CN112022801A - Sustained-release eye drops and preparation method thereof - Google Patents
Sustained-release eye drops and preparation method thereof Download PDFInfo
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- CN112022801A CN112022801A CN202010797120.4A CN202010797120A CN112022801A CN 112022801 A CN112022801 A CN 112022801A CN 202010797120 A CN202010797120 A CN 202010797120A CN 112022801 A CN112022801 A CN 112022801A
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- Prior art keywords
- release
- sustained
- drug
- nanoparticles
- ophthalmic
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Abstract
Description
技术领域technical field
本发明属于生物医药技术领域，涉及一种缓释滴眼液及其制备方法。The invention belongs to the technical field of biomedicine, and relates to a sustained-release eye drop and a preparation method thereof.
背景技术Background technique
眼部疾病的局部治疗以滴加眼药水为主，然而常规眼药水的生物利用率非常有限，95％以上的药物不能进入眼内，且进入体循环的药物还会造成一定的不良反应，因此提高眼药水的生物利用率非常重要。The topical treatment of eye diseases is mainly based on the addition of eye drops. However, the bioavailability of conventional eye drops is very limited. More than 95% of the drugs cannot enter the eyes, and the drugs entering the systemic circulation will also cause certain adverse reactions. The bioavailability of eye drops is very important.
另一方面，长期频繁的眼表给药还会导致患者依从性变差，只有31％-67％的患者能够坚持使用12个月，从而严重影响治疗效果。然而，眼部疾病的治疗，尤其是慢性眼病的治疗，往往最后会进入一种迁延不断治疗和复发的状态。On the other hand, long-term and frequent ocular surface administration will also lead to poor patient compliance, with only 31%-67% of patients being able to adhere to it for 12 months, which seriously affects the treatment effect. However, the treatment of eye diseases, especially chronic eye diseases, often ends up in a state of protracted treatment and recurrence.
因此，眼药水的生物利用率和患者依从性都亟待提高。Therefore, both the bioavailability and patient compliance of eye drops need to be improved.
缓释给药为眼部疾病的有效治疗提供了一种全新的思路。缓释制剂能明显延长药物作用时间，减少给药次数，维持稳定的药物浓度，既保证了眼部疾病治疗需要，又避免了大剂量药物对眼睛造成的局部毒性，可以显著减少不良反应，提高患者依从性。大量研究表明，缓释制剂可以很好地满足眼部疾病的长期治疗，然而眼部生理结构特殊，给药方式受限，眼部缓释给药往往需要一定的保障条件，稍显复杂的给药方法会给患者带来诸多不便。如何将药物有效性和给药便利性结合起来，构建出方便有效的缓释滴眼液一直是研究的热点。Sustained-release drug delivery provides a new idea for the effective treatment of ocular diseases. Sustained-release preparations can significantly prolong the action time of the drug, reduce the number of administrations, and maintain a stable drug concentration, which not only ensures the treatment of eye diseases, but also avoids the local toxicity caused by large doses of drugs to the eyes, which can significantly reduce adverse reactions and improve. Patient compliance. A large number of studies have shown that sustained-release preparations can well meet the long-term treatment of eye diseases. However, the physiological structure of the eye is special, and the way of administration is limited. Sustained-release preparations often require certain guarantee conditions, and the slightly complex administration is required. Medication can cause a lot of inconvenience to patients. How to combine drug effectiveness and administration convenience to construct convenient and effective sustained-release eye drops has always been a research hotspot.
就缓释滴眼液而言，目前常用具有良好生物相容性的聚合物增稠滴眼液，以增加药物在眼表的停留时间，如专利201710654331.0，201410369170.7，200410064366.1，201510981480.9，201711214786.7，200910162523.5等；或者通过温度敏感或静电相互作用形成原位凝胶，如专利200510095133.2，201611016165.3，201010148516.2等；纳米粒子负载药物的专利报道仅有少数，如专利201410246481.4等。到目前为止，还没有合适的缓释滴眼液用于临床。As far as sustained-release eye drops are concerned, polymer thickened eye drops with good biocompatibility are commonly used to increase the residence time of drugs on the ocular surface, such as patents 201710654331. Or form an in situ gel through temperature-sensitive or electrostatic interaction, such as patents 200510095133.2, 201611016165.3, 201010148516.2, etc. There are only a few patent reports on nanoparticles loaded with drugs, such as patent 201410246481.4. So far, there are no suitable sustained-release eye drops for clinical use.
发明内容SUMMARY OF THE INVENTION
为了克服现有技术的不足，本发明拟提供一种缓释滴眼液及其制备方法，以期显著提高药物的生物利用率和患者依从性。In order to overcome the deficiencies of the prior art, the present invention intends to provide a sustained-release eye drop and a preparation method thereof, in order to significantly improve the bioavailability of the drug and the compliance of patients.
为了实现上述目的，本发明提供了一种缓释滴眼液，其包括缓释药物和用于分散所述缓释药物的分散液，所述的缓释药物由眼部用药和缓释载体构成，所述缓释载体为复合纳米材料，包含纳米粒子和连接于纳米粒子外部的表面功能修饰层；所述的纳米粒子之间形成若干连通空隙，用于负载或输送所述的眼部用药；所述的表面功能修饰层通过与纳米粒子的连接或断开，控制其所负载的眼部用药的释放和扩散速率。In order to achieve the above purpose, the present invention provides a sustained-release eye drop, comprising a sustained-release drug and a dispersion for dispersing the sustained-release drug, and the sustained-release drug is composed of an ophthalmic drug and a sustained-release carrier , the sustained-release carrier is a composite nanomaterial, comprising nanoparticles and a surface functional modification layer connected to the outside of the nanoparticles; a number of connected voids are formed between the nanoparticles for loading or delivering the ophthalmic medication; The surface functional modification layer controls the release and diffusion rate of the ophthalmic drug loaded by the surface functional modification layer by connecting or disconnecting the nanoparticle.
可选的，所述的纳米粒子构成多层层状纳米结构(单个的纳米粒子呈片状)，层间留置有用于稳定负载药物的若干空隙。所述的复合纳米材料内部的纳米粒子包含大量连通孔隙，用于负载和输送药物；外部的表面功能修饰层连接内部的纳米粒子，并控制所负载药物的释放和扩散速率。复合纳米材料内部和表面的微观孔隙(多个片状纳米粒子组装在一起就可能形成内部孔隙和表面孔隙)是相互连通的，允许物质通过，包括水分子向缓释药物内部的扩散，以及药物分子和复合纳米材料降解产物的扩散排出；可依据所负载药物的物理化学性质和给药要求来调节表面功能修饰层，以实现更好的药物缓释效果。药物物理化学性质包括分子量、水溶性、荷电性和渗透性等。具体给药要求包括药物释放模式、给药周期和药物体内半衰期等；对于一定的缓释体系，其药物释放模式是确定的，或匀速释放，或先快后慢，或先慢后快，或出现更复杂的快慢交替模式；对于需要给药周期长或者半衰期短的药物的输送，需要在一定的释放模式下增加缓释系统中药物的负载量，并调节微观载体材料更慢降解，以实现更长时间的药物平稳释放，或更少的药物损失(失效)。Optionally, the nanoparticles form a multi-layered nanostructure (individual nanoparticles are in the shape of sheets), and several voids for stably loading the drug are left between the layers. The nanoparticle inside the composite nanomaterial contains a large number of interconnected pores for loading and delivering drugs; the outer surface functional modification layer connects the inner nanoparticle and controls the release and diffusion rate of the loaded drug. The microscopic pores inside and on the surface of composite nanomaterials (multiple sheet-like nanoparticles may be assembled together to form internal pores and surface pores) are interconnected, allowing substances to pass through, including the diffusion of water molecules into the interior of the slow-release drug, as well as the drug Diffusion and discharge of degradation products of molecules and composite nanomaterials; the surface functional modification layer can be adjusted according to the physicochemical properties of the loaded drug and drug delivery requirements to achieve better sustained drug release effect. The physicochemical properties of drugs include molecular weight, water solubility, chargeability, and permeability. Specific administration requirements include drug release mode, administration period, and drug in vivo half-life; for a certain sustained-release system, the drug release mode is determined, or uniform release, or fast and then slow, or slow and then fast, or A more complex alternating mode of fast and slow appears; for the delivery of drugs that require a long administration period or a short half-life, it is necessary to increase the drug load in the sustained-release system under a certain release mode, and adjust the microscopic carrier material to degrade more slowly to achieve Longer drug release, or less drug loss (failure).
可选的，所述的纳米粒子选择金属氢氧化物纳米粒子或蒙脱土纳米粒子。纳米粒子构成多层层状纳米结构，层间留有大量空隙，可以稳定负载药物。所述的金属氢氧化物纳米粒子内部纳米层中富含金属阳离子，使纳米粒子具有多余的正电荷，可以与荷负电的药物或聚合物发生静电相互作用，负载药物或吸附固定聚合物；所述的蒙脱土纳米粒子内部包含纳米厚度的带负电的硅酸盐片层，使纳米粒子具有多余的负电荷，可以与荷正电的药物或聚合物发生静电相互作用，负载药物或吸附固定聚合物。特别的，纳米粒子的大小介于10-300nm之间；更特别的，纳米粒子的大小介于20-200nm。在本发明中，用载体材料负载药物，具有如下作用：在给药初期，药物储备充足，此时药物被载体材料束缚，可以避免药物突然大量释放；随着给药过程持续进行，可降解载体材料逐渐降解；在给药后期，药物储备较少，此时可降解载体材料基本降解，解除了对药物的束缚，能保证足够药物释放；采用可降解载体材料负载药物有利于形成稳定的药物浓度。Optionally, the nanoparticles are selected from metal hydroxide nanoparticles or montmorillonite nanoparticles. Nanoparticles form a multi-layered nanostructure with a large number of voids between the layers, which can stably load drugs. The inner nanolayer of the metal hydroxide nanoparticle is rich in metal cations, so that the nanoparticle has excess positive charge, which can electrostatically interact with negatively charged drugs or polymers, load drugs or adsorb and fix polymers; The described montmorillonite nanoparticles contain a nanometer-thick negatively charged silicate sheet, which makes the nanoparticles have excess negative charges, which can electrostatically interact with positively charged drugs or polymers, load drugs or adsorb and fix them. polymer. In particular, the size of the nanoparticles is between 10-300 nm; more particularly, the size of the nanoparticles is between 20-200 nm. In the present invention, the carrier material is used to load the drug, which has the following effects: in the initial stage of administration, the drug reserve is sufficient, and the drug is bound by the carrier material at this time, which can avoid the sudden release of the drug in large quantities; as the administration process continues, the degradable carrier The material is gradually degraded; in the late stage of administration, the drug reserve is small, and the degradable carrier material is basically degraded, which relieves the bondage of the drug and ensures sufficient drug release; using the degradable carrier material to load the drug is conducive to the formation of a stable drug concentration .
可选的，所述的表面功能修饰层的材料选择聚乙二醇、聚乙烯醇、聚乙烯基吡咯烷酮、聚己内酯、聚甲基丙烯酸甲酯，聚甲基丙烯酸羟乙酯、聚乳酸-羟基乙酸共聚物、聚乳酸-羟基乙酸共聚物与聚乙二醇的嵌段共聚物，壳聚糖、海藻酸钠、透明质酸钠、明胶、胶原、聚氨基酸、蛋白质中的任意一种，或者任意两种以上的混合物。Optionally, the material of the surface function modification layer is selected from polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polycaprolactone, polymethyl methacrylate, polyhydroxyethyl methacrylate, polylactic acid. -Glycolic acid copolymer, polylactic acid-glycolic acid copolymer and polyethylene glycol block copolymer, any one of chitosan, sodium alginate, sodium hyaluronate, gelatin, collagen, polyamino acid and protein , or a mixture of any two or more.
可选的，所述的表面功能修饰层通过物理吸附作用连接到纳米粒子表面或者纳米粒子内限定所述空隙的内壁；所述的表面功能修饰层，对内，稳定负载药物并控制药物释放和扩散；对外，通过同性相斥作用保持载体材料在分散液中的均匀分散，通过伪装效应避免载体材料在体内输送过程中被免疫系统清除，通过生物分子特异性识别促进载药纳米粒子向眼内目标组织或细胞的靶向给药。Optionally, the surface functional modification layer is connected to the surface of the nanoparticle or the inner wall of the nanoparticle that defines the void through physical adsorption; the surface functional modification layer, on the inside, stably loads the drug and controls the drug release and release. Diffusion; externally, the uniform dispersion of the carrier material in the dispersion is maintained through homosexual repulsion, the camouflage effect is used to prevent the carrier material from being cleared by the immune system during in vivo delivery, and the specific recognition of biomolecules promotes drug-loaded nanoparticles to the eye. Targeted drug delivery to target tissues or cells.
可选的，所述的缓释载体负载的眼部用药选择如下药物的一种或几种：Optionally, one or more of the following drugs are selected for the ophthalmic drug loaded by the sustained-release carrier:
(1)眼表常用抗生素及抗炎药，其包含如下药物的任意一种或几种：喹诺酮类抗生素；氨基糖苷类抗生素；四环素类抗生素；大环内酯抗生素；皮质类固醇药；非类固醇抗炎药；非穿透性类固醇；游离酸类固醇；抗组胺药；(1) Commonly used antibiotics and anti-inflammatory drugs on the ocular surface, which include any one or more of the following drugs: quinolone antibiotics; aminoglycoside antibiotics; tetracycline antibiotics; macrolide antibiotics; corticosteroids; Inflammatory drugs; non-penetrating steroids; free acid steroids; antihistamines;
(2)抗青光眼药物，其包含如下药物的任意一种或几种：β-肾上腺能受体阻滞剂；α-肾上腺能受体激动剂；碳酸酐酶抑制剂；前列腺素和前列腺素类似物；(2) Anti-glaucoma drugs, which include any one or more of the following drugs: β-adrenergic receptor blockers; α-adrenergic receptor agonists; carbonic anhydrase inhibitors; prostaglandins and prostaglandins similar thing;
(3)免疫调节药物，其包含如下药物的任意一种或几种：环孢霉素，他克莫司，小分子整联蛋白拮抗剂，整合素拮抗剂；(3) immunomodulatory drugs, comprising any one or more of the following drugs: cyclosporine, tacrolimus, small molecule integrin antagonists, and integrin antagonists;
(4)眼用营养类药物，其包含如下药物的任意一种或几种：维生素，脂肪酸，脂肪醇，鲸蜡醇，硬脂醇；所述的脂肪酸优选长链脂肪酸；(4) ophthalmic nutritional medicine, which comprises any one or more of the following medicines: vitamin, fatty acid, fatty alcohol, cetyl alcohol, stearyl alcohol; Described fatty acid is preferably long-chain fatty acid;
(5)抗代谢药物，其包含：丝裂霉素C和/或5-氟尿嘧啶。(5) Antimetabolites comprising: mitomycin C and/or 5-fluorouracil.
可选的，所述的喹诺酮类抗生素选自由诺氟沙星、氧氟沙星、左氧氟沙星、环丙沙星、洛美沙星组成的群组；所述的氨基糖苷类抗生素选自由链霉素、卡那霉素、妥布霉素、新霉素、大观霉素、庆大霉素、西索霉素、小诺霉素、阿米卡星、奈替米星组成的群组；所述的四环素类抗生素选自由四环素、金霉素、土霉素、多西环素、美他环素、强力霉素、米诺环素组成的群组；所述的大环内酯抗生素选自由阿奇霉素、红霉素组成的群组；所述的皮质类固醇药选自由氟米龙、地塞米松、强的松、氢化可的松、氯替泼诺组成的群组；所述的β-肾上腺能受体阻滞剂选自由噻吗洛尔、卡替洛尔、左布诺洛尔、倍他洛尔组成的群组；所述的α-肾上腺能受体激动剂选自由可乐定、溴莫尼定、甲基多巴组成的群组；所述的碳酸酐酶抑制剂选自由多佐胺、或布林佐胺组成的群组；所述的前列腺素和前列腺素类似物选自由比马前列素、曲伏前列素、拉坦前列素、他氟前列腺素组成的群组。Optionally, the quinolone antibiotic is selected from the group consisting of norfloxacin, ofloxacin, levofloxacin, ciprofloxacin, lomefloxacin; the aminoglycoside antibiotic is selected from streptomycin, The group consisting of kanamycin, tobramycin, neomycin, spectinomycin, gentamicin, sisomycin, small noromycin, amikacin, netilmicin; said Tetracycline antibiotics are selected from the group consisting of tetracycline, chlortetracycline, oxytetracycline, doxycycline, metacycline, doxycycline, and minocycline; the macrolide antibiotics are selected from azithromycin, The group consisting of erythromycin; the corticosteroid drug is selected from the group consisting of fluorometholone, dexamethasone, prednisone, hydrocortisone, and loteprednol; the β-adrenergic receptor The body blocker is selected from the group consisting of timolol, carteolol, levobunolol, and betaxolol; the α-adrenergic receptor agonist is selected from clonidine, brimonil The group consisting of dexamethasone and methyldopa; the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide or brinzolamide; the prostaglandin and prostaglandin analogs are selected from bimatoprost group consisting of travoprost, latanoprost, and tafluprost.
可选的，所述的眼部用药在缓释载体中的负载量占缓释药物总质量的不超过30％；特别的，所述的眼部用药在缓释载体中的负载量占缓释药物总质量的0.5-10％；更特别的，所述的眼部用药在缓释载体中的负载量占缓释药物总质量的1-5％。Optionally, the loading of the ophthalmic drug in the sustained-release carrier accounts for no more than 30% of the total mass of the sustained-release drug; in particular, the loading of the ophthalmic drug in the sustained-release carrier accounts for the sustained-release drug 0.5-10% of the total mass of the drug; more particularly, the loading amount of the ophthalmic drug in the sustained-release carrier accounts for 1-5% of the total mass of the sustained-release drug.
可选的，所述的缓释药物和分散液分别封装，使用时再即时混匀。Optionally, the sustained-release drug and the dispersion are packaged separately, and then mixed immediately during use.
本发明还提供了一种所述缓释滴眼液的制备方法，其包含：The present invention also provides a preparation method of the sustained-release eye drops, comprising:
步骤1，合成具有层状纳米结构的纳米粒子；Step 1, synthesizing nanoparticles with a layered nanostructure;
步骤2，在所述的纳米粒子表面或其内部空隙表面构建表面功能修饰层，形成缓释材料；
步骤3，将眼部用药负载于所述缓释材料内部的空隙中，并制备成固体缓释药物粉末；Step 3, loading the ophthalmic medicine into the space inside the slow-release material, and preparing it into a solid slow-release medicine powder;
步骤4，将所述的固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。
和现有技术相比，本发明的有益效果在于：Compared with the prior art, the beneficial effects of the present invention are:
本发明提供了一种缓释滴眼液，依靠复合纳米材料多孔结构及表面功能修饰层，在载体材料逐渐降解过程中实现所负载药物的平稳释放。该缓释滴眼液制备方法简单、成本低廉、能高效平稳释放药物，便于长期稳定存储；患者可以根据自身病情简单且方便使用；该缓释滴眼液技术可以对眼表、泪道以及眼内给药。The invention provides a sustained-release eye drop, which relies on the porous structure of the composite nanomaterial and the surface functional modification layer to realize the steady release of the loaded drug during the gradual degradation of the carrier material. The sustained-release eye drops have a simple preparation method, low cost, can efficiently and stably release drugs, and are convenient for long-term stable storage; patients can use it simply and conveniently according to their own conditions; Internal administration.
附图说明Description of drawings
图1为本发明的一种缓释滴眼液示意图。FIG. 1 is a schematic diagram of a slow-release eye drop of the present invention.
图2为分别采用常规滴眼液(a)和本发明的缓释滴眼液(b)用药后，药物浓度曲线示意图。Figure 2 is a schematic diagram of the drug concentration curve after the conventional eye drops (a) and the sustained-release eye drops (b) of the present invention are respectively used for administration.
图3a为本发明的一种缓释滴眼液的缓释载体的表面修饰和载药示意图。Figure 3a is a schematic diagram of surface modification and drug loading of a sustained-release carrier of a sustained-release eye drop of the present invention.
图3b为本发明采用的金属氢氧化物纳米粒子的SEM图。Figure 3b is a SEM image of the metal hydroxide nanoparticles used in the present invention.
图4a为本发明采用的蒙脱土纳米粒子的SEM图。Figure 4a is a SEM image of the montmorillonite nanoparticles used in the present invention.
图4b为本发明的另一种缓释滴眼液的缓释载体的表面修饰和载药示意图。Figure 4b is a schematic diagram of the surface modification and drug loading of the sustained-release carrier of another sustained-release eye drop of the present invention.
图5为溴莫尼定@金属氢氧化物纳米粒子和溴莫尼定@金属氢氧化物纳米粒子@聚合物纳米胶束体外缓释曲线。Figure 5 shows the sustained release curves of brimonidine@metal hydroxide nanoparticles and brimonidine@metal hydroxide nanoparticles@polymer nanomicelles in vitro.
附图标记说明Description of reference numerals
缓释滴眼液100Sustained Release Eye Drops 100
缓释药物1Sustained Release Drug 1
分散液2
眼部用药10
纳米粒子21
表面功能修饰层22。Surface
具体实施方式Detailed ways
下面将结合附图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做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 with reference to the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
在本发明的描述中，需要说明的是，术语“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本发明和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本发明的限制。In the description of the present invention, it should be noted that the orientation or positional relationship indicated by the terms "inside", "outside", etc. is based on the orientation or positional relationship shown in the accompanying drawings, and is only for the convenience of describing the present invention and simplifying the description, It is not intended to indicate or imply that the device or element referred to must have a particular orientation, be constructed and operate in a particular orientation, and therefore should not be construed as limiting the invention.
在本发明的描述中，需要说明的是，除非另有明确的规定和限定，术语“安装”、“相连”、“连接”应做广义理解，例如，可以是固定连接，也可以是可拆卸连接，或一体地连接；可以是机械连接；可以是直接相连，也可以通过中间媒介间接相连，可以是两个元件内部的连通。对于本领域的普通技术人员而言，可以具体情况理解上述术语在本发明中的具体含义。In the description of the present invention, it should be noted that the terms "installed", "connected" and "connected" should be understood in a broad sense, unless otherwise expressly specified and limited, for example, it may be a fixed connection or a detachable connection Connection, or integral connection; it can be a mechanical connection; it can be a direct connection, or an indirect connection through an intermediate medium, and it can be the internal communication of two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood in specific situations.
如图1所示，一种缓释滴眼液100包括：缓释药物1和用于分散所述缓释药物的分散液2。As shown in FIG. 1 , a sustained-
如图3a所示，所述的缓释药物1由眼部用药10和缓释载体构成，所述缓释载体为复合纳米材料，包含若干纳米粒子21和连接于纳米粒子外部的表面功能修饰层22；所述的纳米粒子之间形成若干连通空隙，用于负载或输送所述的眼部用药10；所述的表面功能修饰层22通过与纳米粒子21的连接或断开，控制其所负载的眼部用药10的释放和扩散速率。As shown in Figure 3a, the sustained-release drug 1 is composed of an
纳米材料是由多个片状纳米粒子组装形成，片状纳米粒子之间形成空隙，片状纳米粒子不一定是平行组装，可以以一定的角度组装。多个片状纳米粒子组装在一起就可能形成内部孔隙和表面孔隙；如果是平行组装，涉及到内部空隙；如果是非平行组装，就会存在内部孔隙和表面孔隙；这里所述的复合纳米材料泛指能独立分散的纳米粒子或纳米粒子组合体。Nanomaterials are formed by the assembly of multiple sheet-like nanoparticles, and voids are formed between sheet-like nanoparticles. Sheet-like nanoparticles are not necessarily assembled in parallel, but can be assembled at a certain angle. Multiple sheet-like nanoparticles assembled together may form internal pores and surface pores; if parallel assembly, internal voids are involved; if non-parallel assembly, there will be internal pores and surface pores; the composite nanomaterials described here are generalized. Refers to nanoparticles or nanoparticle assemblies that can be dispersed independently.
如图2所示，分别采用常规滴眼液(a)和本发明的缓释滴眼液(b)用药后，眼中药物浓度曲线示意图。可见，本发明的缓释滴眼液能高效平稳释放药物，患者可以根据自身病情灵活使用。As shown in FIG. 2 , after the conventional eye drops (a) and the sustained-release eye drops (b) of the present invention are respectively used for administration, the schematic diagram of the drug concentration curve in the eye. It can be seen that the sustained-release eye drops of the present invention can release medicines efficiently and stably, and patients can use them flexibly according to their own conditions.
所述的表面功能修饰层22由具有良好生物相容性的生物材料构成；包括聚乙二醇、聚乙烯醇、聚乙烯基吡咯烷酮、聚甲基丙烯酸甲酯，聚甲基丙烯酸羟乙酯、聚乳酸-羟基乙酸共聚物、聚乳酸-羟基乙酸共聚物与聚乙二醇的嵌段共聚物，壳聚糖、海藻酸钠、透明质酸钠、明胶、胶原、聚氨基酸、蛋白质，或者它们的混合物。The surface
所述的表面功能修饰层通过物理吸附作用连接到载体材料表面，或者载体材料内部孔隙表面。连接于纳米粒子表面或孔隙表面的表面功能修饰层的作用包括：1)对内：稳定负载药物，并控制药物释放和扩散，表面功能修饰层与纳米粒子一起形成了药物释放双重调节机制；2)对外：(1)通过同性相斥作用力保持载体材料在分散液中的均匀分散，纳米粒子体系属于胶体系统，保持纳米粒子之间的相互排斥才能稳定胶体系统，得到分散良好的缓释滴眼液；(2)通过伪装效应避免复合纳米材料在体内输送过程中被免疫系统清除，具有良好生物相容性的聚合物分子修饰的纳米粒子能够一定程度被体内免疫系统容忍，增加载药纳米粒子的体内循环时间；(3)通过生物分子识别促进复合纳米材料向眼内渗透扩散，特定表面修饰分子能够被细胞膜表面的蛋白质识别，增加目标细胞吞噬载药纳米粒子的比例，提高药物作用效率。The surface functional modification layer is connected to the surface of the carrier material or the inner pore surface of the carrier material through physical adsorption. The functions of the surface functional modification layer connected to the surface of the nanoparticle or the pore surface include: 1) Internally: stabilize the loaded drug, and control the release and diffusion of the drug, the surface functional modification layer and the nanoparticle together form a dual regulation mechanism for drug release; 2 ) External: (1) The uniform dispersion of the carrier material in the dispersion liquid is maintained through the same-sex repulsion force. The nanoparticle system belongs to the colloidal system, and the colloidal system can be stabilized only by maintaining the mutual repulsion between the nanoparticles, and a well-dispersed sustained-release droplet can be obtained. Eye drops; (2) Avoid composite nanomaterials from being cleared by the immune system during in vivo delivery through the camouflage effect. Nanoparticles modified by polymer molecules with good biocompatibility can be tolerated by the immune system to a certain extent, increasing the number of drug-loaded nanomaterials. The in vivo circulation time of the particles; (3) Promote the penetration and diffusion of composite nanomaterials into the eye through biomolecular recognition, specific surface modification molecules can be recognized by proteins on the surface of the cell membrane, increase the proportion of target cells phagocytosing drug-loaded nanoparticles, and improve the efficiency of drug action .
实施例1Example 1
一种缓释滴眼液，其包含缓释药物1和分散液2。如图3a所示，缓释药物1包含眼部用药10和缓释载体。该缓释载体包含：纳米粒子21及表面功能修饰层22。其中，所述的纳米粒子21选择金属氢氧化物纳米粒子，其SEM图如图3b所示；构成所述表面功能修饰层22的生物材料为透明质酸钠。缓释载体负载的眼部用药10为小分子整联蛋白拮抗剂(small-molecule integrin antagonist)，其在缓释载体中的负载量占缓释药物1总质量的2％。A sustained-release eye drop comprising a sustained-release drug 1 and a
本发明的缓释滴眼液的制备方法包含：The preparation method of the sustained-release eye drops of the present invention comprises:
步骤1，采用水热法合成金属氢氧化物纳米粒子，具体包括：分别配制氯化镁和氯化铝两种盐溶液，与氢氧化钠碱溶液；将盐溶液与碱溶液混合，形成混悬液，装入高压反应釜中，加热高压高热，形成粒径均匀的纳米粒子。该方法只是一种示例，采用其他现有方法制备的金属氢氧化物纳米粒子也适用本发明。Step 1, adopting a hydrothermal method to synthesize metal hydroxide nanoparticles, which specifically includes: separately preparing two salt solutions, magnesium chloride and aluminum chloride, and sodium hydroxide alkali solution; mixing the salt solution and the alkali solution to form a suspension, Put it into an autoclave, heat under high pressure and high heat to form nanoparticles with uniform particle size. This method is just an example, and the metal hydroxide nanoparticles prepared by other existing methods are also applicable to the present invention.
步骤2，采用透明质酸钠，通过物理吸附的方法，修饰所述的金属氢氧化物纳米粒子；即，将纳米粒子分散液与表面修饰材料溶液(透明质酸钠)混合，搅拌，然后离心，即可；
步骤3，然后将小分子整联蛋白拮抗剂(small-molecule integrin antagonist)负载于表面修饰后的金属氢氧化物纳米粒子中，冷冻干燥获得载药固体粉末；最后，将固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。所述载药的过程，是将表面修饰后的纳米粒子与小分子整联蛋白拮抗剂混合，搅拌，离心，即可。In step 3, the small-molecule integrin antagonist (small-molecule integrin antagonist) is then loaded into the surface-modified metal hydroxide nanoparticles, and freeze-dried to obtain a drug-loaded solid powder; finally, the solid sustained-release drug powder is sterilized. The bacteria, together with the dispersion liquid, are separately packaged in dry and wet separation type eye drop bottles. In the process of drug loading, the surface-modified nanoparticles are mixed with the small molecule integrin antagonist, stirred and centrifuged.
在缓释滴眼液制备过程中，为了实现不同的阶段目标，所用的溶液需要调整，比如有机相或水相，或者不同的pH环境等。During the preparation of sustained-release eye drops, in order to achieve different stage goals, the solution used needs to be adjusted, such as organic phase or aqueous phase, or different pH environment.
实施例2Example 2
一种缓释滴眼液，其中，所述的纳米粒子21选择蒙脱土纳米粒子，其SEM图如图4a所示；由于蒙脱土团聚严重，因此SEM图中纳米粒子轮廓不是很清楚。构成所述表面功能修饰层22的生物材料为阳离子明胶；蒙脱土纳米粒子、表面功能修饰层和载药的结构示意图如图4b所示。缓释载体负载的眼部用药10为抗炎药类药物地塞米松(dexamethasone)；该药物在缓释载体中的负载量占缓释药物1总质量的3％。A sustained-release eye drop, wherein the
在制备过程中，首先合成蒙脱土纳米粒子，再用阳离子明胶通过物理吸附的方法修饰蒙脱土纳米粒子，然后将地塞米松(dexamethasone)负载于表面修饰后的蒙脱土纳米粒子中，冷冻干燥获得载药固体粉末；最后，将固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。In the preparation process, montmorillonite nanoparticles were first synthesized, and then cationic gelatin was used to modify the montmorillonite nanoparticles by physical adsorption, and then dexamethasone was loaded into the surface-modified montmorillonite nanoparticles. The drug-loaded solid powder is obtained by freeze-drying; finally, the solid sustained-release drug powder is sterilized, and together with the dispersion liquid, it is separately packaged in a dry and wet separation type eye drop bottle.
蒙脱土是一类由纳米厚度的表面带负电的硅酸盐片层，依靠层间的静电作用而堆积在一起构成的土状矿物。蒙脱土的合成一般包括分离提纯和改性，因为是自然界天然矿物，因此需要去掉杂质，只保留纳米级别的纳米粒子，改性主要是酸化或者有机化，为了增加蒙脱土的负载能力和生存能力。Montmorillonite is a kind of soil-like mineral composed of nanometer-thick negatively charged silicate sheets stacked together by electrostatic interaction between the layers. The synthesis of montmorillonite generally includes separation, purification and modification. Because it is a natural mineral, it is necessary to remove impurities and only retain nano-sized nanoparticles. The modification is mainly acidification or organicization. In order to increase the load capacity of montmorillonite and survivability.
明胶本身是电荷平衡的生物大分子，为了增加明胶分子的电吸附性能，本发明采用某些小分子与明胶表面的羧基反应，闭合掉相应的负电荷，使明胶分子中氨基过剩，整体表现为荷正电，即得到阳离子明胶。阳离子明胶荷正电，可以与荷负电的蒙脱土纳米粒子发生静电吸附作用，从而表现改性纳米粒子。Gelatin itself is a charge-balanced biological macromolecule. In order to increase the electro-adsorption performance of gelatin molecules, the present invention adopts some small molecules to react with carboxyl groups on the surface of gelatin to close off the corresponding negative charges, so that amino groups in the gelatin molecules are excessive, and the overall performance is a charge. Positively charged, cationic gelatin is obtained. Cationic gelatin is positively charged and can electrostatically adsorb with negatively charged montmorillonite nanoparticles, thereby expressing modified nanoparticles.
地塞米松是荷正电的药物分子，通常为了增加水中溶解性，制备成醋酸地塞米松水溶液，荷正电的地塞米松与荷负电的蒙脱土纳米了粒子相互吸引，负载地塞米松到纳米粒子中，具体方法类似于前面描述的搅拌吸附法。Dexamethasone is a positively charged drug molecule. Usually, in order to increase the solubility in water, it is prepared into an aqueous solution of dexamethasone acetate. into nanoparticles, the specific method is similar to the previously described stirring adsorption method.
实施例3Example 3
一种缓释滴眼液，所述的纳米粒子21选择金属氢氧化物纳米粒子；构成所述表面功能修饰层的生物材料为海藻酸钠；缓释载体负载的眼部用药为左氧氟沙星(levofloxacin)；眼部用药在缓释载体中的负载量占缓释药物总质量的1.5％。A sustained-release eye drop, the
在制备过程中，首先通过水热合成法制备金属氢氧化物纳米粒子，再用海藻酸钠通过物理吸附的方法修饰金属氢氧化物纳米粒子，然后将左氧氟沙星(levofloxacin)负载于表面修饰后的金属氢氧化物纳米粒子中，冷冻干燥获得载药固体粉末；最后，将固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。In the preparation process, metal hydroxide nanoparticles were first prepared by hydrothermal synthesis, then the metal hydroxide nanoparticles were modified by physical adsorption with sodium alginate, and then levofloxacin was loaded on the surface-modified metal In the hydroxide nanoparticles, freeze-drying is performed to obtain a drug-loaded solid powder; finally, the solid sustained-release drug powder is sterilized, and together with the dispersion, it is packaged in a dry and wet separation type eye drop bottle.
实施例4Example 4
一种缓释滴眼液，所述的纳米粒子21选择蒙脱土纳米粒子；构成所述表面功能修饰层的生物材料为聚乙烯基吡咯烷酮(荷正电型)；缓释载体负载的药物为噻吗洛尔(timolol)；药物在缓释载体中的负载量占缓释药物总质量的4.5％。A sustained-release eye drop, the
在制备过程中，首先制备蒙脱土纳米粒子；再用聚乙烯基吡咯烷酮通过静电吸附法修饰蒙脱土纳米粒子，然后将噻吗洛尔(timolol)负载于表面修饰后的蒙脱土纳米粒子中，冷冻干燥获得载药固体粉末；最后，将固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。In the preparation process, montmorillonite nanoparticles were first prepared; then polyvinylpyrrolidone was used to modify the montmorillonite nanoparticles by electrostatic adsorption, and then timolol was loaded on the surface-modified montmorillonite nanoparticles In the process, the drug-loaded solid powder is obtained by freeze-drying; finally, the solid sustained-release drug powder is sterilized, and together with the dispersion liquid, it is respectively packaged in a dry and wet separation type eye drop bottle.
实施例5Example 5
一种缓释滴眼液，所述的纳米粒子21选择金属氢氧化物纳米粒子；构成所述表面功能修饰层的生物材料为聚乙二醇-聚乳酸-羟基乙酸共聚物-聚乙二醇嵌段共聚物；缓释载体负载的眼部用药为酒石酸溴莫尼定(brimonidine tartrate)；眼部用药在缓释载体中的负载量占缓释药物总质量的1.5％。A slow-release eye drop, the
在制备过程中，首先通过水热法制备金属氢氧化物纳米粒子；再用聚乙二醇-聚乳酸-羟基乙酸共聚物-聚乙二醇嵌段共聚物通过物理吸附法修饰金属氢氧化物纳米粒子，然后将酒石酸溴莫尼定(brimonidine tartrate)静电吸附负载于表面修饰后的金属氢氧化物纳米粒子中，冷冻干燥获得载药固体粉末；最后，将固体缓释药物粉末灭菌，连同分散液一起，分别封装于干湿分离型滴眼液瓶中。溴莫尼定@金属氢氧化物纳米粒子(Bri@LDH)和溴莫尼定@金属氢氧化物纳米粒子@聚合物纳米胶束(Bri@LDH@Polymer)体外缓释曲线如图5所示，可见，增加聚合物表面修饰层后，溴莫尼定的缓释效果更好。单纯的纳米粒子缓释药物作用较弱，突释现象明显，持续时间较短，而用聚合物表面修饰纳米粒子之后，水分子的渗入和药物的释放溶出都变得较为困难，药物释放曲线舒缓了很多，突释现象被抑制了，药物释放持续时间也变长了。用复合材料的两级释放控制明显优于纳米粒子的一级释放控制。In the preparation process, metal hydroxide nanoparticles were first prepared by hydrothermal method; then metal hydroxide was modified by physical adsorption method with polyethylene glycol-polylactic acid-glycolic acid copolymer-polyethylene glycol block copolymer. Nanoparticles, then brimonidine tartrate is electrostatically adsorbed and loaded into the surface-modified metal hydroxide nanoparticles, and freeze-dried to obtain drug-loaded solid powder; finally, the solid sustained-release drug powder is sterilized, together with The dispersions are packaged together in wet and dry separate eye drop bottles. The sustained release curves of brimonidine@metal hydroxide nanoparticles (Bri@LDH) and brimonidine@metal hydroxide nanoparticles@polymer nanomicelles (Bri@LDH@Polymer) in vitro are shown in Fig. 5 , it can be seen that after adding the polymer surface modification layer, the sustained release effect of brimonidine is better. Simple nanoparticle sustained-release drug has weaker effect, obvious burst release phenomenon, and short duration. However, when nanoparticles are modified with polymer surface, the infiltration of water molecules and the release and dissolution of drugs become more difficult, and the drug release curve is relieved. A lot, the burst release phenomenon is suppressed, and the drug release duration is also longer. The two-stage release control with composites is significantly better than the one-stage release control with nanoparticles.
所述的物理吸附法是指：聚乙二醇-聚乳酸-羟基乙酸共聚物-聚乙二醇嵌段共聚物在水中溶解后会形成纳米胶束，纳米胶束空心核内可以负载纳米粒子，聚合物分子可以自组装到纳米粒子表面。The physical adsorption method refers to: the polyethylene glycol-polylactic acid-glycolic acid copolymer-polyethylene glycol block copolymer will form nano micelles after dissolving in water, and nanoparticles can be loaded in the hollow core of the nano micelles. , polymer molecules can self-assemble onto the nanoparticle surface.
所述的静电吸附法是指：酒石酸溴莫尼定在酒石酸过量情况下荷负电，可以负载到荷正电的金属氢氧化物纳米粒子中。The electrostatic adsorption method means that brimonidine tartrate is negatively charged in the case of excess tartaric acid, and can be loaded into positively charged metal hydroxide nanoparticles.
本文所述的眼部用药可以是如下药物的一种或几种：(1)眼表常用抗生素及抗炎药：喹诺酮类抗生素(quinolone)，如诺氟沙星(norfloxacin)、氧氟沙星(ofloxacine)、洛美沙星(lomefloxacin)、左氧氟沙星(levofloxacin)、环丙沙星(ciprofloxacin)；氨基糖苷类抗生素(aminoglycesides)，如卡那霉素(kanamycin)、妥布霉素(tobramycin)、链霉素(streptomycin)、新霉素(neomycin)、大观霉素(spectinomycin)、庆大霉素(gentamicin)、西索霉素(sisomicin)、小诺霉素(micronomicin)、阿米卡星(amikacin)、奈替米星(netilmicin)；四环素类抗生素，如四环素(tetracycline)、美他环素(methacycline)、强力霉素(medomycin)、金霉素(chlotetracycline)、土霉素(oxytetracycline)、多西环素(doxycycline)、米诺环素(minocycline)；大环内酯抗生素(macrolides antibiotics)，如阿奇霉素(azithromycin)、红霉素(erythromycin)；皮质类固醇药(corticosteroids)，如强的松(prednisone)、氢化可的松(hydrocortisone)、氟米龙(fluoromethalone)、地塞米松(dexamethasone)、氯替泼诺(loteprednol)；非类固醇抗炎药(nonsteroidal anti-inflammatory drugs)；非穿透性类固醇(non-penetrating steroid)；游离酸类固醇(freeacid of steroid)；抗组胺药(antihistamine)。(2)抗青光眼药物：β-肾上腺能受体阻滞剂(β-receptor blocker)，如噻吗洛尔(timolol)、左布诺洛尔(levobunolol)、倍他洛尔(betaxolol)、卡替洛尔(carteolol)；α-肾上腺能受体激动剂(α-adrenoceptoragonists)，如可乐定(clonidine)、溴莫尼定(brimonidine)、甲基多巴(methytdopa)；碳酸酐酶抑制剂(carbonic anhydrase inhibitor)，如多佐胺(dorzolamide)、布林佐胺(brinzolamide)；前列腺素(prostaglandin)和前列腺素类似物(prostaglandin analog)，如比马前列素(bimatoprost)、拉坦前列素(latanoprost)、曲伏前列素(travoprost)、他氟前列腺素(tafluprost)。(3)免疫调节药物：环孢霉素(cyclosporine A)，他克莫司(tacrolimus)，小分子整联蛋白拮抗剂(small-molecule integrin antagonist)，整合素拮抗剂(lifitegrast)。(4)眼用营养类药物：维生素(vitamine)，脂肪酸(fatty acid)，长链脂肪酸(long chain fatty acid)，脂肪醇(fatty alcohol)，鲸蜡醇(cetyl alcohol)，硬脂醇(stearyl alcohol)。(5)抗代谢药物：丝裂霉素C(mitomycin C)和5-氟尿嘧啶(5-fluorouracil)。The ophthalmic medication described in this paper can be one or more of the following drugs: (1) Commonly used antibiotics and anti-inflammatory drugs on the ocular surface: quinolone antibiotics (quinolone), such as norfloxacin (norfloxacin), ofloxacin ofloxacine, lomefloxacin, levofloxacin, ciprofloxacin; aminoglycesides such as kanamycin, tobramycin, chain Streptomycin, neomycin, spectinomycin, gentamicin, sisomicin, micronomicin, amikacin ), netilmicin; tetracycline antibiotics, such as tetracycline, methacycline, medomycin, chlotetracycline, oxytetracycline, polytetracycline Doxycycline, minocycline; macrolides antibiotics, such as azithromycin, erythromycin; corticosteroids, such as prednisone ( prednisone, hydrocortisone, fluoromethalone, dexamethasone, loteprednol; nonsteroidal anti-inflammatory drugs; non-penetrating Steroid (non-penetrating steroid); free acid steroid (freeacid of steroid); antihistamine (antihistamine). (2) Anti-glaucoma drugs: β-adrenergic receptor blocker (β-receptor blocker), such as timolol (timolol), levobunolol (levobunolol), betaxolol (betaxolol), card Carteolol; α-adrenoceptoragonists such as clonidine, brimonidine, methyldopa; carbonic anhydrase inhibitors ( carbonic anhydrase inhibitor) such as dorzolamide, brinzolamide; prostaglandin and prostaglandin analogs such as bimatoprost, latanoprost ( latanoprost), travoprost, tafluprost. (3) Immunomodulatory drugs: cyclosporine A, tacrolimus, small-molecule integrin antagonist, and lifitegrast. (4) Ophthalmic nutritional drugs: vitamin, fatty acid, long chain fatty acid, fatty alcohol, cetyl alcohol, stearyl alcohol alcohol). (5) Antimetabolites: mitomycin C (mitomycin C) and 5-fluorouracil (5-fluorouracil).
本发明提供的缓释滴眼液包含的固态缓释药物和液态的分散液可分别储存于干湿分离型滴眼液瓶，其内部包含主体腔和辅助腔，两腔之间设置隔水薄膜，主体腔内装载分散液，辅助腔内存放固体缓释药物粉末。使用时，用力挤压主体腔，分散液冲破两腔之间设置的隔水薄膜，进入辅助腔，稍加摇动，即可分散溶解固体缓释药物粉末，形成缓释滴眼液。The solid sustained-release drug and liquid dispersion contained in the sustained-release eye drops provided by the present invention can be respectively stored in a dry-wet separation type eye-drop bottle, the interior of which includes a main cavity and an auxiliary cavity, and a water-proof film is arranged between the two cavities. , the main cavity is loaded with dispersion liquid, and the auxiliary cavity is stored with solid slow-release drug powder. When in use, squeeze the main cavity with force, and the dispersion liquid breaks through the water barrier film set between the two cavities, enters the auxiliary cavity, and shakes a little to disperse and dissolve the solid sustained-release drug powder to form sustained-release eye drops.
本发明中，分散液以人工泪液为主，包含基本的盐，及抗菌物质，如羟苯乙酯等。In the present invention, the dispersion liquid is mainly artificial tears, and contains basic salts and antibacterial substances, such as ethyl paraben.
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。While the content of the present invention has been described in detail by way of the above preferred embodiments, it should be appreciated that the above description should not be construed as limiting the present invention. Various modifications and alternatives to the present invention will be apparent to those skilled in the art upon reading the foregoing. Accordingly, the scope of protection of the present invention should be defined by the appended claims.
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