WO2019233368A1 - 含有纳米交联透明质酸的脂质体微乳及其制备方法和应用 - Google Patents

含有纳米交联透明质酸的脂质体微乳及其制备方法和应用 Download PDF

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WO2019233368A1
WO2019233368A1 PCT/CN2019/089792 CN2019089792W WO2019233368A1 WO 2019233368 A1 WO2019233368 A1 WO 2019233368A1 CN 2019089792 W CN2019089792 W CN 2019089792W WO 2019233368 A1 WO2019233368 A1 WO 2019233368A1
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solution
eye
liposome
hydration
lipid
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PCT/CN2019/089792
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French (fr)
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何浩明
杨一菲
于一帆
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常州药物研究所有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions

Definitions

  • the invention relates to a liposome microemulsion containing nano-crosslinked hyaluronic acid, and a preparation method and application thereof.
  • Dry eye is mainly divided into dry eye with water deficiency, dry eye with excessive evaporation and mixed dry eye.
  • Water-deficiency dry eye is caused by insufficient secretion of tear fluid.
  • Over-evaporated dry eyes are caused by excessive loss of tears on the surface of the exposed eyeball when the tear secretion function is normal.
  • the cause is exogenous (such as ocular surface diseases caused by wearing contact lenses or vitamin A deficiency) and endogenous Etiology (such as meibomian gland dysfunction and eyelid closure disorder).
  • this lipid experience spray lacks hyaluronic acid, a moisturizing factor recognized to be effective for "dry eye disease”; after testing, if hyaluronic acid is added to this prescription, precipitation will occur, causing the entire lipid
  • the plastid microemulsion system is unstable and cannot form a commercial product.
  • a liquid crystal drug delivery system is prepared as follows: forming a first solution containing a lipid component and an alcohol, The first solution is maintained at a first temperature of 40-55 ° C; a second solution comprising a mucoadhesive hydrophilic polymer and a buffer is obtained, the second solution is aqueous and is maintained at a second temperature of 5 -55 ° C; mixing the first solution and the second solution to form a combined nano / micro-dispersion, the mixing is achieved by a high-energy mixing process; Microfluidize at three temperatures of 40-55 ° C to form a nano-dispersion; and incubate the nano-dispersions at 2-5 ° C to form a liquid crystal drug delivery system.
  • the liquid crystal drug delivery system may be a spray, an injection, or formulated as an eye drop.
  • the liquid crystal drug delivery system may be a high viscosity liquid that is pre-filled in a syringe.
  • the storage stability of the liquid crystal drug delivery system is not long enough, and the maintenance time is only 3-6 months. It cannot form a product with a sufficiently long shelf life, and its component does not contain a hygroscopic factor hyaluronic acid. Sodium, the use value is not good.
  • the technical problem to be solved by the present invention is to provide a stable, long-storage hyaluronic acid-containing liposome solution, and a preparation method and application thereof.
  • a technical solution for achieving the first object of the present invention is a liposome microemulsion, which is composed of the following components by weight percentage: phospholipid 0.5% to 1.5%, cholesterol 0.1% to 0.6%, nano-crosslinked hyaluronic acid or sodium thereof
  • the salt is 0.05% ⁇ 0.5%
  • the medicinal surfactant is 0.1% ⁇ 0.6%
  • the balance of water is.
  • the particle diameter of the nano-crosslinked hyaluronic acid or its sodium salt is 50 nm to 250 nm.
  • the medicinal surfactant is one of Tween, Span, and Poloxamer.
  • the technical solution for achieving the second object of the present invention is the first preparation method of the liposome microemulsion as described above, including the following steps:
  • the second method for preparing the liposome microemulsion as described above includes the following steps:
  • the resulting mixed solution was made into a microemulsion to obtain a liposome solution containing hyaluronic acid.
  • the technical solution for achieving the third object of the present invention is the application of a liposome microemulsion as described above in the preparation of an ophthalmic preparation for treating or alleviating dry eye.
  • the liposome solution is the active ingredient and ophthalmic nutrition in the ophthalmic preparation. Carrier.
  • the ophthalmic preparation is an eye spray.
  • the eye spray is composed of the following components by weight percentage: phospholipids 0.5% to 2.1%, cholesterol 0.1% to 0.6%, nano-crosslinked hyaluronic acid or its sodium salt 0.05% to 0.5%, and a medicinal surface
  • the active agent is 0.1% to 0.6%
  • the eye nutritional agent is 0.001% to 1%
  • the balance of water is 0.1% to 0.6%
  • the eye nutrition agent is one or one of taurine, hypromellose, Va, Ve, Vc, lutein, zeaxanthin, ⁇ -carotene, anthocyanin, DHA, and vitamin B6. A combination of the above.
  • a first method for preparing an eye spray as described above includes the following steps:
  • the mixed solution was made into a microemulsion to obtain a liposome solution containing hyaluronic acid.
  • a second method for preparing an eye spray as described above comprising the following steps:
  • the resulting mixed solution was made into a microemulsion to obtain a liposome solution containing hyaluronic acid.
  • Example 1 is a particle size distribution diagram of the liposome solution of Example 1;
  • Example 2 is a zeta potential map of the liposome solution of Example 1;
  • Example 3 is a particle size distribution diagram of the liposome solution of Example 2.
  • Example 4 is a zeta potential map of the liposome solution of Example 2.
  • Example 5 is a particle size distribution diagram of the liposome solution of Example 3.
  • Example 6 is a zeta potential map of the liposome solution of Example 3.
  • Example 7 is a particle size distribution diagram of the liposome solution of Example 4.
  • FIG. 8 is a zeta potential map of the liposome solution of Example 4.
  • Example 9 is a particle size distribution diagram of the liposome solution of Example 5.
  • Example 10 is a zeta potential map of the liposome solution of Example 5.
  • Example 11 is a particle size distribution diagram of the liposome solution of Example 6.
  • Example 13 is a particle size distribution diagram of the liposome solution of Example 7.
  • Example 15 is a particle size distribution diagram of the liposome solution of Example 8.
  • Example 16 is a zeta potential map of the liposome solution of Example 8.
  • the liposome solution containing hyaluronic acid in this embodiment is a microemulsion, and the liposome solution is composed of the following components by weight percentage: phospholipid 1%, cholesterol 0.2%, nano-crosslinked hyaluronic acid Acid or its sodium salt 0.1%, Tween 80 0.20%, water balance.
  • the medicinal surfactant used in this embodiment is Tween 80.
  • the medicinal surfactant can also be one of Span and Poloxamer.
  • the phospholipid is soybean lecithin.
  • the nano-crosslinked hyaluronic acid or its sodium salt raw material is prepared by the method of the Chinese patent document entitled "Nano-crosslinked sodium hyaluronate gel and its preparation method and application” applied by the applicant in 2016 Crosslinked sodium hyaluronate gel with an average particle size of 100 nm to 250 nm.
  • the weighed phospholipid, cholesterol and Tween 80 are dissolved in ethanol, shaken to obtain a lipid solution, and the ethanol is distilled off under reduced pressure to obtain a lipid film.
  • the temperature during the reduced pressure distillation does not exceed 45 ° C.
  • the nano-crosslinked sodium hyaluronate gel is mixed with water as a dispersant to obtain a hydration solution.
  • step 3 Mix the lipid film obtained in step 1 with the hydration solution obtained in step 2 to obtain a mixed solution; use the film-ultrasonic dispersion method (or high-pressure homogenizer) to make a microemulsion to obtain hyaluronic acid. Liposome microemulsion solution.
  • the size of the microemulsion solution was measured using the Mastersizer 2000 particle size analyzer from Malvern, UK, and the potential was measured.
  • 0.1g of the liposome microemulsion solution prepared above was sent to a particle size analyzer for measurement.
  • the measured particle size distribution is shown in Figure 1.
  • the average particle diameter of each component in the prepared liposome microemulsion solution was 102.0nm.
  • the osmotic pressure of liposome solution was detected by OM815 freezing point osmotic pressure detector.
  • composition of the hyaluronic acid-containing liposome solutions of Examples 2 to 8 is shown in Table 1.
  • the absolute zeta potential of the liposome solution of the present invention is high, the system has high stability, and the storage time can be as long as more than 24 months.
  • the preparation method of this embodiment prepares the liposome solution containing hyaluronic acid of Example 1 and includes the following steps:
  • the nano-crosslinked sodium hyaluronate gel is mixed with water as a dispersant to obtain a hydration solution.
  • step 3 Mix the lipid solution obtained in step 1 with the hydration solution in step 2 and stir to obtain a microemulsion; distill the microemulsion at 45 ° C to remove ethanol under reduced pressure; the microemulsion after removing alcohol is passed through a high-pressure homogenizer, A liposome microemulsion solution containing hyaluronic acid was obtained.
  • the eye spray is composed of a liposome solution containing hyaluronic acid and an eye nutrition agent.
  • the eye spray is composed of the following components by weight percentage: phospholipids 0.5% to 2.1%, cholesterol 0.1% to 0.6%, and nano-crosslinking.
  • Hyaluronic acid or its sodium salt 0.05% to 0.5%, medicinal surfactants 0.1% to 0.6%, eye nutritional agents 0.001% to 1.05%, the balance of water.
  • the eye nutrition agent is one or more combinations of taurine, hypromellose, Va, Ve, Vc, lutein, zeaxanthin, ⁇ -carotene, anthocyanin, DHA, and vitamin B6 .
  • the eye spray of this embodiment is composed of the liposome solution of Example 1 and an eye nutritional agent. Specifically, it is composed of the following components by weight percentage: phospholipid 1%, cholesterol 0.2%, nano-crosslinked hyaluronic acid Or its sodium salt 0.1%, Tween 80 0.20%, Va 0.025%, Ve 0.002%, the balance of water.
  • the nano-crosslinked sodium hyaluronate gel is mixed with water as a dispersant to obtain a hydration solution.
  • step 3 Mix the lipid film obtained in step 1 with the hydration solution obtained in step 2, and wrap the ocular nutrition agent to obtain a mixed solution; use the thin film-ultrasonic dispersion method (or high-pressure homogenizer) to make the mixed solution.
  • Milk that is, a liposome microemulsion solution containing hyaluronic acid is obtained.
  • composition of the ocular sprays of Examples 11 to 19 are shown in Table 3.
  • an eye nutrition agent is added to the corresponding liposome solution and mixed.
  • the preparation process of the eye spray of the present invention can wrap most fat-soluble eye nutrients, and when the liposome microspheres enter the target such as the eyeball, it can release the nutrients encapsulated therein, so as to improve eye comfort Degree and the role of nutritional eyeballs.
  • the added Va and Ve can also increase the elasticity of the skin of the eye; the added cross-linked hyaluronic acid can more effectively calm fine lines and prevent wrinkles , Delay the aging of the skin around the eyes, and also tighten the bags under the eyes. Long-term use can make the skin of the eyes soft, tender and elastic.
  • the liposome solution of the present invention is used as a carrier of an ophthalmic preparation such as an eye spray, and delivers ocular nutrients to the surface of the eyeball, and lipid substances are simultaneously delivered to the eyeball, thereby improving the "lipid body disorder” "Dry eye syndrome”; and the moisturizing factor nano-crosslinked sodium hyaluronate is added to the liposome solution.
  • an ophthalmic preparation such as an eye spray
  • cross-linked sodium hyaluronate nanoparticles can reach the surface of the eye through the eyelid, and play a role of "moisturizing" the eye;
  • Cross-linked sodium hyaluronate works with liposome microemulsion and Va, Ve and other eye nutrients wrapped by the microemulsion, which nourish and nourish the eyes, make the entire eye moisturizing, soothing and clear purpose .
  • the added Va and Ve can also increase the elasticity of the skin of the eye; the added cross-linked hyaluronic acid can more effectively calm the fine lines It can prevent wrinkles, delay the aging of the skin around the eyes, and also tighten the bags under the eyes. Long-term use can make the eye skin soft, tender and elastic.
  • the invention solves the problem of adding hyaluronic acid to the liposome solution, and the problem is solved by adding nano-crosslinked hyaluronic acid to the liposome solution instead of the small molecule hyaluronic acid (although the small molecule hyaluronic acid It can also be absorbed by the skin, but it will quickly degrade and lose its moisturizing effect.)
  • the surfactant is formulated so that the entire liposome solution containing hyaluronic acid has good stability and quality controllability. Storage It lasts more than 24 months.
  • the preparation process of the eye spray of the present invention can wrap most of the fat-soluble eye nutrients, and when the liposome microspheres enter the target such as the eyeball, it can release the nutrients encapsulated therein, thereby achieving improvement.

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Abstract

一种含有透明质酸的脂质体微乳及其制备方法，所述脂质体微乳按重量百分比由以下组分组成：磷脂0.5％～1.5％，胆固醇0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.5％，药用表面活性剂0.1％～0.6％，水余量。所述脂质体微乳用于制备治疗或缓解干眼症眼科制剂。

Description

含有纳米交联透明质酸的脂质体微乳及其制备方法和应用 技术领域
本发明涉及一种含有纳米交联透明质酸的脂质体微乳及其制备方法和应用。
背景技术
目前用于治疗干眼症的主要方式是滴加眼药水或人工“泪液”，不幸的是这些眼药水或人工“泪液”并不总是有效。究其原因，这是由于“干眼症”的产生不全部是由于泪液太少，有些是由于眼球表面的脂质体紊乱而引起的脂质快速流失造成的。
干眼症主要分为水液缺乏型干眼、蒸发过强型干眼和混合型干眼。水液缺乏型干眼是由泪液分泌不足引起。蒸发过强型干眼是在泪液分泌功能正常的情况下，由暴露的眼球表面泪液过量损失引起，其病因有外因性病因(如佩戴隐形眼镜或维生素A缺乏引起的眼表疾病)、内因性病因(如睑板腺功能障碍和眼睑闭合障碍)。
对于蒸发过强型干眼和混合型干眼，滴加眼药水或人工“泪液”效果不佳，缓解症状的方法是补充脂质。
关于治疗干眼症的产品，德国市场上有一款“脂质体眼喷雾剂”，商品名为“tears again”(A new therapy concept with a liposome eye spray for the treatment of the“dry eye”(Germ)[J].Dkgest of the World Latest Medical Information,2005.)。此喷雾剂具有很好的生物相容性，无毒以及无免疫原性的优点，其疗效经临床检验确实胜过普通滴眼液。但是该款脂质体验喷雾剂的处方中，缺少了公认对“干眼症”有效的保湿因子透明质酸；经试验，在该处方中若加入透明质酸则会产生沉淀，从而造成整个脂质体微乳体系的不稳定，无法形成商品。
中国专利文献CN 106459137A(申请号201580019868.9)公开了一种用于治疗眼部病症的膜附着性自组装体系，液晶药物递送体系的制备方法如下：形成含有脂质组分和醇的第一溶液，所述第一溶液被维持在第一温度40-55℃；获得包含粘膜粘附性亲水聚合物和缓冲剂的第二溶液，所述第二溶液是水性的并且被维持在第二温度5-55℃；将所述第一溶液和所述第二溶液混合以形成组合的纳米/微米-分散体，所述混合通过高能混合过程实现；对所述组合的纳米/微米-分散体在第三温度40-55℃进行微流化以形成纳米-分散体；以及在2-5℃温育所述纳米-分散体以形成液晶药物递送体系。所述液晶药物递送体系可以是喷雾剂、注射剂，或被配制成滴眼剂。
所述液晶药物递送体系可以是被预装入注射器中的高粘度液体。但是据该专利文 献的记载，该液晶药物递送体系的储存稳定性不足够长，维持时间仅3-6个月，无法形成具有足够长保质期的商品，且其组分内不含有保湿因子透明质酸钠，使用价值欠佳。
发明内容
本发明所要解决的技术问题是提供一种稳定、储存期长的含有透明质酸的脂质体溶液及其制备方法和应用。
实现本发明第一目的的技术方案是一种脂质体微乳，按重量百分比由以下组分组成：磷脂0.5％～1.5％，胆固醇0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.5％，药用表面活性剂0.1％～0.6％，水余量。
其中纳米交联透明质酸或其钠盐的粒径为50nm～250nm。
所述药用表面活性剂为吐温、司盘、泊洛沙姆中的一种。
实现本发明第二目的的技术方案是如上所述的脂质体微乳的第一种制备方法，包括以下步骤：
①将称量的磷脂、胆固醇溶解在乙醇中，得到脂质溶液，加热蒸发去除乙醇得到脂质膜；
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
③将脂质膜与水化液混合，得到混合溶液；其中药用表面活性剂在脂质膜与水化液混合之前添加在脂质溶液或者水化液中；将混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
如上所述的脂质体微乳的第二种制备方法，包括以下步骤：
①将称量的磷脂、胆固醇溶解在乙醇中，得到脂质溶液；
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
③将脂质溶液与水化液混合，得到混合溶液；其中药用表面活性剂在脂质溶液与水化液混合之前添加在脂质溶液或者水化液中；加热蒸发去除乙醇；将除醇后的混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
实现本发明第三目的的技术方案是一种如上所述的脂质体微乳在制备治疗或缓解干眼症眼科制剂中的应用,脂质体溶液为眼科制剂中的有效成分及眼部营养剂的载体。
所述眼科制剂为眼部喷雾剂。
所述的眼部喷雾剂，按重量百分比由以下组分组成：磷脂0.5％～2.1％，胆固醇 0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.5％，药用表面活性剂0.1％～0.6％，眼部营养剂0.001％～1％，水余量。
进一步的，眼部营养剂为牛黄酸、羟丙甲纤维素、Va、Ve、Vc、叶黄素、玉米黄素、β胡萝卜素、花青素、DHA、维生素B6中的一种或一种以上的组合。
一种如上所述的眼部喷雾剂的第一种制备方法，包括以下步骤：
①将称量的磷脂、胆固醇、眼部营养剂溶解在乙醇中，混匀、高速搅拌，眼部营养剂被脂质体包裹，加热蒸发去除乙醇得到脂质膜；
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
③将脂质膜与水化液混合，得到混合溶液；其中药用表面活性剂在脂质膜与水化液混合之前添加在脂质溶液或者水化液中；
将混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
一种如上所述的眼部喷雾剂的第二种制备方法，包括以下步骤：
①将称量的磷脂、胆固醇、眼部营养剂溶解在乙醇中，混匀、高速搅拌，眼部营养剂被脂质体包裹，得到脂质溶液；
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
③将脂质溶液与水化液混合，得到混合溶液；其中药用表面活性剂在脂质溶液与水化液混合之前添加在脂质溶液或者水化液中；加热蒸发去除乙醇；将除醇后的混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
附图说明
图1为实施例1的脂质体溶液的粒径分布图；
图2为实施例1的脂质体溶液的zeta电位图；
图3为实施例2的脂质体溶液的粒径分布图；
图4为实施例2的脂质体溶液的zeta电位图；
图5为实施例3的脂质体溶液的粒径分布图；
图6为实施例3的脂质体溶液的zeta电位图；
图7为实施例4的脂质体溶液的粒径分布图；
图8为实施例4的脂质体溶液的zeta电位图。
图9为实施例5的脂质体溶液的粒径分布图；
图10为实施例5的脂质体溶液的zeta电位图；
图11为实施例6的脂质体溶液的粒径分布图；
图12为实施例6的脂质体溶液的zeta电位图；
图13为实施例7的脂质体溶液的粒径分布图；
图14为实施例7的脂质体溶液的zeta电位图；
图15为实施例8的脂质体溶液的粒径分布图；
图16为实施例8的脂质体溶液的zeta电位图；
具体实施方式
(实施例1、含有透明质酸的脂质体溶液)
本实施例的含有透明质酸的脂质体溶液，该脂质体溶液为微乳液，按重量百分比该脂质体溶液由以下组分组成：磷脂1％，胆固醇0.2％，纳米交联透明质酸或其钠盐0.1％，吐温80 0.20％，水余量。
本实施例的药用表面活性剂使用的是吐温80，药用表面活性剂还可以选用司盘、泊洛沙姆中的一种。
所述磷脂为大豆卵磷脂。
纳米交联透明质酸或其钠盐原料是采用本申请人于2016年申请的发明名称为《纳米交联透明质酸钠凝胶及其制备方法和应用》的中国专利文献的方法制备得到的交联透明质酸钠凝胶，平均粒径为100nm至250nm。
本实施例的含有透明质酸的脂质体溶液的制备方法包括以下步骤：
①将称量的磷脂、胆固醇和吐温80溶解在乙醇中，摇匀得到脂质溶液，减压蒸馏去除乙醇得到脂质膜，减压蒸馏时温度不超过45℃。
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合均匀，得到水化液。
③将步骤①得到的脂质膜与步骤②得到的水化液混合，得到混合溶液；将混合溶液采用薄膜-超声分散法(或高压均质机)制成微乳，即得到含有透明质酸的脂质体微乳溶液。
使用英国Malvern公司的Mastersizer 2000型粒度测定仪对微乳溶液进行粒度检测和电位检测。
将上述制得的脂质体微乳溶液0.1g送入粒度测定仪检测，测得的粒度分布见图1，制得的脂质体微乳溶液中各组分的平均粒径为102.0nm。
采用OM815型号的冰点渗透压检测仪检测脂质体溶液的渗透压。
(实施例2至实施例8、含有透明质酸的脂质体溶液)
实施例2至实施例8的含有透明质酸的脂质体溶液的组成见表1。
表1 含有透明质酸的脂质体溶液的组成(wt％)
Figure PCTCN2019089792-appb-000001
实施例1至实施例8的脂质体溶液的平均粒径、zeta电位、渗透压见表2。
平均粒径、zeta电位、渗透压的测定仪器与实施例1相同。
表2
实施例序号 平均粒径(nm) zeta电位(mv) 渗透压(mosm/L)
1 102.0 -18.4 537
2 57.49 -11.5 537
3 256.8 -21.3 536
4 58.22 -10.2 537
5 70.75 -9.95 537
6 68.94 -10.3 538
7 123.6 -16.0 537
8 133.0 -13.3 537
从检测结果来看，本发明的脂质体溶液zeta电位绝对值高，体系稳定性高，储存时间可长达24个月以上。
(实施例9、含有透明质酸的脂质体溶液的制备方法)
本实施例的制备方法制备的是实施例1的含有透明质酸的脂质体溶液，包括以下步骤：
①将按照重量百分比称量的磷脂、胆固醇和吐温80溶解在乙醇中，摇匀得到脂质溶液。
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合均匀，得到水化液。
③将步骤①得到的脂质溶液与步骤②的水化液混合，搅匀后得到微乳液；对微乳液在45℃下减压蒸馏去除乙醇；除醇后的微乳液经过高压均质机，得到含有透明质酸的脂质体微乳溶液。
(实施例10、眼部喷雾剂)
眼部喷雾剂由含有透明质酸的脂质体溶液和眼部营养剂组成，具体的，按重量百分比由以下组分组成：磷脂0.5％～2.1％，胆固醇0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.5％，药用表面活性剂0.1％～0.6％，眼部营养剂0.001％～1.05％，水余量。
眼部营养剂为牛黄酸、羟丙甲纤维素、Va、Ve、Vc、叶黄素、玉米黄素、β胡萝卜素、花青素、DHA、维生素B6中的一种或一种以上的组合。
本实施例的眼部喷雾剂由实施例1的脂质体溶液和眼部营养剂组成，具体的，按重量百分比由以下组分组成：磷脂1％，胆固醇0.2％，纳米交联透明质酸或其钠盐0.1％，吐温80 0.20％，Va 0.025％，Ve0.002％，水余量。
本实施例的眼部喷雾剂的制备方法包括以下步骤：
①将称量的磷脂、胆固醇、Va、Ve和吐温80溶解在乙醇中，高速搅拌混匀，眼部营养剂Va、Ve被脂质体包裹，得到脂质溶液，减压蒸馏去除乙醇得到脂质膜，减压蒸馏时温度不超过45℃。
②将纳米交联透明质酸钠凝胶与作为分散剂的水混合均匀，得到水化液。
③将步骤①得到的脂质膜与步骤②得到的水化液混合，进行眼部营养剂的包裹，得到混合溶液；将混合溶液采用薄膜-超声分散法(或高压均质机)制成微乳，即得到含有透明质酸的脂质体微乳溶液。
(实施例11至实施例19、眼部喷雾剂)
实施例11至实施例19的眼部喷雾剂的组成见表3。
表3 眼部喷雾剂的组成(wt％)
Figure PCTCN2019089792-appb-000002
Figure PCTCN2019089792-appb-000003
表格3中余量为水。
眼部喷雾剂制备时，将眼部营养剂添加在对应的脂质体溶液中，混匀即可。
本发明的眼部喷雾的制备工艺对于大部分脂溶性眼部营养剂能进行包裹，在脂质体微球进入眼球等靶位时，能释放出里面包裹的营养物质，从而达到改善眼部舒适度和营养眼球的作用。
本发明的眼部喷雾剂除了有治疗“干眼症”的作用，其中添加的Va、Ve还能增加眼部皮肤的弹性；添加的交联透明质酸，更能有效平复细纹和预防皱纹，延缓眼周肌肤衰老，同时也能收紧眼袋，长期使用可使眼部皮肤变得柔软，细嫩，富有弹性。
工业应用性
本发明具有积极的效果：
(1)本发明的脂质体溶液作为眼科制剂如眼部喷雾剂的载体，将眼部营养物质输送至眼球表面，脂质物质同时输送至眼球，因而能改善因脂质体紊乱造成的“干眼症”；并且脂质体溶液中加入了保湿因子纳米交联透明质酸钠，交联透明质酸钠纳米微粒能够透过眼皮到达眼球表面，起到“滋润”眼球的作用；另外纳米交联透明质酸钠与脂质体微乳以及该微乳所包裹的Va、Ve等眼部营养物质共同作用，起到滋润营养眼睛的作用，使整个眼部达到润泽，舒缓以及明目的作用。
(2)本发明的眼部喷雾剂除了有治疗“干眼症”的作用，其中添加的Va、Ve还能增加眼部皮肤的弹性；添加的交联透明质酸，更能有效平复细纹和预防皱纹，延缓眼周肌肤衰老，同时也能收紧眼袋，长期使用可使眼部皮肤变得柔软，细嫩，富有弹性。
(3)市场上现有的眼部喷雾，如果其中添加了磷脂，其中就不会含有透明质酸，因为根据实际操作，向磷脂溶液中添加透明质酸后溶液体系不稳定，会有沉淀物；本 发明解决了向脂质体溶液中增加透明质酸的问题，通过向脂质体溶液中添加纳米交联透明质酸，而不是小分子的透明质酸解决问题(虽然小分子透明质酸也能被皮肤吸收，但是很快就会降解，丧失了保湿效果)，同时调配好表面活性剂，使得整个含有透明质酸的脂质体溶液具有很好的稳定性和质量可控性，储存时间长达24个月以上。
(4)本发明的眼部喷雾的制备工艺对于大部分脂溶性眼部营养剂能进行包裹，在脂质体微球进入眼球等靶位时，能释放出里面包裹的营养物质，从而达到改善眼部舒适度和营养眼球的作用。

Claims (11)

  1. 一种脂质体微乳，其特征在于：按重量百分比由以下组分组成：磷脂0.5％～1.5％，胆固醇0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.6％，药用表面活性剂0.1％～0.6％，水余量。
  2. 根据权利要求1所述的脂质体微乳，其特征在于：纳米交联透明质酸或其钠盐的粒径为50nm～250nm。
  3. 根据权利要求1所述的脂质体微乳，其特征在于：药用表面活性剂为吐温、司盘、泊洛沙姆中的一种。
  4. 一种如权利要求1所述的脂质体微乳的制备方法，包括以下步骤：
    ①将称量的磷脂、胆固醇溶解在乙醇中，得到脂质溶液，加热蒸发去除乙醇得到脂质膜；
    ②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
    ③将脂质膜与水化液混合，得到混合溶液；其中药用表面活性剂在脂质膜与水化液混合之前添加在脂质溶液或者水化液中；
    将混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
  5. 一种如权利要求1所述的脂质体微乳的制备方法，包括以下步骤：
    ①将称量的磷脂、胆固醇溶解在乙醇中，得到脂质溶液；
    ②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
    ③将脂质溶液与水化液混合，得到混合溶液；其中药用表面活性剂在脂质溶液与水化液混合之前添加在脂质溶液或者水化液中；加热蒸发去除乙醇；将除醇后的混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
  6. 一种如权利要求1所述的脂质体微乳在制备治疗或缓解干眼症眼科制剂中的应用,脂质体溶液为眼科制剂中的有效成分及眼部营养剂的载体。
  7. 根据权利要求6所述的脂质体微乳在制备治疗或缓解干眼症眼科制剂中的应用，其特征在于：所述眼科制剂为眼部喷雾剂。
  8. 根据权利要求7所述的眼部喷雾剂，其特征在于按重量百分比由以下组分组成：磷脂0.5％～2.1％，胆固醇0.1％～0.6％，纳米交联透明质酸或其钠盐0.05％～0.6％，药用表面活性剂0.1％～0.6％，眼部营养剂0.001％～1.05％，水余量。
  9. 根据权利要求5至7之一所述的眼部喷雾剂，其特征在于：眼部营养剂为牛黄酸、羟丙甲纤维素、Va、Ve、Vc、叶黄素、玉米黄素、β胡萝卜素、花青素、DHA、维生素B6中的一种或一种以上的组合。
  10. 一种如权利要求7所述的眼部喷雾剂的制备方法，包括以下步骤：
    ①将称量的磷脂、胆固醇、眼部营养剂溶解在乙醇中，混匀、高速搅拌，眼部营养剂被脂质体包裹，加热蒸发去除乙醇得到脂质膜；
    ②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
    ③将脂质膜与水化液混合，得到混合溶液；其中药用表面活性剂在脂质膜与水化液混合之前添加在脂质溶液或者水化液中；
    将混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
  11. 一种如权利要求7所述的眼部喷雾剂的制备方法，包括以下步骤：
    ①将称量的磷脂、胆固醇、眼部营养剂溶解在乙醇中，混匀、高速搅拌，眼部营养剂被脂质体包裹，得到脂质溶液；
    ②将纳米交联透明质酸钠凝胶与作为分散剂的水混合，得到水化液；
    ③将脂质溶液与水化液混合，得到混合溶液；其中药用表面活性剂在脂质溶液与水化液混合之前添加在脂质溶液或者水化液中；加热蒸发去除乙醇；将除醇后的混合溶液制成微乳，得到含有透明质酸的脂质体溶液。
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