WO2008122192A1 - Véhicule pharmaceutique liposomal et son procédé de préparation - Google Patents

Véhicule pharmaceutique liposomal et son procédé de préparation Download PDF

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Publication number
WO2008122192A1
WO2008122192A1 PCT/CN2008/000511 CN2008000511W WO2008122192A1 WO 2008122192 A1 WO2008122192 A1 WO 2008122192A1 CN 2008000511 W CN2008000511 W CN 2008000511W WO 2008122192 A1 WO2008122192 A1 WO 2008122192A1
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liposome
polyethylene glycol
liposomes
drug carrier
diglyceride
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PCT/CN2008/000511
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English (en)
French (fr)
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Hongliang Guo
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Guangzhou Li En Biotechnologies Co., Ltd
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    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to a liposome drug-loaded raft, and the present invention relates to a process for the preparation of a pharmaceutical carrier. Background technique
  • Liposomes are vesicle-encapsulated sacs formed by the phospholipid bilayer membrane and form a directional drug carrier, which is a new dosage form for targeted drug delivery systems.
  • the active material in the solution or solution is embedded in particles of nanometer diameter.
  • the liposome was selected as a phospholipid.
  • Phospholipids are the main chemical constituents of liposomes, the most representative of which is egg pity.
  • Cholesterol is another important component of liposomes.
  • the phospholipids When the phospholipids are dispersed in water, they can form multi-layer microcapsules; and each layer is a lipid bilayer, which is separated by water, and the microcapsules are liposomes. Liposomes can be divided into single-chamber liposomes, multi-chamber liposomes, and surfactant-containing lipids. :
  • lipid rafts 3 ⁇ 43 ⁇ 4 ⁇ 4 to be fat-loaded phosphorus to make a solid; alcohol ⁇ ⁇ 3 ⁇ 4 ⁇ S into a solution, and then evaporated to remove organic solvents, forming a bilayer lipid raft film on the wall, the enamel film collected and The aqueous solution is stirred and mixed to form a liposome.
  • the waxy body is often a multi-chamber liposome having a large diameter, which must be processed to produce a practical lipid microsphere.
  • the methods for preparing lipid microspheres are mainly ultrasonic, ultrafiltration, high pressure pulverization and mechanical milling.
  • Phospholipids can be packaged into a lipid ball (mm). After the lipid microspheres are in contact with human skin or in the body for a long time, they use the similar features of the pancreatic membrane pancreas to fuse with the cell membrane or by endocytosis.
  • the drug is delivered to the target cells.
  • the drug passes through the lipid carrier and can pass through the stratum corneum of the epidermis, providing an effective method for the preparation of external medicines and A ⁇ care products.
  • the drug sensitive to the cavity and stomach can be protected from the damage of the oral cavity and stomach enzymes after being wrapped with lipid rafts, so that it can safely reach the intestinal tract and use the lipid to give structural similarity to the intestinal cell membrane.
  • the drug is introduced into the cells more effectively, thereby improving the therapeutic indication of the drug, reducing the dose of the drug and reducing the toxicity of the drug.
  • liposome As a drug carrier has many advantages and characteristics, it still has considerable limitations. Since the British scientist Leimen et al. began to use liposome as a drug carrier in 2011, It has been more than 30 years::: The development of fat and saliva is slow, and one of the few drugs is rare. Among them, the main record is: South: : :
  • the preparation of liposomes poses great difficulties for industrial production.
  • the production process is complex and the requirements for equipment are high.
  • the current production process cannot control the size of the liposome and the structure of the sac, which results in uneven size of the produced liposomes, and the structure of the sac is different.
  • the stability of the liposome is not good, and the stability requirement of the drug burst can be ensured.
  • Liposome production processes often require warming and changing pressure to remove the wonderful agent; then use extreme means such as milling or ultrasonic to prepare lipid microspheres with small diameters. These extreme measures require high temperature and high pressure to cause fat. Decomposition of the substance and its packaged drug.
  • liposomes are not easily sterilized, especially sterilizing too much lipid sterilized cockroaches, and steroids are a necessary route for drug production.
  • the bacteria should be i3 ⁇ 4 pack heat disinfection, alcohol disinfection, oxidative sterilization, gamma ray disinfection and bacterial ultrafiltration. Only 3 ⁇ 4 sterile ultrafiltration is suitable for the sterilizing of liposomes, while the ultrafiltration of liposomes has been Proof is very difficult.
  • liposomes are highly susceptible to aggregation and fusion. During the preservation of liposomes, or when temperature changes are encountered, and different additives or excipients are added, the liposomes may adsorb and aggregate with each other: resulting in instability of the liposomes.
  • Lipids plastids are difficult to contain, especially for some water-soluble drugs, and the drug is easily leaked from liposomes.
  • Another object of the present invention is to provide a process for preparing a liposome drug carrier which is simple in process.
  • the present invention has been implemented through the use of a technical solution:
  • the polyethylene glycol diglyceride is polyethylene glycol 200 diglyceride, polyethylene glycol 400 diglyceride, polyethylene glycol 600 diglyceride, polyethylene glycol 800 diglyceride Or polyethylene glycol 1500 glycerol diester.
  • composition of the liposome further comprises a phosphate ester, and the phosphate ester is preferably a phosphate ester POPC in an amount of from 0 to 30% of the polyethylene glycol diglyceride.
  • composition of the liposome further includes trehalose, and the content of trehalose is 0.2 to 5% of the total amount of the liposome.
  • composition of the liposome further comprises an antioxidant amino acid, and the antioxidant amino acid is tryptophan, tyrosine, cysteine or methionine.
  • the preparation method of a liposome drug carrier is as follows: the main component of the liposome, polyethylene glycol glyceride diester, is automatically formed into a liposome by mixing and stirring with an aqueous solution at room temperature or under normal temperature and pressure.
  • One or a mixture of a phosphate ester, a trehalose, and an antioxidant amino acid may be optionally added to the polyethylene glycol glycerin diester solution for the preparation of the liposome.
  • Typical liposomes are microspheres. As shown in Figure 1, the inner and outer surfaces of the microspheres are respectively polar hydrophilic phosphate bilayers (Fig. 1:, A, B), polar hydrophilic microspheres. Hydrophilic drug molecules can be encapsulated (Fig. 1, B3 ⁇ 4 and fat-soluble drug molecules are embedded in the middle of the lipid bilayer (Fig. 1, C), and D is a polar hydrophilic phospholipid bipartite surface.
  • the first consideration is the molecular geometry of lipids.
  • the molecule forming the liposome must be a hydrophilic and lipophilic parent molecule, and this structure It is very common in glycerides, but not both parental molecules can form pharmaceutically acceptable liposomes.
  • the hydrophilic group (head) of the amphiphilic lipid molecule and the structure of the lipophilic carbon chain (tail) must conform to the requirements for the formation of the plastid, and the structure that must first be provided is a sub-structure.
  • This intimate geometry of the street can be represented by a surface activity parameter (S): As shown in Figure 2, it represents the accumulation of the lipophilic moiety; it represents the length of the hydrocarbon chain. Indicates the effective area of the hydrophilic head.
  • S surface activity parameter
  • the surface activity parameter reflects the geometry of the amphiphilic molecule and is directly related to the bending rate at which the molecule aggregates.
  • the activity parameter is less than 1/3, the solid sphere is formed after the molecules are aggregated, and the drug encapsulation ability is not obtained; when the parameter is I: the base crucible will be flat, and it is difficult to form a sphere:; and this parameter is greater than 1
  • the lipophilic carbon chain 1 ⁇ 2 outer body can be dissolved with the polar ft solvent; only 3 ⁇ 4 when the surface activity parameter is 1/3 ⁇ 1, ideal vesicle microspheres; * can be formed. By drawing this, liposome lipid molecules can be initially screened by evaluating the surface activity parameters of the molecules.
  • Glyceride as a major component of biofilms is naturally the preferred molecule for liposome lipids.
  • the basic structure of phosphoglycerides is shown in Figure 3.
  • S-value of the mono-carbon chain #ester ester tends to be less than 173 and therefore cannot be used for the preparation of liposomes, the double-carbon bond 3 ⁇ 4 oil; the ester will be the main molecule of the liposome lipid.
  • the melting point of the lipid molecule In order for the lipid molecule to spontaneously form a liposome under normal temperature and pressure, the melting point of the lipid molecule must be low, that is, it must be liquid at room temperature or appropriately heated, and therefore, the high melting point is excluded when selecting the lipid molecule. Lipid.
  • the carbon chain (lipophilic tail) is selected. This is one of the keys to good skin penetration. Numerous studies have shown that after attachment to polar molecules, various saturated and unsaturated fatty acids have an undesired degree of epidermal permeability. In addition, the unsaturated bond has a cis-trans conformation, the cis-conformation can bend a linear molecule, and the curved cis-conformation (cis-) unsaturated fatty acid: (see Figure 4) can effectively utilize its geometrically curved lake conformation to loosen organisms. The tightly packed lipids between the somatic cells make the biopterin more permeable. Therefore, an appropriate proportion of unsaturated fatty acids can increase the permeability of the skin. We have developed a variety of fatty acid combinations (Table 2) to demonstrate that they can form liposomes spontaneously under appropriate conditions.
  • the ratio of the length of the lipophilic carbon chain of the lipid spear and the volume of the polar hydrophilic group will be the key to determining whether the molecule is formed or not.
  • the hydrophilic group must be relatively bulky to allow the molecule to have sufficient bending rate to form a double-layered lipid raft membrane vesicle liposome.
  • Phosphorus in traditional liposomes In the acid ester, the phosphate group, the R 3 group in Figure 3 attached to the phosphoric acid (see Figure 3), and the charge associated therewith constitute the polar "head".
  • Polyethylene glycol diglyceride can form liposome after mixing with aqueous solution at room temperature and normal pressure, but it is not a constituent lipid of biofilm, so liposome prepared by using polyethylene glycol diglyceride Biocompatibility can be challenged.
  • biofilm phosphate ester is added to the polyethylene glycol 3 ⁇ 4 oil diester solution to increase the purity of the prepared lipid bimolecular membrane and the organism: the phase structure of the ruthenium structure, thereby increasing its biocompatibility. Sex.
  • Liposomes may enter the systemic immune mechanisms initiated within the fire, engulfed by the reticuloendothelial system, and thus targetfully enriched in tissues such as liver, spleen, lung, and bone marrow. This is the passive targeting of liposomes.
  • Phosphate POPC l, palmitoyl, 2-oleoyl phosphatidykhQline
  • the table is phosphate POPC as an example and polyethylene.
  • Figure 1 is a liposome effect diagram
  • Figure 2 is a schematic diagram showing the relationship between surface activity parameters and shape
  • Figure 3 is a molecular structure diagram of a phospholipid
  • Figure 4 is a schematic diagram of cis-trans fatty acids
  • Figure 5 is an electron micrograph of a lipopolyethylene glycol 600 liposome
  • Figure 6 is a schematic diagram of the effect of trehalose on the stability of liposomes:
  • Figure 7 is a graphical representation of the effect of antioxidant amino acids on ester plastid stability. Detailed ways
  • the polyethylene glycol glyceryl diester which is a main component of the liposome of the present embodiment is exemplified by polyethylene glycol oleate.
  • polyethylene glycol oleate When the polyethylene glycol diolein is mixed with the aqueous solution, the liposome is spontaneously formed.
  • Polyethylene glycol 200, 400, 600, 800 and 1500 oleic acid glycerides were synthesized from the DuPont R&D Center (anonymous in Delaware, USA), and the water was bound water.
  • polyethylene glycol 600 bis-oleic acid glyceride the drug-encapsulating function of the liposome was carried out for coffee because of the drug index.
  • concentration of polyethylene glycol 600 diolein was 5% and the concentration of caffeine was 100 mM.
  • the caffeine was first dissolved in water, and then polyethylene glycol 600 dioleic acid glyceride was slowly added to the stirred caffeine solution at room temperature, and stirring was continued for 2:1: The formed lipid raft was observed under a microscope.
  • polyethylene glycol diglycerides can also spontaneously form liposomes, stearic acid (octadecanoic acid), palmitic acid (hexadecanoic acid), myristic acid (ten; tetradecanoic acid), cinnamon Acid: (dodecanoic acid) and their combination with oleic acid (octadecenoic acid), respectively:
  • Polyethylene glycol 600 is eaten into polyethylene glycol cargo oil diester (provided by the DuPont R&D Center) To observe the spontaneous formation of liposomes.
  • the synthesized lipid and purified water were separately equilibrated to the designed temperature, and then the lipid was slowly added to the stirred water, stirred for two hours or until equilibrated to room temperature, and the liposome was observed by light microscopy and electron microscopy, respectively. Formation.
  • the final concentration of polyethylene glycol diglyceride was 5%. Polyethylene glycol bis-stearic acid oleate can be compared
  • Polyethylene glycol 600 oleic acid ester was mixed with the same concentrated phosphoric acid ester: to verify the effect of phosphate on the polyethylene glycol double-sleeve acid ester shape, the effect of: ⁇ . (1-palmitoyl, 2-oleoylphosphoryl:danine), ⁇ gn ⁇ 3 ⁇ 4 paste); buy,: water bound water: p ⁇ e on poly: ethylene glycol:
  • the ratio of 600 oleic acid glyceride 5%, 0%, 15%, 20%, 30%, 50%.
  • test results N2008/000511 also showed that when the concentration of phosphate ester in mixed ester is more than 10%, the formed liposome has a slight mutual aggregation when stored for a long time (more than 20 days, 37 °C). :,: : The more serious the aggregation phenomenon.
  • the mixed ester formed by adding phosphate POPC has a glyceride concentration of 85% phosphate ester concentration of 15%, and the drug package of the liposome is carried out by using ⁇ If due to a drug index.
  • the final concentration of the mixed ester is 5%; the concentration of carbaryl is: lOOinM.
  • the caffeine was first dissolved in water, and then the premixed lipid was slowly added to the caffeine solution of the mash, and the mixture was further stirred for 2 hours, and the formed liposome was observed under a microscope.
  • Trehalose is widely used as a stabilizer for protein molecules. Its main mechanism is that trehalose can bind to certain amino acid molecules by hydrogen bonding to prevent protein aggregation. Trehalose is a self-synthesis product in the human body and is also a drug safety additive recognized by the US FDAi. We added trehalose to phospholipids and found that it is also effective in preventing the mutual aggregation of liposomes and increasing the stability of liposomes. Polyethylene glycol 600 dioleic acid glyceride and POPC (1 palmitoyl: 2-oleoylphosphorylcholine) were mixed and stirred uniformly, and the concentration of polyethylene glycol 600 diolein in the mixed ester was 85 ° /. , POPC is 15%. Trehalose is first dissolved in water at concentrations of 1% and 5%, respectively. Then slowly add the lipid mixture to the stirred
  • Polyethylene glycol 600 double glyceride + 15% POPC liposome + 13 ⁇ 4; trehalose; D, polyethylene glycol 600 bismuth oleate + 15% POPC liposome 5% trehalose: The addition of 1% to 5% of trehalose to the lipid lysate has a significant effect on the stability of the liposome. I also used liposome stability tests with 0.2% and 0.5% trehalose. At this low concentration, the effect of liposome stability was also recommended.
  • the concentration of polyethylene glycol glycerol diester in the mixed ester formed by adding phosphate POPC is 85% phosphate concentration is 15%, which is called the coffee garden drug index.
  • the final concentration of the mixed fat was 5%, :: the concentration of caffeine was 100 mM, and the concentration of trehalose was 1%.
  • Caffeine and trehalose were first dissolved in ice, then the premixed mixed ester was slowly added to the stirred caffeine and trehalose solution at room temperature, and the mixture was stirred for 2 hours. The formed liposomes were observed with a microscope. .
  • an antioxidant amino acid to the liposome dosage form.
  • 50 mM tryptophan, tyrosine, cysteine and methionine were added to the polyethylene glycol 600 bis-oleic acid glyceride + 15% phosphate POPC liposome preparation.
  • the various amino acids were from Sigma.
  • the caffeine fiber suspension stability index of the coffee wrapped in the liposome was purchased.
  • Polyethylene glycol 600 dioleic acid glycerin and iPOEC (1 soft acyl: 2 hydrazine
  • the liposomes were separated from the aqueous solution.
  • the caffeine concentration in the aqueous solution is the caffeine content not encapsulated by the liposome.
  • the residual caffeine in the aqueous solution was not 8-10 mM (Fig. 7, 0 days).
  • A is a control experiment, no amino acid is added; B is the result of adding 50 mM amino acid.
  • the rate of caffeine in the 3 ⁇ 4 body is as high as 90%-92%.
  • the concentration of caffeine in the solution increased gradually in the control group without proline.
  • Polyethylene glycol 600 diolein and phosphate POPC were premixed in a ratio of 20% (5:1) of POPC. Then, cyclosporin A is pre-dissolved in the prepared mixed solution to form a mixture of Ac-tryptophan, tyrosine, 3 ⁇ 4 cysteine and proline.
  • the proline is first formulated into a mother to give a final concentration. It is 50 mM.
  • the trehalose and amino acid mother liquor were first mixed with water to form a mixture B (ingredients Table 4. Then, the mixture A was slowly added to the stirred mixture B, and stirring was continued for two hours. The formation of the liposome was examined by a microscope.

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Description

一种脂质体药物载体及其制备方法 技术领域
本发明涉及一种脂质体药物载鉢 , 本发明 涉及 3旨 伴药物载体的制备方 法。 背景技术
脂质体是利用磷脂双分 层膜辨形成的囊泡包裹蒲物分 而形戒 fe—种定 向药物载体，属于靶向给药系统的^种新剂型。¾»将溶液或溶液中的活性物 质包埋在直径为纳米级的微粒中。 前，脂质体的 要瘰料为磷脂， 磷脂是构成 脂质体的主要化学成分，其中最具有代表性的是卵憐脂。胆固醇也是脂质体另一 个重要组成成分，它本身并不形成膜结构，但是能够以; 1 : 1甚至 2; 1的摩尔比插 入磷脂膜中。加入胆固醇可以政变脂膜的相变温度， 而影响嫫的通透性和流动 性， 增加磷脂膜的稳定性。
磷脂分散在水中时能形成多层微囊，;且每层均为脂质双分子层，各 之间被 水相隔幵， 这种微囊就是脂质体。脂质体可分为单室脂质体、多室脂质体， 含有 表面活性剂的脂质 。 :
制备脂癀体的¾¾¾要 将 脂载磷聘 幽固;醇瘠^ |¾镲 S成溶液， 然后蒸发除去有机溶剂，在器壁上形成双分子层脂瑭薄膜，将此獰膜收集并与水 溶液搅拌混合形成脂质体。此时的腊质体往往是直径很大的多室脂质体，必须经 过处理制成有实用价值的脂质微球。制备脂质微球的方法主要是超声波、超过滤、 高压粉碎及机械碾磨。
脂质体的应用 分广泛。：磷脂可将各种葯 包 成脂 球 mm )， 该 脂质微球在与人体皮肤接触或进久 体内后，：利用荬膜 细胞胰结构相似 特 征，与细胞膜进行融合或通过细胞内吞作用将药物载送到靶点细胞内。药物通过 脂质载体，可以顺刹穿过表皮的角质层，为备种外麵药及 A鉢护理用品的开发提 供 有效的方法。両对 腔及胃部敏感的药物经脂质钵的 裹后，可使其免受口 腔及胃酶的破坏，使其安全的到达肠道,利用脂 赠与肠 细胞膜的结构相似性， 更有效地将药物导入到细胞内，从而提高药物的治疗指辫，减少药物的绐疗剂量 和降低药物的毒性。
脂质体作为药物载体的应用虽然 备 15许多优点和特点，但就目前来看，也 还存在相当的局限性， 自从 1 1年英国科学家莱门等人 始将脂质体用作药物 载体以来已三十多年时间：，：脂唾体拨歩发展缓慢，鹰铕 J质体顿制的药品少之又 少便是佐证之一。 其中主要 錄可 纳 以 ：南: : :
首先， 脂质体的制备技术给工业化生产带来 艮大难度。生产工艺复杂， 对 设备的要求高。而且， 目前的生产工艺无法控制脂质体的大小和室囊结构， 使生 产的脂质体大小不均， 室囊结构多样不一。
第二， 脂质体的稳定性不佳， 能保证药物幵发的稳定性要求。脂质体生产 过程往往需要加温和改变压力来去除有妙 剂；然后用机滅碾磨或超声波等极端 手段来制备直径微小的脂质微球，这些极端措施需要或 生高温高压而导致脂质 和其封包的药物分解。
第三， 脂质体不易被无菌化， 特别是太容量脂滅体昀无菌化更是一大挑战， 而无啬体是药物生产的必须途径。 菌 的 要 i¾包齄热消毒、酒精消毒、氧 化杀菌、 gamma射线消毒和 菌超过滤 ό 些方法中只 ¾无菌超过滤适合脂质 体的无菌化， 而脂质体的超过滤已被证明十分困难。
第四， 脂质体极易相互吸附聚集并融合。在脂质体的保存过程、或遇到温度 变化以及加入不同添加剂或辅料，脂质体都有可能相互吸附聚集并融合，:导致脂 质体的不稳定。
第五， 包封率低。 自前以磷脂为主要療料:的脂:质体难药物 包容率低， 特别 是对于某些水溶性药物包封率更低， 且药物易从脂质体中渗漏。
基于以上原因， 开发一种稳定的、易生产的 髙包封率的新型脂质体来克服 目前现有脂质体的不足袅十分必要的。 发明内容
本发明的目的是提供一种稳定的、易生产的、高包封率的新型脂质体药物载 体。
本发明的另一目的是提供一种工艺简单的脂质体药物载体的制备方法。 为达上述:目的， 本发明逋过采敏以 Τ技术方案予以实现： 一种脂质体药物载体， 该脂质体的主要成分为聚乙二醇甘油双酯， 其分子式 为：
Figure imgf000004_0001
其中， 为饱和或不饱和酰基、 R2 为饱和或不饱和酰基、 R3 为 (C2H40)n-OH, n = l-35。
上述方案中， 所述的聚乙二醇甘油双酯为聚乙二醇 200甘油双酯， 聚乙二醇 400甘油双酯、聚乙二醇 600甘油双酯，聚乙二醇 800甘油双酯或聚乙二醇 1500 甘油双酯。
所述的脂质体的成分中还包括有磷酸酯， 磷酸酯优选磷酸酯 POPC, 其含量 为聚乙二醇甘油双酯的 0-30%。
所述的脂质体的成分中还包括有海藻糖， 海藻糖的含量为脂质体总量的 0.2-5%。
所述的脂质体的成分中还包括有抗氧化氨基酸，抗氧化氨基酸为色氨酸、酪 氨酸、 半胱氨酸或甲硫氨酸。
本发明提供的一种脂质体药物载体的制备方法是：脂质体的主要成分聚乙二 醇甘油双酯在室温或加温和常压下与水溶液混合搅拌即自动形成脂质体，其中聚 乙二醇甘油双酯溶液中可选择添加磷酸酯、海藻糖和抗氧化氨基酸中的一种或几 种混合物用于制备脂质体。
传统脂质体是一种由憐酸酯双分子层膜形成的囊泡，具有包裹药物分子能力 和靶向给药功能的药物剂型。 典型的脂质体为微球形， 如图 1所示， 微球的内外 表面分别为极性亲水磷酸酯双分子表层 (图 1:, A, B), 极性亲水的微球内腔可 包囊亲水的药物分子（图 1， B¾ 而脂溶性的药物分子则^镶嵌在脂质双分子层 中间 （图 1， C)， D为极性亲水的磷脂双分 表面。 倦统磷酸酯脂质体的最大 不足就是稳定性差、 生产过程繁琐、」设备要求高， 而这些不足均起源于用于生产 脂质体的原始材料磷酸酯:， 因此筛选一种或多 更稳定 更 有自；我囊泡形成功 能的脂质作为原材料便是解决传统脂质体不足的 ¾要园素。
影响脂质分子形成脂质体的因素很多， 首先要考虑的是脂质的分子几何结 构。 如前所述， 形成脂质体的分子必须是既亲水又亲脂的双亲分子， 而这种结构 在甘油酯中非常常见，然而并非所赛的双亲分子都能形成药用脂质体。双亲脂质 分子的亲水基团（头部）和亲脂的碳链（尾部）的绮构必须符合形成旨质体的要 求，而首先必须具备的结构是分 的几 结构。街这 亲分 的几何结构又可 以用一种叫表面活性参数（S)来表示：
Figure imgf000005_0001
如图 2所示， 表示亲脂部分的鉢积， ；代表碳氢链的长度， 。表示亲水 头部的有效面积。表面活性参数反映了双亲分子的几何结构，与该分子聚集时的 弯曲率直接枏关。 当此活性参数小于 1/3时， 分子聚集后建成实心球体， 不具备 药物包裹能力； 当此参数为I时:， 基 机枸将是平梃， 很难形成球体:; 而此参数 大于 1时， 形成反向微球， 亲脂碳链 ½外躯能与极 ft溶剂兼溶； 只 ¾在表面活 性参数在 1/3〜1之何时， 理想的囊泡微球； *能形成。画此， 通过对分子的表面活 性参数的评估便可初步筛选脂质体脂质分子。
甘油酯作为生物膜的主要组成部分自然是脂质体脂质的首选分子，磷酸甘油 酯的基本结构如图 3所示。 就甘油酯而言， 单碳链#油酯的 S值往往小于 173， 因此不能用于脂质体的制备， 双碳键 ¾油;酯将是脂质体脂质的主要分子。
为了使脂质分子能自发地在常温常压下形成脂质体， 脂质分子的熔点必须 低， 即在室温或适当加温时必须是液体， 因此， 在选择脂质分子时排除高熔点的 脂质。
碳链（亲脂的尾部)选 该分 杏観然: Ιί形 脂质体弁具有良好的表 皮穿透性的关键之一。众多的研究表明，;在与极性分子连接后， 各种饱和与不饱 和脂肪酸均有不伺程度的表皮渗透性。另外， 不饱和键有顺反式构象， 顺式构象 可使直链分子弯曲， 弯曲的顺式构象 (cis-)不饱和脂肪酸： (见图 4) 能有效地 利用其几何弯湖构象松动生物体細胞间紧密棑列的脂质 使生物嫫变得更具通 透性。 因此， 适当比例的不饱和脂肪酸可以增加皮肤的通透性。我们应甩了多种 脂肪酸组合 (表二）， 证明均可以在适当条件下自发的形成脂质体。
正如前面表面活性参数所描述，脂质分矛的亲脂碳链的长度和极性亲水基团 体积的比例将是决定此分子楚否自:己形成脂质体的关键。亲水基团必须相对庞大 才能使此分子有足够的弯曲率形成双层脂璩膜的囊泡脂质体。在传统脂质体的磷 酸酯中， 磷酸基画、 与磷酸相连的图 3中的 R3基团 (见图 3 ) 以及与之相关的 电荷构成了极性 "头部"。 但由于传统脂质体的不稳定性和生产的难度必然与磷 酸酯有直接的关系，我们采用了非磷酸酯作为本脂质 的基本脂质分子。被美国 FDA批准可作为药用辅料的聚乙二醇具有良好的极性， 并可选择其链的长度而 改变"夹部" ;的大小 聚乙 醇 #抻 酯被证明是理想酌月旨质体脂质。通过显微 镜的观察， 当聚乙二醇甘油双酯被加到搅拌中的水溶液中:时，:在室温或适当加温 条件下脂质体便自动产生（见图 5)， 无需有机溶剂和高温加压等附加条件的帮 助。 聚乙二醇 200甘油双酯、 聚乙二醇 400甘油双酯、 聚乙二醇 600甘油双酯， 均被证明为理想的脂质分子， 聚乙二醇 800甘油双酯 聚乙^：醇 1500甘油双酯 就已缺乏在室温条件下自动形成脂质体的能力 然而在适当的温度条（37Ό或 50°C )件下也能自发形成脂质体。
聚乙二醇甘油双酯能在室温和常压下在与水溶液混合后 动形成脂质体，但 它不是生物膜的组成脂质，因此用聚乙二醇甘油双酯制备的脂质体的生物兼容性 可能受到挑战。为了解决这个 题，生物膜磷酸酯被加入到聚乙二醇 ¾油双酯溶 液中， 以增加所制备的脂质双分子膜与生物体细： 腠结构的相类性，从而增加其 生物兼容性。 良好的生物兼容性可能使脂质体进入火体内部启动的系统免疫机 制， 被网状内皮系统吞噬， 从而在肝、脾、肺和骨髓等组织中靶向性地富集。这 就是脂质体的被动靶向性。
过髙浓度的磷酸酯导致了聚乙二醇 油双酯失去了在常温常压下自动形成 脂质体的能力。磷酸酯 POPC(l，软脂酰， 2-油酰磷酸酰胆碱 X 1-palmitoyl, 2-oleoyl phosphatidykhQline)是最常用的脂质体磷酸酯之 ，表 是磷酸酯 POPC为例和 聚乙二醇 600甘油双酯混合脂在常温或适当加温及常压下形成脂质体的试验结 果。当磷酸酯的浓度在混合酯! ΐ低于 30%时不影响聚乙二醇！ "油双酯的自发形成 脂质体的能力，而遛过 30%的磷脂 膨:聚¾ ^醇 翻欢酷觀脂质体形成的自发 性即受到影响。为了尽可能保持聚乙 j醇铺油双酯:的脂癀体发生的：自发性， 同时 增加与生物膜的兼容性，我们的结果显示含 0-30%磷酸酯的聚乙二醇甘油双酯和 磷酸酯的混合酯为较佳药物载体脂质体脂质。
不稳定性是传统磷酸酯脂质体的一大不足之一。磷酸酯脂质^^的不稳定性表 现在两个方面：脂质分子的不稳定:性，主要表现在磷酸酯分子易被氧化性和易水 解性； 另一种不稳定性则是脂质体相互聚集而导致脂质体团的形成，而磷脂酯脂 00511 质体聚集的另一种结果则是脂质体相互融合形成超大脂质体^ Ϊ影响载体导入效 果， 这过程还将导致包容药物的泄漏， 降低包埋率。经长时间保存， 磷酸酯脂质 体的相互聚集而导致稳定性下降是限制 謹药物 发 ΐ应用的一个主要原因之 一，增进脂质体的长效稳定性有着卡分重要;的意义。;我们在自发性脂质体的制备 过程中加入了海藻糖， 以及抗氧化氨基酸， 明显拖提高了脂 体的稳定性， 从而 增加了其实用性。 附图说明
图 1为脂质体效果图
图 2为表面活性参数与形状的关系示意图；
图 3为磷脂的分子结构图；
图 4为顺反式脂肪酸示意图；
图 5为油脂聚乙二醇 600脂质体电子显微鏡照片;
图 6为海藻糖对脂质体稳定性的影响示意图:；
图 7为抗氧化氨基酸对酯质体稳定性的影响示意图。 具体实施方式
实施例 1
自发脂质体的制备
本实施例的脂质体的主要成分聚乙二醇甘油双酯以聚乙二醇双油酸甘袖酯 为例进行说明。当聚乙二醇双油酸甘油酯与水溶液混合后，脂质体便自发性的形 成。聚乙二醇 200， 400, 600, 800 and 1500双油酸甘油酯从杜邦研发中心（美国德 拉瓦州崴名登市）合成获得，水为缚净水。将脂质和水分别预热至设计温度（见 表一）， 然后将各种聚乙二醅双油酸 油酯脂璩分别缓每地加入到搅拌的水溶液 中，再搅拌两小吋或直至平衡致室温，分别甩光学显微镜和电子显微镜来观察脂 质体的形成。 聚乙二醇双油酸甘油酯的最终浓度为 10%， 在室温 （20 °C) 聚乙 二醇 200， 400, 600双油酸 油酯均自发的产生了脂质体（见表一)， 在 37°C， 聚乙二醇 200， 400， 600， 800双油酸靜油酯均自发产生 脂质体， 在 50°C， 聚 乙二醇 200， 400， 600， 800、 1500双油酸甘袖酯均 发产生了脂质体。 我们甩 最终聚乙二醇双油酸甘油酯浓度 1%和 5%进行了类似的实验， 结果与 10%的相 2008/000511 同。图 5是聚乙二醇 600双油酸 #油酯赠质体电 显微镜照片，插图为多囊泡脂 质体 <■
Figure imgf000008_0001
自发性脂质体的药物包裹作用
用聚乙二醇 600双油酸甘油酯为例，以咖啡因为药物指标进行了该脂质体的 药物包裹功能。聚乙二醇 600双油酸甘油酯的浓度 5%，咖啡因的浓度为 100mM。 咖啡因先溶于水，然后将聚乙二醇 600双油酸甘油酯在室温 缓慢的加到搅拌中 的咖啡因溶液中， 继续搅拌 2：小时: 所形成的脂癍体用显微镜观察。脂质体形成 后经超速离心机（ Beckman L8-55 ) 5万 RPM离心 3小时后， 脂质体和水溶液被 分开， 脂质体沉淀， 未被包裹的咖啡因:继续留在液柑中， 液相中的咖啡因浓度 未被脂质体包裹的咖啡因含量。咖啡因含量用 HPLC方法检测。经五次试验平均， 该脂质体对咖啡因的包容率很高， ^均在 87-91% ;向 实施例 2
不同脂肪酸链聚乙二醇甘油双酯的自发性脂质体的制备
为了说明其他聚乙二醇甘油双酯也能自发形成脂质体，硬脂酸（十八垸酸)、 软脂酸（十六垸酸）、 肉豆蔻酸 (十；四垸酸)、 桂酸： (十二烷酸) 以及他们与油 酸 (十八碳烯酸)进行分别组合、用：聚乙 2醇 600 食成聚乙二醇货油双酯 （由 美国杜邦研发中心提供)， 来观测其自发形成脂质体的情况。 将合成的脂质和纯 净水分别平衡到所设计温度，然后将脂质缓慢地加入到搅拌中的水中，再搅拌两 小时或直至平衡致室温， 分别用光学显微镜和电 显微镜来观察脂质体的形成。 聚乙二醇甘油双酯的最终浓度为 5%。 聚乙二醇双硬脂酸 油酯铈能由于熔点较
Figure imgf000009_0001
Figure imgf000009_0002
实施例 3
磷酸酯自发性脂质体
用聚乙二醇 600:錄油酸 油酯为纏与 同浓 磷 酯混合，：来验证磷酸 酯对聚乙二醇双袖酸 油酯形攝自发德脂 的影晌，：麵 ^酯为 ΦΘΡ。（1-软脂 酰， 2-油酰磷酸酰:旦碱)， ^gn^ ¾糊 )；买，:水 缚 水 : p< e对聚:乙二醇：
600双油酸甘油酯：的比例分别为 5%， 0%， 15%，: 20%， 30%, 50%。 POPC和 聚 二醇 双油酸翁幽 截先捧匕剁灣錄 ί| 均 ，；龜食后的脂质和水分别预 热至要求温度 (室温， 37 °C和 50°C, 表三）， 然后将混合脂慢慢加 到搅拌中 的水中 继续搅拌两 或直至萆温；，：: 蜣痕 镜和 寒显徼镜来观察脂 质体的形成， 本实验的最终脂质浓度为 5%。实验结果 明 (表三）， 20%或少于 20%的磷酸脂对聚乙二醇 600双油酸甘油酯自发形成脂质体没有影响，磷酸酯在 混合酯中的浓度等于 30%时， 只 在加棒至 SO D 吋，：海合酯才能自发地形成脂 质体（表三)。 此可见， 磷酸酯麼混合旨^: 浓度对 ¾发 成脂质钵影响很大， 自发性脂质体的混合酯中磷酸酯的浓度应该低于 ％ -30% 间）。 试验结果 N2008/000511 也表明，磷酸酯在混合酯中的浓度大于 10%时，所形成的脂质体在长期保存时 (大 于 20天， 37 °C)有轻微相互聚集想象，麟脂的百 鳞高 :，: :聚集现象越严重。
表三. ' ■ .
Figure imgf000010_0001
含磷酸酯自发性脂质体的药物包裹作用
用聚乙二醇 600双油酸甘油酯为例，加入磷酸酯 POPC形成的混合酯中甘油 酯浓度为 85%磷酸酯浓度为 15%， 用呶 If因 药物指标进行 该脂质体的药物 包裹功能。混合酯的最后浓度为 5%;咖唯因的浓度为： lOOinM。咖啡因先溶于水， 然后将预混合的脂质在室温下缓慢的加到攆拌 ΐ的咖啡因溶液中，继续搅拌 2小 时，所形成的脂质体用显微镜观察。脂质体形成后经超速离心机（Beckman L8-55 ) 5万 RPM离心 3小时后， 脂质体和水溶液分开， 水溶液中的咖啡因浓度为未被 脂质体包裹的咖啡因含量。咖啡因含量用 HPLC方法检测。经五次试验平均， 该 脂质体对咖啡因的包容率在 85-90%之间。 实施例 4
海藻糖增加脂质体的稳定性
海藻糖（trehalose) 是被广泛用来作为蛋白分子的稳定剂， 其主要机理是海 藻糖可以与某些氨基酸分子以氢键相结合 ^而防止蛋白^ ^相互聚集。海藻糖是 人体体内自我合成分予 也是美国 FDAi认定的药物安全添加剂。 我们将海藻糖 加入到磷酸脂质体中，发现也能有效地防止脂质体的相互聚集，增加脂质体的稳 定性。 聚乙二醇 600双油酸甘油酯和 POPC ( 1软脂酰 : 2-油酰磷酸酰胆碱）混合 搅拌均匀， 混合酯中聚乙二醇 600双油酸甘油酯浓度为 85°/。， POPC为 15%。海 藻糖先溶于水， 浓度分别为 1%和 5%。 然后将脂质混合物慢慢加入到搅拌中的
Figure imgf000011_0001
聚乙二醇 600双池酸甘油酯 +15%POPC:脂质体 +1¾；海藻糖; D， 聚乙二醇 600 双油酸甘浊酯 +15%POPC脂质体 5%海藻糖: ) 在脂 賴中加入 1%到 5%的海 藻糖对脂质体有明显的增加稳定性的作用。 我 扉也用 : 0.2<%和 0.5%的海藻糖 进行了脂质体稳定性试验， 在此低浓度的条翁 也荐增加脂质体稳定性的作用。
含海藻糖脂质体的药物包裹作用
用聚乙二醇 600双油酸甘油酯为例，加入磷酸酯 POPC形成的混合酯中聚乙 二醇甘油双酯浓度为 85%磷酸酯浓度为 15%，稱咖啡园 药物指标进行了该混 合酯的药物包裹功能。混合脂的最后浓度为 :5%，::咖啡因的浓度为 lOOmM, 海藻 糖的浓度为 1%。。咖啡因和海藻糖先溶于氷，然后将预混 的混合酯在室温下缓 慢的加到搅拌中的咖啡因和海藻糖溶液中，继续搅楼 2小时，所形成的脂质体用 显微镜观察。脂质体形成后经超速离 机 (B^km ;L8-5$) 5 ¾" RPM离心 3小 时后，脂质体和水溶液分幵，」求溶液中的咖啡因浓度为未被脂质体包裹的咖啡因 含量。咖啡因含量用 HPLC:方法检测。经 次试验 均，该脂质体对咖啡因的包 容率在 85-90%之间。 实施例 5
抗氧化氨棊酸对脂质体稳定性的影响
为了增加脂质体的抗氧化稳定性，我们在脂质体剂型中加入了抗氧化的氨基 酸。在聚乙二醇 600双油酸甘油酯 +15%磷酸酯 POPC脂质体制剂中加入了 50mM 色氨酸、酪氨酸、半胱氨酸和甲硫氨酸， 各种氨基酸分别从 Sigma公司购得， 咖 啡因为被包裹活性物， 包裹在脂质体中的咖啡因纖續 稳定性指标。
聚乙二醇 600双油酸甘油 和 iPOEC ( 1软脂酰 :2働 |磷酸酰胆碱)混合 搅拌均匀， 比例为聚乙二醇 600双油酸甘油酯 85%, P0PC为 15%。 色氨酸、 酪氨酸、半胱氨酸和甲硫氨酸以及咖啡因先溶于水，各种氨基酸的浓度为 50mM， 咖啡因的浓度为 100mM。 对照试验只加咖啡因，：不加氨基酸。 将混合脂质缓慢 地加到搅拌中的咖啡因和氨基酸溶 继 ft拌两 脂瘐体形成后经超速 离心机（Beckman L8-55 ) 5万 RPM禽心 3小时后， 脂质体和水溶液分开， 水溶 液中的咖啡因浓度为未被脂质体包裹的咖啡因含量。脂质体刚形成时，咖啡因在 水溶液中的残留未 8-10 mM (图 7， 0天）， 图 7中 A为对照实验， 不加氨基酸； B为加了 50mM氨基酸后的结果。 ¾旨 体对咖啡因的包 率浪高， 达 90%-92%。 经过 30天在 50度温度的加速稳定性试验，不加氨 酸的对照组，溶液中的咖啡 因浓度逐歩增加， 到第 30 时迗到 18h M， ：说 脂质雜的稳定 ft逐歩下降， 咖 啡因从脂质体漏出。 而加了氨基酸的脂质体的稳定桂明显好于对照:， 到第 30天 时溶液中的咖啡因浓度才 llmM,基本保持原有水平。此试验表明加入抗氧化氨 基酸后脂质体的稳定性明显增加。 实施例 6
自发稳定脂质体的药物环孢霉素包裹试验
聚乙二醇 600双油酸甘油酯和磷酸酯 POPC先预混合，比例为 POPC占脂质 的 20% (5:1 )。 然后将环孢霉素 A预溶于事先准备好的 质混合液中成混合液 Ac色氨酸、酪氨酸、 ¾胱氨酸和;甲癞氨酸先配成母 ，使某的最后浓度为 50mM。 海藻糖及氨基酸母液先与水混合成混 液 B (成分 表四 。然后将混合液 A缓 慢地加入到搅拌中的混合液 B中， 继续搅拌两小时。 脂质体的形成情况用显微 镜检测。
表四
成分
聚乙二醇 600双油酸甘油酯 5%
磷酸酯 POPC 1%
环孢霉素 A 1%
海藻糖 1%
氨基酸溶液母液 50mM
水 加至 100% 用超高速离心方法将脂质体和液相分离后， 液相中的环孢霉素的余留用
HPLC检测， 五次试验结果表鴨 脂质体的环孢霉素包裹率在 S3-91%之间。
自发稳定脂质体的抗癌药物; AM B包裹^ : "
聚乙二醇 600双油酸甘油酯和磷酸酯 POPC先预混合，比例为 POPC占脂质 的 20% (5:1 )。 然后将抗癌药 AMPB (2-4，amin0-3-metliylphenyl benz0thiazole) (Sigma公司)预溶 事先准备好的脂质混 裤中 乘 A。：色氨酸、酪氨酸、 半胱氨酸和甲硫氨酸先配 母 :: 的 后浓 50¾1。海藻糖及氨基酸母 液先与水混合成混合液 B (成分见表五）。 然后将脂质混合液 A缓慢地加入到搅 拌中的水溶液 B中， 继续搅拌两小时。 脂质体的形成情况用显微镜检测。
表五
Figure imgf000013_0001
超高速离心后， 液相中的 A PB的余留用 HPLC检测， 五次试验结果表明， 脂质体的 AMPB包裹率平均在 91%左右。

Claims

权 利 要 求
1、 一种脂质体药物载体， 其特征在于： 所述的脂质体的主要成分为聚乙二 醇甘油双酯， 其分子式为：
Figure imgf000014_0001
其中， 为饱和或不饱和酰基、 R2 为饱和或不饱和酰基、 R3 为 (C2H40)n-OH， n = 35。
2、 根据权利要求 1所述的脂质体药物载体， 其特征在于： 所述的聚乙二醇 甘油双酯为聚乙二醇 200甘油双酯， 聚乙二醇 400甘油双酯、聚乙二醇 600甘油 双酯， 聚乙二醇 800甘油双酯或聚乙二醇 1500甘油双酯。
3、 根据权利要求 1所述的脂质体药物载体， 其特征在于： 所述的脂质体的 成分中还包括有磷酸酯。
4、 根据权利要求 3所述的脂质体药物载体， 其特征在于： 所述的磷酸酯为 磷酸酯 POPC, 其含量为聚乙二醇甘油双酯的 0-30%。
5、 根据权利要求 1所述的脂质体药物载体， 其特征在于： 所述的脂质体的 成分中还包括有海藻糖。
6、 根据权利要求 5所述的脂质体药物载体， 其特征在于： 所述的海藻糖的 含量为脂质体总量的 0.2-5%。
7、 根据权利要求 1所述的脂质体药物载体， 其特征在于： 所述的脂质体的 成分中还包括有抗氧化氨基酸。
8、 根据权利要求 7所述的脂质体抗氧化氨基酸， 其特征在于： 所述的抗氧 化氨基酸为色氨酸、 酪氨酸、 半胱氨酸或甲硫氨酸。
9、 一种权利要求 1所述的脂质体药物载体的制备方法， 其特征在于： 所述 的脂质体的主要成分聚乙二醇甘油双酯在室温或加温和常压下与水溶液混合搅 拌即自动形成脂质体。
10、根据权利要求 9所述的脂质体药物载体的制备方法， 其特征在于： 所述 的聚乙二醇甘油双酯溶液中选择添加磷酸酯、海藻糖和抗氧化氨基酸中的一种或 几种混合物制备脂质体。
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