WO2003004024A1 - Microspheres injectables a liberation prolongee de composes d'huperzine a - Google Patents

Microspheres injectables a liberation prolongee de composes d'huperzine a Download PDF

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Publication number
WO2003004024A1
WO2003004024A1 PCT/CN2002/000472 CN0200472W WO03004024A1 WO 2003004024 A1 WO2003004024 A1 WO 2003004024A1 CN 0200472 W CN0200472 W CN 0200472W WO 03004024 A1 WO03004024 A1 WO 03004024A1
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Prior art keywords
huperzine
sustained
release
microspheres
acid
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PCT/CN2002/000472
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English (en)
French (fr)
Inventor
Wanhui Liu
Jilun Song
Dafeng Chu
Ke Liu
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Shandong Luye Pharmaceutical Co., Ltd.
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Priority to DE10297018T priority Critical patent/DE10297018B4/de
Priority to PCT/CN2002/000472 priority patent/WO2003004024A1/zh
Priority to US10/482,631 priority patent/US20040266813A1/en
Publication of WO2003004024A1 publication Critical patent/WO2003004024A1/zh

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to sustained-release microspheres for injection of Huperzine A or a derivative or salt thereof (hereinafter also referred to as "Huperzine A compound"). More specifically, the present invention relates to injection of Huperzine A compound A method for treating acetylcholinesterase-related diseases and a method for treating senile dementia by using slow-release microspheres, a preparation method thereof, and a huperzine A compound preparation. Background technique
  • Huperzine A (Formula (I), its scientific name is (5R, 9R, 11E) -5-amino-11-ethylene-5,6,9,10-tetrahydro-7-form -5,9-methylenecycloarsino-2 (1H) -pyridine, which is derived from the plant ⁇ ⁇ Lycopodiaceae Reichb., Clubmoss Family) plant Huperzia serrata (Chinese medicine name: Melaleuca tower)
  • Huperzine A is a highly effective and reversible acetylcholinesterase inhibitor (Chinese Pharmaceutical Journal, ibid .; WO02 / 11712; EP806416A1, etc.). It has been reported to be used to treat Alzheimer's disease. (Chinese Pharmaceutical Journal, ibid .; CN1279065A; WOOl / 00215; WO02 / 11712, etc.) In addition, by modifying its structure, it was found that some of its derivatives also have similar effects (W099 / 11525; EP1167354A2; US5869672; US5547960; W092 / 19238; EP806416A1, etc.).
  • Huperzine A there are many known formulations of Huperzine A in the form of tablets, capsules, transdermal absorbents, injections and the like (WO02 / 11712; CN1047732C; CN1279065A, etc.).
  • the existing clinical application forms of Huperzine A whether oral preparations, injections or transdermal absorption agents, have several shortcomings in clinical use.
  • huperzine A has a short biological half-life and large side effects from huperzine A, the main manifestations are: dizziness, nausea, sweating, inability to sit still, anxiety, vomiting, muscle tremor, heart rate changes, pupil changes, etc.
  • Huperzine A tablets are used in the clinical application at a frequency of 2 to 3 times a day for a long time, and side effects cannot be avoided.
  • transdermal absorption dosage form may achieve long-term effect to a certain extent (CN1047732C), its long-acting effect is obviously insufficient compared with Alzheimer's disease, and if transdermal absorption is to achieve long-term effect, it is necessary to increase the dose May cause local irritation to the skin. Therefore, there is an urgent need to develop a new type of long-acting preparation, which can reduce the number of administrations and facilitate the medication for patients, and the probability of side effects is small.
  • the object of the present invention is to provide a sustained-release microsphere for injection of huperzine A compounds, which can reduce the frequency of drug use from 2 to 3 times a day to half a month, 1 month or even 2 months, greatly reducing The number of medications can greatly improve the quality of life of the majority of patients with dementia.
  • Another object of the present invention is to provide a method for preparing the sustained-release microspheres for injection of the huperzine A-type compound.
  • Still another object of the present invention is to provide a method for treating a disease related to acetylcholinesterase and a method for treating Alzheimer's disease with a preparation of Huperzine A compound.
  • a first aspect of the present invention is a sustained-release microsphere of a huperzine A compound, characterized in that the slow-release microsphere is composed of a huperzine A compound represented by the following general formula (la) and biodegradable Composed of degraded medicinal polymer excipients,
  • X and Y represent a hydrogen atom or a methyl group, respectively, 2 1 and ⁇ 2 represent a hydrogen atom or a group together to represent a group
  • the second aspect of the present invention is a method for preparing slow-drying microspheres of huperzine A compounds.
  • the organic solvent is used to dissolve the huperzine A compounds and biodegradable pharmaceutical excipients.
  • Sustained-release microspheres are then obtained from the emulsified liquid prepared by a water-soluble macromolecule of medicine by a solvent volatilization method.
  • the third aspect of the present invention is another method for preparing sustained-release microspheres of huperzine A compounds, which is to dissolve huperzine A compounds and biodegradable polymer medicinal excipients with an organic solvent and adopt spray drying. Microspheres were made by law.
  • a fourth aspect of the present invention is a method for treating an Alzheimer's disease patient using the sustained-release microspheres of the first aspect.
  • Fig. 1 is a line chart of the cumulative release rate of the sustained-release microspheres obtained in Example 1 in a simulated release solution of pH4.
  • FIG. 2 is a line chart of the daily release rate of the sustained-release microspheres obtained in Example 1 in a simulated release solution of pH 4 during the measurement period.
  • FIG. 3 is a line chart showing the cumulative release rate of the sustained-release microspheres obtained in Example 4 in a simulated front discharge solution at pH 4.
  • Fig. 4 is a line chart of the daily release rate of the sustained-release microspheres obtained in Example 4 in a simulated release solution of pH 4 during the measurement period.
  • Example 5 is a line chart showing the cumulative dry release rate of the sustained-release microspheres obtained in Example 4 in a simulated dry discharge solution at pH 5.5.
  • Fig. 6 is a line chart of the daily release rate of the sustained-release microspheres obtained in Example 4 in a simulated release solution of pH 5.5 during a measurement period. The best way to implement the invention
  • sustained-release microspheres of huperzine A-type compounds of the present invention are formed from huperzine A-type compounds and biodegradable medicinal polymer auxiliary materials.
  • huperzine A compounds of the present invention are the general term for compounds (huperzine A, its derivatives, analogs, and pharmaceutically acceptable salts) having a structure represented by the following general formula (la):
  • X and Y each represent a hydrogen atom or a methyl group
  • 2 1 and 2 each represent a hydrogen atom or together represent a group.
  • the sustained-release microspheres of the present invention are suitable for
  • the aforementioned Huperzine Class A compound is at least one selected from the compounds (1), (11), (111), (IV) or (V) or an acid addition salt thereof in the following table.
  • the compound (I) is named Huperzine A as the mother core
  • the compound (II) is N5- (3, -hydroxy-4, -methoxy-phenylmethylene) Huperzine A
  • the compound (II)) is (10S) -10-methylhuperzine A
  • compound (IV) is (10R) -10-methylhuperzine A
  • compound (V) is 10, 10-dimethylhuperzine A .
  • Huperzine A is most preferred, that is, Compound (1) among them.
  • the huperzine A-based compound may be used in the form of a free base or an acid addition salt.
  • the acid that forms the acid addition salt include hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid, or citric acid.
  • the medicinal polymer auxiliary materials are various polymer materials that are biodegradable but not easily soluble in water, such as, but not limited to, polylactide-glycolide, polylactic acid, polyglycolic acid, and poly- 3-hydroxybutyrate, polylactone, polyanhydride, polyhydroxybutyrate-hydroxyvalerate, polypropylene dextran, polylactic acid-polyethylene glycol, polyglycolic acid-polyethylene glycol, and the like. Its molecular weight is between 5000-1,000,000 Daltons.
  • the medicinal polymer auxiliary material is selected from polylactide-glycolide, polylactic acid, polyhydroxybutyrate-hydroxyvalerate, and the like. Its preferred molecular weight is between 12,000 and 30,000 Daltons.
  • the biodegradable medicinal macromolecule excipients of the above fans are preferably polylactide-glycolide and polyanhydride, and most preferably polylactide-glycolide. If polylactide-glycolide is used, the polymerization ratio of lactide and glycolide is between 95: 5 to 5:95, preferably 40:60 to 75:25, and most preferably about 50:50.
  • the sustained-release microspheres of huperzine A compounds according to the present invention should have a particle size between 1-250 ⁇ m in view of maintaining certain aging, biodegradability, and not affecting blood circulation after injection into the body. If the particle size is too small, it is difficult to maintain long-term efficacy, and at the same time, it may block capillaries and affect the microcirculation. If the particle size is too large, the initial release is too slow to achieve the therapeutically effective blood concentration.
  • the content of huperzine A compounds is not particularly limited, but from the sustained-release effect that guarantees a sufficient long-term effective blood drug concentration and the guaranteed sustained-release effect In terms of equilibrium, it is preferred that Huperzine A compounds account for 0.2 to 50% by weight of the microspheres, and more preferably not less than 4% by weight; medicinal polymer excipients account for 50 to 99.8% by weight, preferably not more than 96% by weight . If the content of huperzine compounds is less than 0.2% by weight, a sufficiently high blood drug concentration cannot be guaranteed; on the other hand, if it is higher than 50% by weight, the smooth release of the drug may not be guaranteed, which may cause side effects.
  • microspheres of the present invention can be prepared by conventional preparation methods such as spray drying and solvent evaporation.
  • the microspheres of the present invention are prepared by a solvent volatilization method
  • Huperzine A compounds and biodegradable pharmaceutical excipients are first dissolved with an organic solvent to prepare an organic phase.
  • a continuous aqueous phase is prepared with a water-soluble pharmaceutically acceptable polymer compound, and the organic phase is slowly injected into the continuous phase through a thin tube. Under mechanical stirring or ultrasonic stirring, it is fully emulsified to form microspheres, and then dried.
  • the organic solvent was used to filter and separate the formed microspheres, and then dried.
  • the microspheres can also be subjected to post-treatments such as water washing and fractionation according to conventional methods, dried under reduced pressure or lyophilized, and then packed.
  • organic solvent should be sufficiently volatile and have a low residual low boiling point from an operating point of view.
  • Organic solvents include, for example, dichloromethane, chloroform, ethyl acetate, diethyl ether, and mixed solvents composed of them.
  • Pharmaceutical polymer compounds for preparing a continuous aqueous phase include, but are not limited to, polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sodium polymethacrylate, and sodium polyacrylate.
  • the content of huperzine A compounds and degradable pharmaceutical excipients in organic solvents is not limited as long as the organic solvents can be dissolved, but from the balance of feasible concentration and viscosity and the use of less organic solvents From the perspective, the preferred concentration is 1-30% (w / v).
  • the continuous aqueous phase is prepared with polyethoxylate, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polysodium methacrylate, and sodium polyacrylate
  • its concentration is not particularly limited, but according to its solubility in water
  • the content in the phase is preferably 0.01-12.0% (w / v), more preferably 0.01-10.0% (w / v), and more preferably 0.1-5% (w / v).
  • the volume ratio of the organic phase to the aqueous phase should be sufficient to sufficiently disperse the organic phase in the aqueous phase to form microspheres of sufficiently fine particle size and uniformity, but If there are too many water phases, the post-processing is complicated and the cost increases. From the above perspective, the volume ratio of the organic phase to the water phase is approximately 1: 4 to 100.
  • Microspheres can also be prepared by spray drying. When the slow-release microspheres of Huperzine A or its derivatives are prepared by a spray drying method, Huperzine A compounds and biodegradable pharmaceutical excipients are fully dissolved in an organic solvent to prepare an organic solution. Microspheres were made by conventional spray-drying methods. If necessary, the microspheres can also be washed and fractionated by conventional methods, and then packed.
  • dichloromethane, chloroform, ethyl acetate, dioxane, diethyl ether, acetone, tetrahydrofuran, hydroacetic acid, and a mixed solvent composed of them can be used as an organic solvent, but it is not limited thereto .
  • the content of the pharmaceutical excipients in the organic solvent is not limited as long as the organic solvent can dissolve the excipients.
  • the preferred concentration is 1-30% ( w / v).
  • the microspheres of huperzine A or its derivatives according to the present invention may be classified after particle size classification or if the particle size is sufficiently uniform. After washing and drying, they can be divided into packages according to a prescribed dose and can be made into Powder injections are formulated into injections in the situ when in use.
  • the powder injection can be made directly from the microspheres. Before use, the injection is suspended with physiological saline for injection. It is also possible to mix a prescribed amount of isotonicity salt, glucose, etc. into the microspheres, and add a prescribed amount of pure water for injection to the injection to prepare an injection solution. Alternatively, the microspheres can be suspended and lyophilized according to the injection amount, and then rehydrated before use.
  • the method for treating diseases related to acetylcholinesterase according to the present invention and the treatment for patients who require the above treatment are performed.
  • the method of administration can be used as long as it can be used as an injection. Examples include intramuscular injection, subcutaneous injection, intradermal injection, and intraperitoneal injection. From the standpoint of ease of administration, intramuscular injection is preferred.
  • the dosage of the Huperzine A compound sustained-release microspheres described in the present invention is huperzine A as an example.
  • the injection volume of Huperzine A is 1 ⁇ 50mg, at least every 15 days. Specific changes can be made according to the actual conditions of the patient's age, weight, and disease status.
  • the sustained-release microspheres of huperzine A-type compounds of the present invention can realize the sustained-release of huperzine A-type compounds.
  • the mechanism of action of the sustained-release microspheres of the present invention is that when it is injected into the body, it gradually diffuses with the blood circulation. Ester is insoluble in water, but can be gradually degraded by the body, and as it is gradually degraded, the drugs contained in the microspheres are gradually released, thereby achieving sustained release and long-term effect.
  • the sustained-release microspheres of huperzine A-type compounds of the present invention can achieve long-lasting effects of huperzine A-type compounds that have not been achieved before, and can be used for a period of not less than 10 days, for example.
  • the interval is preferably no less than 15 days, more preferably no less than 20 days, and it can even be administered at intervals of more than 2 months. Therefore, it is expected to greatly improve the amount of life shield of patients with Alzheimer's disease, while reducing the time per day.
  • the manpower and material resources required for dosing are of great significance. Examples
  • the particle sizes of the microspheres in the following examples were measured using a L2000-type full-automatic laser particle size analyzer (Beckman coulter) familiar to those skilled in the art.
  • the concentration is determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the method is based on literature methods. For example, it can be based on, for example, the Journal of Modern Applied Pharmacy, 1993, 10 (1), 51-52; Chinese Journal of Pharmaceutical Industry, 1999, 30 (8), 363. -Disclosed by 365 etc.
  • the sustained-release microspheres were tested in vivo on rabbits.
  • the dose is 300 ⁇ 13 ⁇ 4, the microspheres are suspended in physiological saline for injection, administered intramuscularly, and the blood is collected within 1 to 20 days, HPLC-MS detection, the blood concentration is 0.1-25ng / ml. It was confirmed that the sustained-release microspheres of the present invention can achieve smooth dry release in at least 20 days.
  • the sustained-release microspheres were tested in vivo on dogs. The dose was 20 g / kg. The microspheres were suspended in physiological saline and administered intramuscularly. Blood was collected within 1 to 28 days and detected by HPLC-MS. The blood concentration was determined to be 0.1-5 ng / ml.
  • the sustained-release microspheres of the present invention can achieve smooth release in at least 4 weeks.
  • microspheres of Examples 1 and 4 were used. Dry release test by simulating in vivo degradation conditions Check.
  • a buffer solution (citrate buffer solution) with a certain pH value (pH 4.0, 5.5) is used, and the drug release behavior is similar to that in the body. Therefore, although the pH value is different from the human internal environment, it is roughly It is thought that the release pattern in vivo can be expressed.
  • Sampling method Centrifuge the tube at 3600rpm for 20min, accurately suck 3ml of solution, and add 3ml of release medium to the centrifuge tube at the same time.
  • the 0th day refers to the drug concentration before the administration on the day of administration.
  • the present invention adopts biodegradable polymer-encapsulated huperzine A compounds to prepare microsphere preparations for injection, which can be maintained for 15 days or longer with one injection.
  • biodegradable polymer-encapsulated huperzine A compounds to prepare microsphere preparations for injection, which can be maintained for 15 days or longer with one injection.
  • Alzheimer's disease and other diseases related to acetylcholinesterase The patient is undoubtedly an excellent gospel.

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Description

石杉碱甲类化合物的注射用缓释微球 技术领域
本发明涉及石杉碱甲或其衍生物或盐（以下也称为 "石杉碱甲 类化合物" ） 的注射用緩释微球， 更具体的， 本发明涉及石杉碱甲 类化合物的注射用緩释微球及其制备方法以及使用本石杉碱甲类化 合物制剂治疗与乙酰胆碱酯酶有关的疾病的方法和治疗老年痴呆症 的方法。 背景技术
石杉碱甲（Huperzine A )， 式（I )，其学名为 (5R，9R，llE)-5- 氨基 -11-亚乙基 -5,6,9,10-四氢 -7-甲基 -5，9-亚甲环芳辛并 -2(1H)-吡啶 , 是从石 ^^{Lycopodiaceae Reichb., Clubmoss Family)植物蛇足 石杉（中药名： 千层塔）
Figure imgf000003_0001
生物碱（中国药学杂志， 32 ( 5 ) , 260 - 261, 1997； W092/19238 等）：
Figure imgf000003_0002
根据报道， 石杉碱甲是一种高效、 可逆的乙酰胆碱酯酶抑制剂 (中国药学杂志， 同上； WO02/11712; EP806416A1等） 。 据报 导， 它可以用来治疗老年性痴呆症。 （中国药学杂志， 同上； CN1279065A; WOOl/00215; WO02/11712等） 另外， 通过对其结 构进行改造， 发现它的一些衍生物也具有相似的作用 ( W099/11525； EP1167354A2； US5869672； US5547960； W092/19238; EP806416A1等）。 已知石杉碱甲的制剂有片剂、 胶嚢剂、 透皮吸收剂、 注射剂等 多种（WO02/11712; CN1047732C; CN1279065A等）。 但是现有 的石杉碱甲的各种临床应用的剂型， 无论是口服制剂、 注射剂还是 透皮吸收剂， 在临床使用上均存在若干不足。 因为石杉碱甲生物半 衰期较短， 而且石杉碱甲副作用较大， 主要表现为： 头昏、 恶心、 多汗、 静坐不能、 焦虑、 呕吐、 肌肉震颤、 心率变化、 瞳孔变化 等。 目前石杉碱甲片在临床应用是以每天服 2 ~ 3次的频率， 长期 服用， 不能避免副作用的发生。
对于老年痴呆症患者来说， 显然无论是长期按时按量服药， 或 者长期每日注射都是不现实的。 透皮吸收剂型虽然有可能在一定程 度上实现长效（CN1047732C ) ， 但是其长效效果相对于老年痴呆 症来说， 显然不够充分， 而且透皮吸收如果要实现长效， 势必需要 加大剂量， 有可能造成对皮肤局部的刺激。 因此， 迫切需要开发一 种新型长效制剂， 可以减少给药次数， 方便患者用药， 同时副作用 发生的概率小。 发明目的
本发明的目的就是提供一种石杉碱甲类化合物的注射用緩释微 球， 能够将药物使用频率从一天 2 ~ 3次降低至半个月、 1个月甚至 2个月一次， 大大减少用药次数， 从而极大地提高广大老年痴呆患 者的生活质量。
本发明的另一个目的是提供上述石杉碱甲类化合物的注射用緩 释微球的制备方法。
本发明的再一个目的是提供一种用石杉碱甲类化合物制剂治疗 与乙酰胆碱酯酶有关的疾病的方法和治疗老年痴呆症的方法。
上迷本发明的目的通过以下所述的技术方案可以得到实现。 发明概述
本发明的第 1方面， 是一种石杉碱甲类化合物的緩释微球， 其 特征在于该緩释微球是由如下通式（la )所示的石杉碱甲类化合物 和可生物降解的药用高分子辅料组成的，
Figure imgf000005_0001
式中， X和 Y分别表示氢原子或者甲基， 21和∑2分别表示氢 原子或者合在一起表示基团
Figure imgf000005_0002
本发明第 2方面是石杉碱甲类化合物的緩幹微球的制备方法， 是用有机溶剂把石杉碱甲类化合物和可生物降解的药用辅料溶解， 将有机溶剂相注入到用可药用水溶性高分子配制的乳化液中， 然后 通过溶剂挥发法得到緩释微球。
本发明的第 3方面是另一种石杉碱甲类化合物的緩释微球的制 备方法， 是用有机溶剂溶解石杉碱甲类化合物和可生物降解的高分 子药用辅料， 采用喷雾干燥法制得微球。
本发明的第 4方面是采用上述第 1方面的緩释微球对老年痴呆 患者进行治疗的方法。
本发明的其它内容和优点通过以下佯细叙述可以进一步明确。 附图简要说明
图 1是实施例 1所得的緩释微球在 pH4的模拟释放液中的累积 释放率折线图。
图 2是实施例 1所得的緩释微球在 pH4的模拟释放液中在测定 期间的每日莽放率的折线图。 图 3是实施例 4所得的緩释微球在 pH4的模拟鋒放液中的累积 释放率折线图。
图 4是实施例 4所得的緩释微球在 pH4的模拟释放液中在测定 期间的每日释放率的折线图。
图 5是实施例 4所得的緩释微球在 pH5.5的模拟幹放液中的累 积幹放率折线图。
图 6是实施例 4所得的緩释微球在 pH5.5的模拟释放液中在测 定期间的每日释放率的折线图。 实施发明的最佳方式
本发明的石杉碱甲类化合物的緩释微球， 是由石杉碱甲类化合 物和可生物降解的药用高分子辅料形成的。
本发明所迷的石杉碱甲类化合物是具有如下通式（la ) 所示的 结构的化合物 （石杉碱甲、 其衍生物、 类似物和可药用盐） 的总 称：
Figure imgf000006_0001
式中， X和 Y分别表示氢原子或者甲基， 21和 2分别表示氢 原子或者合在一起表示基团 本发明的緩释微球适合以
Figure imgf000006_0002
上所有的石杉碱甲或其衍生物或者类似物以及这些化合物的可药用 盐。
优选的， 上述的石杉碱甲类化合物是选自下表中化合物 ( 1 ) 、 （11 ) 、 （111 ) 、 （IV ) 或（V ) 或其酸加成盐的至少一 种。
Figure imgf000007_0001
如果以化合物（I) 为石杉碱甲为母核进行命名， 化合物（II) 为 N5- (3，-羟基- 4，-甲氧基-苯基亚甲基）石杉碱甲， 化合物 (ΙΠ) 为 （10S) -10-甲基石杉碱甲， 化合物 （IV) 为 （10R) -10-甲基石杉碱甲， 化合物（V) 为 10, 10-二甲基石杉碱甲。
上迷化合物中， 最优选石杉碱甲， 即其中的化合物（1)。
上述石杉碱甲类化合物可以以游离碱或者酸加成盐的形式使 用， 作为形成酸加成盐的酸， 例如有盐酸、 醋酸、 磷酸、 硫酸、 乳 酸或柠檬酸等。
上述緩释微球中， 药用高分子辅料为各种可以生物降解但不易 溶于水的高分子材料， 例如包括但不限于聚丙交酯 -乙交酯、 聚乳 酸、 聚乙醇酸、 聚 -3-羟基丁酸酯、 聚内酯、 聚酸酐、 聚羟基丁酸 酯-羟基戊酸酯、 聚丙烯葡聚糖、 聚乳酸 -聚乙二醇、 聚羟乙酸 -聚乙 二醇等。 其分子量在 5000 - 1,000,000道尔顿之间。
优选的， 药用高分子辅料选自聚丙交酯-乙交酯、 聚乳酸、 聚 羟基丁酸酯-羟基戊酸酯等。 其优选分子量为 12000- 30000道尔顿 之间。
上迷可生物降解药用高分子辅料再优选聚丙交酯 -乙交酯、 聚 酸酐， 最优选聚丙交酯-乙交酯。 如果采用聚丙交酯-乙交酯的话， 其中丙交酯和乙交酯聚合比 在 95:5-5:95之间， 优选为 40: 60 - 75： 25, 最优选大约 50: 50。
本发明所述的石杉碱甲类化合物的缓释微球， 从保持一定时 效、 生物降解性和注射入体内后不影响血液循环来看， 粒径应当处 于 1-250μπι之间。 粒径过小， 难以维持长时间的药效， 同时有可能 阻塞毛细血管， 影响微循环； 粒径过大， 初期释放太慢， 达不到治 疗有效血药浓度。
本发明的緩释微球中， 只要能够实现緩幹的目的， 石杉碱甲类 化合物的含量没有特别限制， 但是从保证足够长时间的有效血药浓 度的緩释效果和保证緩释效果的平衡角度来说， 优选石杉碱甲类化 合物占微球的 0.2 ~ 50重量％, 再优选不低于 4重量％; 药用高分 子辅料占 50 ~ 99.8重量％, 优选不高于 96重量％。 如果石杉碱类 化合物含量少于 0.2重量％， 不能保证足够高的血药浓度； 反之， 如果高于 50重量％, 则有可能不能保证药物平稳释放， 可能造成 副作用的发生。
本发明所述的微球可以采用微^^的常规制备方法制得， 如采用 喷雾干燥法和溶剂挥发法。
当用溶剂挥发法制备本发明的微球时， 首先用有机溶剂把石杉 碱甲类化合物和可生物降解的药用辅料溶解， 配制成有机相。 另外 用水溶性可药用高分子化合物配制连续水相， 将有机相通过细管慢 慢注入到连续相中， 在机械搅拌或者超声波作用等剧烈搅拌作用 下， 充分乳化以形成微球， 然后挥干有机溶剂， 过滤分离所形成的 微球， 干燥即得。 在必要的情况下， 也可以按照常规方法对微球进 行水洗、 级分等后处理， 进行減压烘干或者冻干等干燥处理， 然后 分装。
以上操作中， 石杉碱类化合物和可生物降解的药用辅料如前所 迷。 有机溶剂从操作角度应为具有足够挥发性、 低残留的低沸点有 机溶剂， 具体说例如二氯甲烷、 氯仿、 乙酸乙酯、 乙醚、 以及由它 们所組成的混合溶剂等。 配制连续水相的药用高分子化合物例如， 聚乙烯醇、 羧甲基纤维素钠、 聚乙烯基吡咯烷酮、 聚甲基丙烯酸 钠、 聚丙烯酸钠等， 但不仅限于此。
在配制有机相的时候， 石杉碱甲类化合物和可降解药用辅料在 有机溶剂中的含量， 只要有机溶剂能够溶解， 就没有限制， 不过从 可行浓度及粘度的平衡和少用有机溶剂的角度出发， 优选浓度为 1 - 30 % ( w/v ) 。 在用聚乙蹄醇、 羧甲基纤维素钠、 聚乙烯基吡咯 烷酮、 聚甲基丙烯酸钠、 聚丙烯酸钠配制连续水相时， 其浓度没有 特别限制， 但根据其在水中的溶解度， 在水相中的含量优选 0.01- 12.0 % ( w/v ) ， 再优选 0.01-10.0 % ( w/v ) , 更优选 0.1-5 % ( w/v )。 在将有机相注入水相并剧烈搅拌以形成微球时， 有机相 和水相的体积比应足以使有机相在水相中充分分散以形成足够细的 粒度和均句度的微球， 但是如果水相过多， 后处理复杂， 成本提 高， 从以上角度出发， 有机相与水相的体积比大致为 1:4 ~ 100。
也可以采用喷雾干燥法制备微球。 当采用喷雾干燥法制备石杉 碱甲或其衍生物的緩释微球时， 是以有机溶剂把石杉碱甲类化合物 和可生物降解的药用辅料充分溶解配制成有机溶液； 过滤， 以常规 喷雾干燥法制成微球。 在必要的情况下， 也可以按照常规方法对微 球进行水洗、 级分等后处理， 然后分装。
上述喷雾干燥法制备微球时， 有机溶剂可以使用二氯甲烷、 氯 仿、 乙酸乙酯、 二氧六环、 乙醚、 丙酮、 四氢呋喃、 水醋酸及由它 们所組成的混合溶剂等， 但不仅限于此。
在配制有机相的时候， 药用辅料在有机溶剂中的含量， 只要有 机溶剂能够溶解该辅料， 就没有限制， 不过从可行浓度和节约有机 溶剂的平衡角度出发， 优选浓度为 1 - 30% ( w/v ) 。
制备微球溶剂挥发法和喷雾干燥法相比， 从制成的微球的粒径 均匀度和操作简便性等来说， 优选喷雾干燥法。 从降低初始释放的 角度来说， 优选溶剂挥发法。 ， 本发明所述的石杉碱甲或其衍生物的微球制成后， 经过粒径分 级或者如果粒径足够均匀的话也可以不分级， 清洗、 干燥后按照规 定剂量分装， 可以制成粉针剂注射剂， 使用时在现场 （in situ ) 配 成注射剂。 粉针剂可以是直接由上迷微球制成， 使用前用注射用生 理盐水均句混悬， 制成注射液。 也可以在微球中混配规定量的等渗 用盐、 葡萄糖等， 使用前在其中加入规定量的注射用纯水， 制成注 射液。 或者也可以先按照注射用量将微球混悬后冻干， 使用前再复 水。
本发明所述的治疗与乙酰胆碱酯酶有关的疾病的方法和治疗老 予需要上述治疗的患者来进行的。 给药方式只要是可以使用注射剂 的， 可以不拘使用。 例如肌肉注射、 皮下注射、 皮内注射、 腹内注 射等。 从给药方便角度来说， 优选肌肉注射给药。
本发明所述的石杉碱甲类化合物的緩释微球剂的给药剂量， 以 石杉碱甲为例， 对于体重 60k 的患者， 以石杉碱甲计， 每次注射 量为 l ~ 50mg， 至少每 15天注射一次。 具体可以根据患者的年 龄、 体重、 疾病状况等实际情况加以适当变化。
采用本发明的石杉碱甲类化合物的緩释微球， 可以实现石杉碱 甲类化合物的緩释。 虽不拘于已有理论， 但可以认为本发明緩释微 球的作用机理是当其注射入体内以后， 随血液循环逐步扩散， 体内 循环过程中， 因为可生物降解树脂如聚丙交酯-乙交酯不溶于水， 但可以被机体逐步降解， 随着其逐步降解， 微球中所包含的药物被 逐步释放出来， 由此实现緩释和长效。
采用本发明的石杉碱甲类化合物的緩释微球， 可以实现以往没 有做到的石杉碱甲类化合物的长效化， 可以以例如不少于 10天的 间隔， 优选不少于 15天， 更优选不少于 20天， 甚至可以达到长达 2个月以上的间隔给药， 因此有望极大地改善老年痴呆症患者的生 活盾量， 同时减少每曰按时定量给药所需花费的人力物力， 具有非 常大的意义。 实施例
以下将通过实施例来进一步说明本发明所述的石杉碱甲及其衍 生物的微球的制备方法和緩释效果， 但以下实施例不对本发明构成 任何限制。
以下实施例中微球的粒径采用本领域技术人员熟悉的 L2000型 全自动激光粒度仪 ( Beckman coulter公司） 测定。 浓度采用高效 液相色谱法（HPLC ) 测定， 方法按照文献方法， 例如可以按照如 现代应用药学杂志， 1993， 10 ( 1 ) ， 51 - 52; 中国医药工业杂 志， 1999, 30 ( 8 ) , 363 - 365等所公开者。
实施例 1
将 lOOmg石杉碱甲 、 900mg聚丙交酯-乙交酯（丙交酯： 乙交 酯 =50: 50, 分子量 13, 000 )溶于 10ml二氯甲烷中， 在剧烈搅拌 ( 1200rpm ) 下将其滴至 500ml 0.5% PVA水溶液中， 滴完后继续 剧烈搅拌 3-10分钟， 然后降低搅拌速度至 300rpm, 挥发溶剂 4-6 小时， 过滤， 用蒸馏水洗微球三次， 冻干。 粒径为 1-200 μ ιη。
实施例 2
称取石杉碱甲 A O.lg, 聚丙交酯-乙交酯 （丙交酯： 乙交酯 =50:50, 分子量 13,000 ) 2.0g, 加二氯甲烷 30ml, 搅拌至充分溶 解， 用微孔滤膜过滤， 采用常规喷雾干燥法制备微球， 测得粒径 1 - 80μιη, 灭菌， 分装。
将本緩释微球对家兔进行体内释放试验。 剂量为 300μ 1¾, 微 球混悬于注射用生理盐水中， 肌注给药， 在 1到 20 日内， 取血， HPLC-MS检测， 血药浓度为 0.1 - 25ng/ml。 证实本发明緩释微球 在至少 20曰内可以实现平稳幹放。
实施例 3
称取石杉碱甲 0.2g , 聚丙交酯-乙交酯 （ 丙交酯： 乙交酯 =50:50, 分子量 25，000 ) 4.0g, 加二氯甲烷 40ml, 搅拌至充分溶解 后， 在剧烈搅拌 ( 1200rpm ) 下将其滴加至 500ml 0.5 % PVA水溶 液中， 滴完后继续剧烈搅拌 3-10 分钟， 然后降低搅拌速度至 300rpm, 減压下挥发溶剂 1.5小时， 过滤， 用蒸馏水洗微球三次， 冻干。 粒径为 1-200μιη。
将本緩释微球对狗进行体内释放试验。 剂量为 20(^g/kg， 微球 混悬于生理盐水中， 肌注给药， 在 1到 28日内， 取血， HPLC-MS 检测， 测得血药浓度为 0.1 - 5ng/ml。 证实本发明緩释微球可以在 至少 4周内实现平稳释放。
实施例 4
称取石杉碱甲 100mg、 聚丙交酯-乙交酯 （丙交酯： 乙交酯 =75:25, 分子量 13,000 ) l.Og, 加水醋酸 20ml， 搅拌至充分溶解 后， 采用常规喷雾干燥法制备微球， 测得粒径 1 - ΙΟΟμιη, 灭菌， 分装。 体外模拟释放试验 20天。
实施例 5
称取石杉碱甲 0.5g和 5g聚丙交酯-乙交酯（丙交酯： 乙交酯 =50： 50, 分子量 13,000 ) , 加入 25ml二氯甲烷， 搅拌至充分溶解 后， 在剧烈搅拌下， 将二氯甲烷溶液滴加至 500ml 0.2 %羧甲基纤 维素钠中， 滴加完后继续剧烈搅拌 1 小时， 然后降低速度至 250rpm, 搅拌 4小时， 过滤， 低压冻干即得 1 - 150微米的微球。 实验例 石杉碱甲微球的体外释放试验。
采用实施例 1、 4 的微球。 通过模拟体内降解条件进行幹放试 验。
根据本发明人等的研究， 采用一定 pH值（pH 4.0、 5.5 ) 的緩 冲溶液（柠檬酸緩冲溶液）， 药物释放行为与体内类似， 因此虽然 其 pH值与人体内环境不同， 但是大致认为可以表现体内的释放模 式。
实验仪器： 恒温振荡器、 离心机。
实验条件： 温度： 37±0.5°C, 转速： 30rpm。
实验方法： 精密称取实验样品约 10mg, 置于容积为 15ml的具 盖塑料离心管中， 加 5ml释放介质（pH=4和 5.5柠檬酸钠緩冲溶 液） 置于恒温振荡器中， 保持一定的温度和转速， 按时取样。
取样方法： 离心管在 3600rpm条件下离心 20min, 精确吸取 3ml溶液， 同时向离心管中再补加 3ml 的释放介质， 取出液用 HPLC检测„
取样时间点 （天） ： 0、 1、 2、 4、 6、 8、 10、 12、 14、 16、
18、 20。 其中第 0天是指给药当天的给药前的药物浓度。
实施例 1、 4的微球在不同 pH值的条件下体外释放效果图分别 见附图 1 ~ 6。
实施例 1和 4所得微球的试验结果归纳如下表 1:
表 1石杉碱甲控释微球体外释放试验结果
Figure imgf000014_0001
表 1 (续）
Figure imgf000014_0002
表中当天释放量是由到当天的累积释放量计算得到的。 具体来 讲， 推定在 2次测定间隔中药物释放速度不变。 以公式表示， 当天 释放量 = (到当天的累积释放量-前次测得的累积释放量） "当次 测定与前次测定相隔天数。
例如实施例 1中， 第 0天的释放量是 0, 第 1天的累积译放量 为 7.2, 第 1天的当天释放量 = (7.2 - 0) ÷ (1-0) = 7.2。 第 2天的释放 量 14.6, 第 2天的当天释放量 = (14.6 - 7.2) ÷ (2 - 1) = 7.4。 第 4天 的释放量 20,8， 第 4天的当天幹放量 = (20.8 - 14.6) ÷ (4 - 2) = 3.1。 依此类推。
可以理解， 以上累积释放量超过 100 %是由于试验误差积累放 大所致。
由上表可以看出， 本发明石杉碱甲的緩释微球的释放可以在长 达 20 天以上的时间内稳定释放。 因此对于老年痴呆症的患者来 说， 可以大大减少给药次数， 同时有效控制了剂量， 避免了副作用 的出现。 工业实用性
本发明采用生物可降解高分子包埋石杉碱甲类化合物， 制成注 射用微球制剂， 注射一次可以维持 15天或更长时间， 对于老年痴 呆症和其它与乙酰胆碱酯酶有关的疾病的患者， 无疑是一个极好的 福音。

Claims

权 利 要 求
1. 一种石杉碱甲类化合物的緩释微球， 其特征在于该緩释微球是 由如下通式（la)所示的化合物或其可药用盐与可生物降解的药用 高分子辅料组成的，
Figure imgf000016_0001
式中， X和 Y分别表示氢原子或者甲基， 1和∑2分别表示氢 原子或者合在一起表示基团
Figure imgf000016_0002
2. 按照权利要求 1的緩释微球， 其中所述的石杉碱甲类化合物为 化合物（1)、 （11)、 （111)、 （IV)或（V)或其与选自盐酸、 醋酸、 磷酸、 硫酸、 乳酸、 柠檬酸的有机酸或无机酸所成的盐， 其 中化合物（1)、 （11)、 （111)、 （IV)和（V)分别为石杉碱 甲、 N5- (3， -羟基- 4， -甲氧基-笨基亚甲基） 石杉碱甲、 ( 10S) -10-甲基石杉碱甲、 （10R) - 10-甲基石杉碱甲和 10, 10-二甲基石杉碱甲。
3. 按照权利要求 1或 2的緩释微球， 其中所述的药用高分子辅料 为选自聚丙交酯-乙交酯、 聚乳酸、 聚乙醇酸、 聚 -3-羟基丁酸酯、 聚内酯、 聚酸酐、 聚羟基丁酸酯-羟基戊酸酯共聚物、 聚丙烯葡聚 糖、 聚乳酸 -聚乙二醇、 聚羟乙酸 -聚乙二醇中的一种或其中的两种 或两种以上的混合物。
4. 按照权利要求 3的緩释微球， 其中所述的药用高分子辅料选自 聚丙交酯-乙交酯、 聚乳酸、 聚羟基丁酸酯 -羟基戊酸酯共聚物其中 的一种或其中的两种或两种以上的混合物。
5- 根据权利要求 4 的緩释微球， 其中药用高分子辅料为聚丙交 酯-乙交酯。
6. 按照权利要求 5中的緩释微球， 其中所迷聚丙交酯 -乙交酯分子 量在 12000 - 30000道尔顿之间。
7. 按照权利要求 5或 6所述的緩释微球， 其中聚丙交酯-乙交酯中 丙交酯和乙交酯聚合比例在 95:5-5:95之间。
8. 石杉碱甲类化合物的緩释微球的制备方法， 是用有机溶剂把权 利要求 1或 2的石杉碱甲类化合物和权利要求 3 ~ 7中任一项的可 生物降解的药用辅料溶解， 将有机溶剂相注入到用可药用水溶性高 分子配制的连续水相中以形成微球， 然后挥发掉有机溶剂， 过滤得 到緩释微球。
9. 权利要求 8的制备方法， 其特征在于所述有机溶剂选自二氯甲 烷、 氯仿、 乙酸乙酯、 乙醚、 或由它们的混合溶剂， 可降解药用辅 料在有机溶剂中的含量 1 - 30 % ( w/v ) , 和 /或， 用可药用水溶性 高分子逸自聚乙烯醇、 羧甲基纤维素钠、 聚乙烯基吡咯烷酮、 聚甲 基丙烯酸钠、 聚丙烯酸钠， 在水相中的含量为 0.1-5 ( w/v ) 。 法制得微球。
11. 权利要求 10 的制备方法， 其中有机溶剂选自二氯甲烷、 氯 仿、 乙酸乙酯、 二氧六环、 乙醚、 丙酮、 四氢呋喃、 水醋酸。
12. 治疗老年痴呆症或者与乙酰胆碱酯酶有关的疾病的方法， 包 括将治疗有效量的权利要求 1 ~ 7 中任一项的緩释微球或者根据权 利要求 8 ~ 11 中任一项方法所制得的緩释微球以给定的不少于 10 天的时间间隔注射给予需要上述治疗的患者。
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