良反应较大，如眼部灼烧感、刺痛、视力模糊等。
前列腺素类似物：是临床应用最为广泛的青光眼治疗药物，其能够通过增加房水经脉络膜巩膜或小梁的外流从而降低眼内压，眼内压降低幅度达25％～33％，包括拉坦前列腺素、比马前列腺、曲前列腺素等，常见副作用为结膜充血，睫毛增长和虹膜色素增多等。
β-肾上腺素受体抑制剂：主要作用机理为通过阻断肾上腺素和去甲肾上腺素与β受体的结合，使睫状体上皮细胞中cAMP水平降低，减少房水生成，从而降低眼内压，眼内压降低幅度达20％～25％，包括噻吗洛尔、卡替洛尔和左布诺洛尔等，不良反应多见于心血管系统和呼吸系统。
α-肾上腺素受体兴奋剂：主要作用机理为减少房水生成，减少虹膜静脉压或增加房水经葡萄膜虹膜外流，眼内压降低幅度达20％～25％，主要副作用为结膜充血、过敏反应和疲劳嗜睡等。
碳酸酐酶抑制剂：主要作用机理为减少房水生成，眼内压降低幅度达15％～20％，有滴眼液给药和口服给药两种途径，主要副作用为过敏性皮炎/结膜炎、角膜水肿等。
青光眼视神经损伤最终导致视力功能丧失，眼内压升高是最常见的危险因素，但部分患者眼内压正常后视功能仍然受到持续性的损伤。随着对青光眼视神经损害发病机制的研究深入，有证据显示当视网膜神经节细胞暴露于高眼内压刺激下，导致其出现一系列相关联的细胞下游通路改变，包括线粒体功能异常，蛋白水解级联反应，内质网氧化应激等。因此，视神经保护治疗成为改善青光眼视神经损伤的必要治疗手段。
视神经保护治疗措施包括降低眼内压，使用神经保护剂，如钙拮抗剂、谷氨酸受体拮抗剂、抗氧化剂、神经营养因子等。目前尚无临床应用的视神经保护剂，但大量视神经保护药物已处于临床研究阶段。
谷氨酸受体阻滞剂：青光眼视网膜神经节细胞凋亡研究显示，视网膜神经节细胞上存在兴奋性氨基酸受体(NMDA、AMPA及KA受体)，当细胞缺血或高眼内压时，能够导致节细胞缺氧，引起膜的去极化，谷氨酸盐释放增多，摄取减少，共同导致了细胞外谷氨酸盐的堆积，在其受体的作用下，引起细胞外钙离子内流，造成细胞内的高钙负荷，从而导致诱导型NO合酶、脂质过氧化物酶增加，氧自由基的聚集，线粒体变性，导致视神经节细胞的凋亡。临床研究显示，青光眼病人玻璃体内的谷氨酸浓度明显升高。体外研究表明，视网膜神经节细胞对谷氨酸特别敏感，在细胞培养中，当视网膜神经节细胞接触高浓度的谷氨酸时，节细胞发生凋亡，阻断谷氨酸的过量释放或干涉NMDA受体与谷氨酸的结合可以保护视网膜神经节细胞。NMDA受体拮抗剂美金刚曾作为视神经保护药物进入临床III期研究，遗憾的是，III期第二阶段研究中美金刚治疗组与安慰剂组未显示显著的差异。
一氧化氮供体药物：内皮细胞源性的气体信号分子NO在人体多种组织中发挥着调节作用，NO通过激活血管平滑肌细胞内的鸟苷酸环化酶，导致cGMP增加，血管舒张。近期研究显示，低浓度的NO(pmol或低水平nmol浓度)对青光眼视网膜 具有保护作用，具体表现为舒张眼内平滑肌、小梁网、Schlemm管，从而降低房水循环阻力，降低眼内压；舒张血管，增加血管流量，降低血管阻力；通过舒张毛细血管，改善视网膜微循环等多个方面。目前处于临床研究汇总的NO供体药物有拉坦前列腺素比诺，是最具前景的青光眼治疗药物之一。413例开角型青光眼或高眼内压症的2期临床试验中，经过28天治疗后发现，0.024％拉坦前列腺素比诺的平均日间眼内压减少幅度明显高于0.005％拉坦前列腺素。该药物正处于临床III期研究阶段。
综上所述，同时提供降眼内压和视神经保护作用能够为青光眼提供更好治疗效果，使患者长期获益。专利(申请号：201410235747.5)提供了一种金刚烷胺硝酸酯化合物，该系列化合物同时兼具了NMDA受体拮抗作用和NO释放作用，能够从降低眼内压，并发挥视神经节细胞保护作用。专利(申请号：20160701329)提供了氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用，其中包括在制备预防和治疗青光眼药物中的应用，通过注射或口服的方式给予氨基金刚烷单硝酸酯类化合物能够明显降低眼内压，并改善视神经节细胞存活率。其缺点主要在于：其一，青光眼治疗需要长期用药，注射给药临床依从性较差；其二，注射或口服给药后药物分布全身，靶部位的药物浓度较低，不易达到起效浓度，且由于药物全身暴露，增加了药物毒性反应可能性。基于此，我们开发了氨基金刚烷单硝酸酯类化合物眼用制剂。
发明内容
本发明提供了一种含有氨基金刚烷单硝酸酯类化合物的眼用组合物及其在制备药物中的应用。所述眼用组合物不仅能够充分降低眼内压，而且具有视神经节细胞保护作用，能够使青光眼，以及伴有眼内压升高或视网膜神经节细胞损伤的患者均获得长期受益。
在一方面，本发明提供了一种含有氨基金刚烷胺单硝酸酯类化合物的眼用组合物，其中所述组合物包含质量体积比为0.001％～5.0％的氨基金刚烷胺单硝酸酯类化合物；所述化合物为具有通式(I)的结构或其在药学上可接受的盐：
Figure PCTCN2018000282-appb-000001
其中，R为氢，直链或支链烷基；n为1-6。优选地，所述烷基为C1-C6烷基，例如 为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、环戊基、正己基或环己基。
优选地，所述氨基金刚烷胺单硝酸酯类化合物具有如下结构式：
Figure PCTCN2018000282-appb-000002
所述眼用组合物可被配制为眼用凝胶、眼用溶液、以及还可被配制为适于眼部之中或附近的注射液。优选地，所述眼用组合物可被配制为眼用凝胶或眼用溶液。更为优选地，所述眼用组合物可被配制为眼用凝胶。优选地，所述眼用组合物，作为眼用凝胶时还可包含质量体积比为0.1％～10％的结兰胶、泊洛沙姆407、卡波姆、聚卡波菲、羟丙基甲基纤维素或其组合。所述组合物还可进一步包含缓释剂。
所述眼用组合物还可以进一步包含一种或多种药物制剂上可接受的辅料。所述辅料为可为增稠剂、等渗调节剂、张力调节剂、粘膜粘附剂、防腐剂、络合剂、缓冲剂、pH调节剂。所述眼用组合物可按各种制剂的常规工艺制备。
另一方面，本发明还提供了以上所述的氨基金刚烷胺单硝酸酯类化合物眼用组合物的医药用途，包括在制备药物中的应用，其中所述药物能够用于预防和治疗青光眼、以及其他伴有眼内压升高或视网膜神经节细胞损伤的眼科疾病。
本发明的技术方案具有包括下述的有益效果：
1、本发明提供的氨基金刚烷胺单硝酸酯类化合物眼用组合物，优选为眼用凝胶剂，与滴眼液相比，药物释放持续时间更长，作用更持久，该眼用凝胶制剂降低眼内压的效果要明显强于药物静脉注射给药或者滴眼液滴眼给药。
2、本发明提供的氨基金刚烷胺单硝酸酯类化合物眼用组合物，用于制备药物，具有方便眼科疾病患者使用的优点。相比注射或者口服制剂，该制剂患者使用依从性更好，适用于青光眼，以及伴有眼内压升高或视神经细胞损伤的眼科疾病患者的长期用药；
3、本发明提供的氨基金刚烷胺单硝酸酯类化合物眼用组合物，通过眼部局部给药，避免了注射或口服给药后药物全身暴露，毒性反应增加的缺点。局部给药增加了药物靶部位的药物浓度，药物起效速度快，有效浓度较高，患者获益/风险比更高。
4、本发明提供的氨基金刚烷胺单硝酸酯类化合物组合物，包括滴眼凝胶剂，凝 胶剂在体外为流动性良好的液体，滴入眼内后，能均匀铺展，在眼内停留时间较长，不易流失，能维持更高的局部有效药物浓度，提供药物生物利用度。
附图说明
图1、描述了不同浓度的MN-08滴眼液对新西兰兔短暂性青光眼模型的保护作用。其中，模型组：n＝8只；0.02％MN-08滴眼液组：n＝5；0.1％MN-08滴眼液组：n＝6只；0.5％MN-08滴眼液组：n＝6只；Latanoport(拉坦前列腺素)组：n＝8只。
图2、描述了MN-08凝胶剂(0.5％)对新西兰兔短暂性青光眼模型的保护作用。其中，模型组：n＝8只；0.5％MN-08凝胶剂组：n＝8；Latanoport(拉坦前列腺素)组：n＝8只。
图3、描述了注射剂、滴眼液和凝胶剂对新西兰兔短暂性青光眼模型的保护作用药效学比较。其中，模型组：n＝8只；MN-08(6.25mg/kg)注射液组：n＝5；0.5％MN-08滴眼液组：n＝6只；0.5％MN-08凝胶剂组：n＝8；Latanoport(拉坦前列腺素)组：n＝8只。
图4、列举了不同药物剂型对新西兰兔短暂性青光眼模型眼内压的影响。其中，模型组：n＝8只；MN-08(6.25mg/kg)注射液组：n＝5；0.02％MN-08滴眼液组：n＝5；0.1％MN-08滴眼液组：n＝6只；0.5％MN-08滴眼液组：n＝6只；0.5％MN-08凝胶剂组：n＝8；Latanoport(拉坦前列腺素)组：n＝8只。
具体实施方式
为了对本发明技术方案有较好的理解，下面将结合附图对本发明的具体实施方式或实施例进行较为详细的描述，显然，本文所述的实施例只包括了本发明的一部分而不是全部的实施例。本领域技术人员应当理解，对本发明的具体实施方式或实施例进行修改或者对部分技术特征进行同等替换，而不脱离本发明技术方案的精神，均应涵盖在本发明保护的范围中。
实施例1
1、新西兰兔短暂性青光眼模型的制作
选用体重范围为1.5～2kg的新西兰兔作为模型动物制作高眼内压模型。将新西兰兔置于清洁级动物房适应性饲养3天，达到实验要求体重范围后，开始实验。首先，使用戊巴比妥钠(3％，1ml/kg)麻醉，至无眨眼反射；然后，依次使用复方托 吡卡胺滴眼液扩瞳，盐酸奥布卡因滴眼液局部麻醉，卡波姆滴眼液防眼睛干涩，左氧氟沙星滴眼液消炎，碘酒于眼周围消毒；将0.1ml浓度为5％的高渗生理盐水注射入眼玻璃体内，使用针头为33G针头，注射部位为角膜缘后3.5-4mm，注射深度为5-7mm；抽出针头后。用Tonolab眼内压计测定注射高渗生理盐水后1min的眼内压变化，用以评价模型是否制作成功，眼内压高于70mmHg即可视为造模成功。
2、药物配制
分别秤取MN-08药物粉末，用生理盐水依次配制成质量体积比为0.02％，0.1％，0.5％的MN-08滴眼液；
分别秤取MN-08药物粉末和结兰胶(Gelzan TMCM)粉末，用生理盐水配制含0.5％MN-08和0.6％Gelzan TMCM的MN-08凝胶液；
直接购买0.005％拉坦前列腺素滴眼液(辉瑞)。
3、实验分组及给药
将新西兰兔随机分为生理盐水组、MN-08滴眼液组(0.02％，0.1％，0.5％)、MN-08凝胶液组(0.5％)、阳性对照组(0.005％拉坦前列腺素)，每组5～8只。
新西兰兔短暂性青光眼模型造模成功后，立即给予上述不同浓度的药物或生理盐水滴眼液，检测各时间点眼内压变化。术后使用卡波姆滴眼液、左氧氟沙星滴眼液保持角膜湿润，以预防感染。
4、检测指标
测定注射高渗生理盐水前新西兰兔的眼内压(0min)作为正常眼内压值，分别于造模后1min、10min、30min、60min、90min、180min时间点测试各实验组动物的眼内压，以每个时间点3个眼内压测定值的平均值作为该点眼内压，观测给药后3h内药物对眼内压变化的影响。
5、数据统计
数据均用平均值±标准差表示，组间比较采用Repeated Measures，P＜0.05认为具有统计学差异。
6、实验结果
给药不同剂型和浓度的MN-08、拉坦前列腺素和生理盐水后新西兰兔短暂性青光眼模型眼内压变化情况如图4的列表所示，给予MN-08滴眼液后新西兰兔短暂性青光眼模型眼内压变化折线图如图1所示，给予MN-08凝胶剂后新西兰兔短暂性青 光眼模型眼内压变化如图2所示，MN-08注射液、滴眼液凝胶剂药效比较如图3所示。
研究结果显示，与生理盐水组相比，给予MN-08注射液(P＜0.05)、MN-08滴眼液(P＜0.05)和MN-08凝胶剂(P＜0.05)均能显著的改善新西兰兔短暂性青光眼模型的眼内压，且MN-08滴眼液和MN-08凝胶剂较注射液持续时间长，其中0.5％MN-08滴眼液组在给药90min后，眼内压仍低于生理盐水组，MN-08凝胶剂组在给药120min后，眼内压仍显著低于生理盐水组，表明MN-08眼用制剂较MN-08注射液具有更好的药效。
此外，对比MN-08凝胶剂(0.5％)与MN-08滴眼液(0.5％)数据显示，在相同浓度下，MN-08凝胶剂比滴眼液具有更长的作用时间与更好的降压作用。

Claims (9)

  1. 一种含有氨基金刚烷胺单硝酸酯类化合物的眼用组合物，其特征在于，所述组合物包含质量体积比为0.001％～5.0％的氨基金刚烷胺单硝酸酯类化合物；所述化合物具有通式(I)的结构或其在药学上可接受的盐：
    Figure PCTCN2018000282-appb-100001
    其中，R为氢，直链或支链烷基；n为1-6。
  2. 根据权利要求1所述的眼用组合物，其中所述氨基金刚烷胺单硝酸酯类化合物具有如下之一的结构式：
    Figure PCTCN2018000282-appb-100002
  3. 根据权利要求1所述的眼用组合物，其中所述眼用组合物被配制为眼用凝胶。
  4. 根据权利要求1所述的眼用组合物，其中所述眼用组合物被配制为眼用溶液。
  5. 根据权利要求3所述的眼用组合物，其中所述眼用组合物包含质量体积比为0.1％～10％的结兰胶、泊洛沙姆407、卡波姆、聚卡波菲、羟丙基甲基纤维素或其组合。
  6. 根据权利要求3所述的眼用组合物，其中所述组合物进一步包含缓释剂。
  7. 根据权利要求3或4所述的眼用组合物，其中所述眼用组合物进一步包含一种或多种药物制剂上可接受的辅料。
  8. 根据权利要求7所述的眼用组合物，其中所述辅料为增稠剂、等渗调节剂、张力调节剂、粘膜粘附剂、防腐剂、络合剂、缓冲剂、pH调节剂或其组合。
  9. 权利要求1至8任意一项所述的氨基金刚烷胺单硝酸酯类化合物眼用组合物在制备药物中的应用，其中所述药物用于预防和治疗青光眼或者伴有眼内压升高或视网膜神经节细胞损伤的其他眼科疾病。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101536974A (zh) * 2009-04-08 2009-09-23 南京医科大学 醋甲唑胺眼用温度敏感原位凝胶制剂及其制备方法
CN105294450A (zh) * 2014-05-29 2016-02-03 广州喜鹊医药有限公司 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用
CN106344551A (zh) * 2016-08-22 2017-01-25 广州喜鹊医药有限公司 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用
CN107412211A (zh) * 2017-08-04 2017-12-01 佛山喜鹊医药有限公司 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101536974A (zh) * 2009-04-08 2009-09-23 南京医科大学 醋甲唑胺眼用温度敏感原位凝胶制剂及其制备方法
CN105294450A (zh) * 2014-05-29 2016-02-03 广州喜鹊医药有限公司 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用
CN106344551A (zh) * 2016-08-22 2017-01-25 广州喜鹊医药有限公司 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用
CN107412211A (zh) * 2017-08-04 2017-12-01 佛山喜鹊医药有限公司 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用

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