WO2019228477A1 - 含有多奈哌齐衍生物的缓释注射制剂 - Google Patents

含有多奈哌齐衍生物的缓释注射制剂 Download PDF

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WO2019228477A1
WO2019228477A1 PCT/CN2019/089370 CN2019089370W WO2019228477A1 WO 2019228477 A1 WO2019228477 A1 WO 2019228477A1 CN 2019089370 W CN2019089370 W CN 2019089370W WO 2019228477 A1 WO2019228477 A1 WO 2019228477A1
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sustained
injection preparation
release injection
polyethylene glycol
preparation according
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PCT/CN2019/089370
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English (en)
French (fr)
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张翠霞
刘飞
刘伟
王露露
尹德艳
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南京诺瑞特医药科技有限公司
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Priority to US17/261,379 priority Critical patent/US20210275443A1/en
Publication of WO2019228477A1 publication Critical patent/WO2019228477A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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 invention relates to the field of pharmaceutical preparations, in particular to a sustained-release injection preparation in the form of a suspension, and the use of the preparation to treat diseases caused by abnormal acetylcholinesterase activity.
  • Donepezil is a central acetylcholinesterase inhibitor developed by Eisai Pharmaceutical Co., Ltd. It was first marketed in the United States in 1997 and China in 1999. It is currently sold in many countries in the world. Donepezil has the advantages of low dose, low toxicity and low cost. It is the first drug to treat mild and moderate Alzheimer's disease (AD). In addition, it can also treat memory dysfunction and reduce memory loss in patients with non-senile affective disorder. , Dry mouth, constipation; can also be used to treat diseases such as purpuric rash, vascular dementia, sleep behavior disorders such as rapid eye movement sleep.
  • AD Alzheimer's disease
  • Donepezil has good water solubility, conventional preparations are film-coated tablets, good oral absorption, and high bioavailability, but it needs to be taken every day for a long period of time. After administration, its blood concentration rises rapidly, which may cause vomiting, diarrhea or insomnia The adverse reactions brought great pain and inconvenience to the patients.
  • patients with Alzheimer's have poor memory and often forget to take or take the wrong medicine. Some AD patients often do not admit that they are sick, and refuse to take the medicine. Poor compliance results in a high rate of clinical loss and severely affects the treatment effect.
  • a sustained-release injection preparation which has certain stability and can be stored for a long time.
  • the donepezil content in the plasma can be maintained for a long time in the effective blood concentration range, which significantly prolongs the efficacy and reduces Dosing frequency improves patient compliance and avoids side effects caused by rapid rise in blood concentration.
  • the object of the present invention is to provide a sustained-release injection in the form of a suspension of a donepezil derivative, and its use in the preparation of a medicament for treating a disease caused by abnormal acetylcholinesterase activity.
  • the diseases include Alzheimer's disease.
  • the present invention provides a sustained-release injection preparation in the form of a suspension, characterized in that it comprises a compound of the formula (I), a wetting agent and a suspending agent,
  • R is C 5-17 alkyl.
  • the wetting agent is selected from the group consisting of polysorbates, polyoxyethylene castor oils, poloxamers, teloxamer, povidone, lecithin, One or more of polyoxyethylene hydrogenated castor oil, bile salt or polyoxyethylene polyoxypropylene ether block copolymer; preferably one of polysorbate 20, polysorbate 40 or polysorbate 80 or Multiple; polysorbate 80 is more preferred.
  • the suspending agent is selected from natural polymer suspending agents, synthetic or semi-synthetic polymer suspending agents, preferably from gums, celluloses, and kappa.
  • natural polymer suspending agents synthetic or semi-synthetic polymer suspending agents, preferably from gums, celluloses, and kappa.
  • glycol 1000 polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, or polyethylene glycol 8000.
  • the ratio (weight) of the wetting agent to the suspending agent is: 1: 0.3 to 1:10, preferably from 1: 0.5 to 1: 6, and more preferably From 1: 1, 1: 3, 1: 3.75, 1: 5 or 1: 6.
  • the content of the compound of formula (I) is 8-22 g / 100ml
  • the content of the wetting agent is 0.5-1 g / 100ml
  • the content of the suspending agent is 0.3. ⁇ 5g / 100ml.
  • the content of the compound of the formula (I) is 8g / 100ml, 15g / 100ml, 17g / 100ml, 20g / 100ml, or 22g / 100ml.
  • the content is 0.5g / 100ml, 0.6g / 100ml, 0.8g / 100ml or 1g / 100ml, and the content of the suspending agent is 0.3g / 100ml, 0.5g / 100ml or 3g / 100ml.
  • the suspending agent is not selected from sodium carboxymethyl cellulose, that is, Tween 80 and sodium carboxymethyl cellulose Not at the same time as the sustained-release injection preparation of the present invention.
  • the ratio of the wetting agent to the suspending agent is not greater than 1 :1.
  • the content of the wetting agent is less than the suspending agent.
  • the ratio of the wetting agent to the suspending agent is 1: 1.
  • the sustained-release injection preparation of the present invention further comprises a buffering agent.
  • the buffering agent is a phosphate, preferably disodium hydrogen phosphate or sodium dihydrogen phosphate.
  • R is selected from the group consisting of n-pentyl, n-hexaneyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and n-undecyl Alkyl, n-tridecyl, n-pentadecyl or n-heptadecyl.
  • R is C 6 alkyl.
  • R is n-hexane
  • the compound of the formula (I) is selected from:
  • the present invention provides a sustained-release injection preparation with an extended shelf life, which is characterized by comprising a compound of the formula (I), a wetting agent and a suspending agent,
  • R is C 5-17 alkyl
  • the suspending agent is selected from natural polymer suspending agents, synthetic or semi-synthetic polymer suspending agents, preferably from gums, fibers One or more of carbopols, carbopol, povidone, dextran or polyethylene glycol, more preferably from sodium carboxymethyl cellulose (CMC-Na), methyl cellulose, hydroxypropyl One or more of cellulose, gum arabic, xanthan gum, povidone, or polyethylene glycol, preferably selected from polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol Alcohol 800, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, or polyethylene glycol
  • One or more of the diols 8000 One or more of the diols 8000.
  • the wetting agent is selected from the group consisting of polysorbates, polyoxyethylene castor oils, poloxamers, teloxamers, polyvitamins One or more of ketone, lecithin, polyoxyethylene hydrogenated castor oil, bile salt or polyoxyethylene polyoxypropylene ether block copolymer, preferably from polysorbate 20, polysorbate 40 or polysorbate 80 One or more of them.
  • the ratio (weight) of the wetting agent to the suspending agent is: 1: 0.3 to 1:10, preferably from 1: 0.5 to 1 : 6, more preferably from 1: 1, 1: 3, 1: 3.75, 1: 5 or 1: 6.
  • the content of the compound of the formula (I) is 8-22 g / 100 ml, and the content of the wetting agent is 0.5-1 g / 100 ml.
  • the content of the agent is 0.3 to 5 g / 100 ml.
  • the content of the compound of the formula (I) in the sustained-release injection preparation with an extended shelf life of the present invention is 8g / 100ml, 15g / 100ml, 17g / 100ml, 20g / 100ml, or 22g / 100ml
  • the content of wetting agent is 0.5g / 100ml, 0.6g / 100ml, 0.8g / 100ml or 1g / 100ml
  • the content of suspending agent is 0.3g / 100ml, 0.5g / 100ml or 3g / 100ml.
  • the suspending agent is not selected from the group consisting of sodium carboxymethyl cellulose, that is, Tween 80 and carboxylate.
  • Sodium methylcellulose is not present in the sustained-release injection preparations of the present invention.
  • the wetting agent is selected from Tween 80 and the suspension agent is selected from sodium carboxymethyl cellulose
  • the wetting agent and the suspension agent The ratio is not greater than 1: 1.
  • the content of the wetting agent is less than Suspending agent.
  • the wetting agent is selected from Tween 80 and the suspension agent is selected from sodium carboxymethyl cellulose
  • the wetting agent and the suspension agent The ratio is 1: 1.
  • the sustained-release injection preparation of the present invention further comprises a buffering agent.
  • the buffering agent is a phosphate, preferably disodium hydrogen phosphate or sodium dihydrogen phosphate.
  • R is selected from the group consisting of n-pentyl, n-hexaneyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and n-undecyl Alkyl, n-tridecyl, n-pentadecyl or n-heptadecyl.
  • the compound of the formula (I) is selected from:
  • the sodium dihydrogen phosphate in the present invention includes anhydrous sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium dihydrogen phosphate dihydrate. All forms can be used in the preparation of the present invention.
  • the compound of the formula (I) in the present invention is prepared by the following method.
  • R is C 5-17 alkyl.
  • Donepezil for the preparation of compounds of the formula (I) is commercially available or can be prepared according to known methods.
  • the present invention also provides a method for the sustained-release injection preparation containing a donepezil derivative for treating a disease caused by abnormal acetylcholinesterase activity.
  • the method includes the step of administering a therapeutic amount of the above-mentioned sustained-release injection preparation to a patient in need of treatment. Intravenous or subcutaneously.
  • the disease is Alzheimer's disease.
  • a method for expressing the number of carbon atoms in a group for example, C 1-10 means that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms; the term “or” may Used interchangeably with the term “and / or” unless the context clearly indicates otherwise.
  • Alkyl means a saturated aliphatic hydrocarbon group having said carbon atom, including straight-chain and branched-chain hydrocarbon groups, including, without limitation, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl Base, n-pentyl, n-hexyl and the like.
  • Suspending agents refer to additives that can increase the viscosity of the dispersion medium to reduce the sedimentation rate of the particles or increase the hydrophilicity of the particles, including natural polymer suspensions, synthetic or semi-synthetic polymer suspensions, and include without limitation One or more of gum tree, cellulose, carbopol, povidone, dextran or polyethylene glycol. It may be selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, gum arabic, xanthan gum, povidone, or polyethylene glycol.
  • Wetting agents refer to additives that increase the wetting of hydrophobic drug particles with water, including polysorbates, polyoxyethylene castor oils, poloxamers, teloxamer, povidone, lecithin, polyoxygen One or more of ethylene hydrogenated castor oil, bile salt, or polyoxyethylene polyoxypropylene ether block copolymer, including without limitation one of polysorbate 20, polysorbate 40, or polysorbate 80 Or more.
  • the wetting agent used in the present invention is polysorbate 80.
  • therapeutic amount refers to an amount that results in an improvement in any parameter or clinical symptom. Actual dosages may vary from patient to patient and do not necessarily refer to the total amount of elimination of all disease symptoms.
  • the extended shelf life refers to a period during which extended release injection suspensions of donepezil derivatives do not produce agglomeration and sedimentation after storage at normal temperature (for example, 25 ° C) or high temperature (for example, 40 ° C or more). .
  • the extended shelf life is at least 1 month, preferably at least 2-4 months, more preferably at least 5-6 months, and even more preferably at least 6 months.
  • Figure 1 shows the concentration-time curve of donepezil in rat plasma after intramuscular (i.m.) and subcutaneous (s.c.) administration of donepezil enanthate suspension;
  • Figure 2 shows the concentration-time curve of donepezil in rat plasma after suspension and oil solution of donepezil enanthate after intramuscular (i.m.) administration;
  • Figure 3 shows the concentration-time curves of donepezil and donepezil octoate in the plasma of Beagle dogs after intramuscular (i.m.) administration of the donepezil octoate suspension;
  • Figure 4 shows the concentration-time curves of donepezil and donepezil enanthate in plasma of Beagle dogs after intramuscular (i.m.) administration of the donepezil enanthate suspension.
  • the inventors unexpectedly found that the sustained-release injections in the form of suspensions made of donepezil derivatives, especially specific forms of donepezil derivatives, can have excellent stability and redispersibility and pharmacokinetics. Kinetic properties.
  • the present invention has been completed on this basis.
  • the "donepezil derivative” used in the present invention is a compound having a structure of formula (I),
  • R is a C 5-17 alkyl group.
  • the "donepezil derivative" of the present invention is donepezil enanthate; that is, R is n-hexyl.
  • ester formation is one of the modification methods commonly used in the design of prodrugs
  • the major problem facing ester prodrugs is that it is difficult to predict the pharmacokinetic distribution of ester prodrugs, and due to the alkyl
  • the biotransformation of esters in human blood is relatively slow and incomplete, often making these ester prodrugs less bioavailable than expected. Therefore, it is impossible to predict reasonably which ester prodrugs have excellent pharmacokinetic properties.
  • a person skilled in the art knows that a compound having pharmacological activity is made into various forms of sustained-release injection, but which form of the sustained-release injection can have excellent pharmacokinetic properties cannot be reasonably predicted.
  • the invention discloses a sustained-release injection preparation in the form of a suspension and a preparation method thereof.
  • Those skilled in the art can learn from the content of this article and appropriately improve the process parameters for implementation.
  • all similar replacements and modifications will be apparent to those skilled in the art, and they are all considered to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can modify or appropriately modify and combine the methods and applications described herein without departing from the content, spirit, and scope of the present invention. Apply the technology of the present invention.
  • the oily substance was dissolved by heating with 225 ml of n-heptane and filtered to remove insoluble matters, then 22.5 ml of ethanol was added, and the crystals were cooled at a temperature of -5 to -10 ° C for 1 h, filtered, and cooled with cold n-heptane / ethanol (10: 1 ) 50 ml was washed, dried, and dried under vacuum to obtain 42.30 g (yield: 81.7%) as an off-white solid.
  • X% means that Xg is contained in 100ml of the suspension, for example 0.5%
  • Tween 80 means that 0.5g of Tween 80 is contained in 100ml of the suspension.
  • wetting agents, suspending agents, buffering agents (disodium hydrogen phosphate) and other auxiliary materials are dissolved in an appropriate amount of water for injection, if necessary, adjust the pH with dilute phosphoric acid or sodium hydroxide, and filter and sterilize;
  • step 3 Process the material obtained in step 2 to (ball milling or homogeneous) a suitable particle size, and add water for injection to adjust to the target concentration.
  • the size of the particles in the suspension is not only related to the quality and stability of the suspension, but also affects the drug efficacy and bioavailability of the suspension. Therefore, the determination of the particle size and its distribution in the suspension is an important indicator for assessing the quality of the suspension.
  • the fine suspension should be shaken after storage, and the sediment should be able to be re-dispersed quickly, so as to ensure the uniformity in taking.
  • a Malvern 3000 laser particle size analyzer was used to measure the particle size of the sample, expressed as a volume particle size, and D10 refers to the particle size when the cumulative particle size distribution percentage of the sample reaches 10%, and the unit of particle size is microns. The same applies to D50 and D90.
  • the sample was shaken for 30 seconds to make the particles in the suspension uniformly dispersed.
  • a sample was taken and added to the sample cell (the dispersion medium was purified water). The data was read after the shading was stable (D10 / D50 / D90). If the sample cannot be shaken until it is completely dispersed, it is indicated as "aggregation".
  • WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters of the corresponding compound concentrations at different time points after administration of donepezil enanthate to SD rats i.m. and s.c. according to statistical distance theory. See Table-1 for details.
  • the AUC of the intramuscular injection is higher than the AUC of the subcutaneous injection (sc), which is about 1.3 times the AUC of the subcutaneous injection.
  • the intramuscular injection has more Good absorptive capacity.
  • the suspension of the present invention has no burst release phenomenon after administration, and the blood concentration curve is relatively stable.
  • Beagles weighing 8.6-10.6kg, were purchased from Beijing Mas Biotechnology Co., Ltd.
  • the test animals were all older than 1 year old, and the animals were at least two weeks apart from the previous test.
  • the suspension formulation of donepezil enanthate is: 0.5% T80, 0.5% CMC-Na, and 5% Mannitol (90 mg / ml).

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Abstract

一种含有多奈哌齐衍生物的悬浮液形式的缓释注射制剂，及其该制剂在制备治疗乙酰胆碱酯酶活性异常引起的疾病中的用途。

Description

含有多奈哌齐衍生物的缓释注射制剂 技术领域
本发明涉及药物制剂领域，具体涉及一种悬浮液形式的缓释注射制剂，及应用所述制剂治疗乙酰胆碱酯酶活性异常引起的疾病的用途。
背景技术
多奈哌齐是日本卫材制药有限公司开发的一种中枢性的乙酰胆碱酯酶抑制剂，1997年首先在美国上市，1999年在中国上市，目前在世界上多个国家销售。多奈哌齐具有剂量小、毒性低和费用低等优点，是治疗轻、中度阿尔兹海默症(AD)的首先药物，此外，还可治疗记忆功能障碍，减少非老年性情感障碍患者的记忆丧失、口干、便秘；还可用于治疗紫癜性皮疹、血管性痴呆、快动眼睡眠时相的睡眠行为障碍等疾病。
多奈哌齐水溶性好，常规制剂为薄膜衣片，口服吸收好，生物利用度高，但需要每天服药，服用周期长，给药后，其血药浓度快速升高，可能引发例如呕吐、腹泻或失眠的不良反应，给患者带来极大的痛苦和不便。加之老年痴呆病人记忆力差，常有忘吃药、吃错药的现象，还有些AD患者常常不承认自己有病，而拒绝服药，依从性差，导致临床脱失率高，严重影响治疗效果。
因此，有必要开发一种缓释注射制剂，具有一定的稳定性，能够长期保存，且其给药后，血浆中多奈哌齐含量能够长期维持在有效的血药浓度范围内，显著延长药效，减少给药频率，改善患者依从性，且避免血药浓度快速升高引发的副作用。
发明内容
本发明的目的是提供一种多奈哌齐衍生物的悬浮液形式的缓释注射剂，及其在制备用于治疗由乙酰胆碱酯酶活性异常引起的疾病的药物中的用途。所述的疾病包括阿尔兹海默症。
本发明是通过以下技术方案实现的：
本发明提供了一种悬浮液形式的缓释注射制剂，其特征在于，包含式(I)结构的化合物，润湿剂和助悬剂，
Figure PCTCN2019089370-appb-000001
其中：
R是C 5-17的烷基。
在一实施例中，本发明的缓释注射制剂中，润湿剂选自聚山梨酯类、聚氧乙烯蓖麻油类、泊洛沙姆类、泰洛沙姆、聚维酮、卵磷脂、聚氧乙烯氢化蓖麻油、胆汁盐或聚氧乙烯聚氧丙烯醚嵌段共聚物中的一种或多种；优选自聚山梨酯20、聚山梨酯40或聚山梨酯80中的一种或多种；更优选聚山梨酯80。
在一实施例中，本发明的缓释注射制剂中，助悬剂选自天然的高分子助悬剂、合成或半合成高分子助悬剂，优选自胶树类、纤维素类、卡波普、聚维酮、葡聚糖或聚乙二醇中的一种或多种，更优选自羧甲基纤维素钠(CMC-Na)、甲基纤维素、羟丙基纤维素、阿拉伯胶、黄原胶、聚维酮或聚乙二醇中的一种或多种，最优选自聚乙二醇200、聚乙二醇400、聚乙二醇600、聚乙二醇800、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、聚乙二醇6000或聚乙二醇8000中的一种或多种。
在一实施例中，本发明的缓释注射制剂中，润湿剂与助悬剂的配料比(重量)为：1:0.3～1:10，优选自1:0.5～1:6,更优选自1:1、1:3、1:3.75、1:5或1:6。
在一实施例中，本发明的缓释注射制剂中，式(I)结构的化合物的含量为8～22g/100ml，润湿剂的含量为0.5～1g/100ml，助悬剂的含量为0.3～5g/100ml。
在另一实施例中，本发明的缓释注射制剂中，式(I)结构的化合物的含量为8g/100ml、15g/100ml、17g/100ml、20g/100ml或22g/100ml，润湿剂的含量为0.5g/100ml、0.6g/100ml、0.8g/100ml或1g/100ml，助悬剂的含量为0.3g/100ml，0.5g/100ml或3g/100ml。
在一实施例中，本发明的缓释注射制剂中，当润湿剂选自吐温80时，助悬剂不选自羧甲基纤维素钠，即吐温80和羧甲基纤维素钠不同时存在与本发明的缓释注射制剂中。
在一实施例中，本发明的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂与助悬剂的比例不大于1:1。
在一实施例中，本发明的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂的含量小于助悬剂。
在一实施例中，本发明的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂与助悬剂的比例为1:1。
在一实施例中，本发明的缓释注射制剂，进一步包含缓冲剂。
在另一实施例中，本发明的缓释注射制剂中，缓冲剂为磷酸盐，优选地为磷酸氢二钠、磷酸二氢钠。
在一实施例中，本发明的缓释注射制剂中，R选自正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基、正十一烷基、正十三烷基、正十五烷基或正十七烷基。
在一实施例中，R是C 6烷基。
在更优选的实施例中，R是正己烷基。
在一实施例中，本发明的缓释注射制剂中，式(I)结构的化合物选自：
Figure PCTCN2019089370-appb-000002
Figure PCTCN2019089370-appb-000003
优选
Figure PCTCN2019089370-appb-000004
另一方面，本发明提供了一种具有延长的保质期的缓释注射制剂，其特征在于，包含式(I)结构的化合物、润湿剂和助悬剂，
Figure PCTCN2019089370-appb-000005
其中:
R是C 5-17的烷基；
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，助悬剂选自天然的高分子助悬剂、合成或半合成高分子助悬剂，优选自胶树类、纤维素类、卡波普、聚维酮、葡聚糖或聚乙二醇中的一种或多种，更优选自羧甲基纤维素钠(CMC-Na)、甲基纤维素、羟丙基纤维素、阿拉伯胶、黄原胶、聚维酮或聚乙二醇中的一种或多种，最优选自聚乙二醇200、聚乙二醇400、聚乙二醇600、聚乙二醇800、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、聚乙二醇6000或聚乙
二醇8000中的一种或多种。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，润湿剂选自聚山梨酯类、聚氧乙烯蓖麻油类、泊洛沙姆类、泰洛沙姆、聚维酮、卵磷脂、聚氧乙烯氢化蓖麻油、胆汁盐或聚氧乙烯聚氧丙烯醚嵌段共聚物中的一种或多种，优选自聚山梨酯20、聚山梨酯40或聚山梨酯80中的一种或多种。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，润湿剂与助悬剂的配料比(重量)为：1:0.3～1:10，优选自1:0.5～1:6,更优选自1:1、1:3、1:3.75、1:5或1:6。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，式(I)结构的化合物的含量为8～22g/100ml，润湿剂的含量为0.5～1g/100ml，助悬剂的含量为0.3～5g/100ml。
在另一实施例中，本发明的具有延长的保质期的缓释注射制剂中，式(I)结构的化合物的含量为8g/100ml、15g/100ml、17g/100ml、20g/100ml或22g/100ml，润湿剂的含量为0.5g/100ml、0.6g/100ml、0.8g/100ml或1g/100ml，助悬剂的含量为0.3g/100ml，0.5g/100ml或3g/100ml。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，当润湿剂选自吐温80时，助悬剂不选自羧甲基纤维素钠，即吐温80和羧甲基纤维素钠不同时存在与本发明的缓释注射制剂中。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂与助悬剂的比例不大于1:1。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂的含量小于助悬剂。
在一实施例中，本发明的具有延长的保质期的缓释注射制剂中，当润湿剂选自吐温80，助悬剂选自羧甲基纤维素钠时，润湿剂与助悬剂的比例为1:1。
在一实施例中，本发明的缓释注射制剂，进一步包含缓冲剂。
在另一实施例中，本发明的缓释注射制剂中，缓冲剂为磷酸盐，优选地为磷酸氢二钠、磷酸二氢钠。
在一实施例中，本发明的缓释注射制剂中，R选自正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基、正十一烷基、正十三烷基、正十五烷基或正十七烷基。
在一实施例中，本发明的缓释注射制剂中，式(I)结构的化合物选自：
Figure PCTCN2019089370-appb-000006
Figure PCTCN2019089370-appb-000007
Figure PCTCN2019089370-appb-000008
优选
Figure PCTCN2019089370-appb-000009
本发明中的磷酸二氢钠包括无水磷酸二氢钠、磷酸二氢钠一水合物、磷酸二氢钠二水合物，所有的形式都可以用于本发明制剂。
本发明中式(I)结构的化合物由下列方法制备。
Figure PCTCN2019089370-appb-000010
R是C 5-17的烷基。
用于制备式(I)结构化合物的多奈哌齐可以购自商业，或者可以根据已知的方法制备。
本发明还提供了含有多奈哌齐衍生物的缓释注射制剂用于治疗由乙酰胆碱酯酶活性异常引起的疾病的方法，包括将治疗量的上述缓释注射制剂给予需要治疗的患者的步骤，可以经肌肉内给予或皮下被给予。所述疾病是阿尔兹海默症。
本发明中，除特别说明外，所用到的术语代表的含义如下所述。
基团碳原子个数表示方法，例如C 1-10，是指该基团可以含1个碳原子、2个碳原子、3个碳原子等，直至包含10个碳原子；术语“或”可与术语“和/或”互换使用，除非上下文另有清楚指明。
烷基表示具有所述碳原子的饱和的脂烃基，包括直链和支链烃基，非限制性地包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等。
助悬剂表示能增加分散介质的黏度以降低微粒的沉降速度或增加微粒亲水性的附加剂，包括天然的高分子助悬剂、合成或半合成高分子助悬剂，非限制性地包括胶树类、纤维素类、卡波普、聚维酮、葡聚糖或聚乙二醇中的一种或多种。可选自羧甲基纤维素钠、甲基纤维素、羟丙基纤维素、阿拉伯胶、黄原胶、聚维酮或聚乙二醇中的一种或多种。
润湿剂表示能增加疏水性药物微粒被水湿润的附加剂，包括聚山梨酯类、聚氧乙烯蓖麻油类、泊洛沙姆类、泰洛沙姆、聚维酮、卵磷脂、聚氧乙烯氢化蓖麻油、胆汁盐或聚氧乙烯聚氧丙烯醚嵌段共聚物中的一种或多种，非限制性地包括聚山梨酯20、聚山梨酯40或聚山梨酯80中的一种或多种。在优选的实施方式中，用于本发明中的润湿剂是聚山梨酯80。
本发明中所使用的术语“治疗量”指导致任何参数或者临床症状改进的数量。实际的剂量可能随着每个患者的不同而变化，并且不一定指消除所有疾病症状的总量。
本发明中所描述的“延长保质期”指延长多奈哌齐衍生物的缓释注射悬浮液在常温(例如，25℃)或高温(例如，40℃或以上)存放后不会产生颗粒聚集沉降现象的期间。该延长的保质期至少为1个月，优选为至少2-4个月，更优选为至少5-6个月，又更优选为至少6个月。
附图说明
图1显示了庚酸多奈哌齐酯混悬液分别肌肉注射(i.m.)和皮下注射(s.c.)给药后大鼠血浆中多奈哌齐的浓度-时间曲线；
图2显示了庚酸多奈哌齐酯的混悬液和油溶液经肌肉注射(i.m.)给药后大鼠血浆中多奈哌齐的浓度-时间曲线；
图3显示了辛酸多奈哌齐酯混悬液经肌肉注射(i.m.)给药后比格犬血浆中多奈哌齐及辛酸多奈哌齐酯的浓度-时间曲线；
图4显示了庚酸多奈哌齐酯混悬液经肌肉注射(i.m.)给药后比格犬血浆中多奈哌齐及庚酸多奈哌齐酯的浓度-时间曲线。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现利用多奈哌齐衍生物，特别是特定形式的多奈哌齐衍生物制成的悬浮液形式的缓释注射剂能够具备优异的稳定性和再分散性以及药代动力学性质。在此基础上完成了本发明。
本发明中所用的“多奈哌齐衍生物”是具有式(I)结构的化合物，
Figure PCTCN2019089370-appb-000011
其中R是C 5-17的烷基。
在具体的实施方式中，本发明的“多奈哌齐衍生物”是庚酸多奈哌齐酯；即，R为正己基。
本领域技术人员知晓，成酯虽然是前药设计中常用的修饰手段之一，然而，酯类前药面临的重大问题是很难预测酯类前药的药代动力学分布，并且由于烷基酯在人体血液中的生物转化相对较慢且不完全，常使得这些酯类前药的生物利用度比预期的低。因此，哪种酯类前药能够具备优异的药代动力学特性是无法合理预知的。进一步地，本领域技术人员知晓将具有药学活性的化合物制成各种形式的缓释注射剂，然而哪种形式的缓释注射剂能够具备优异的药代动力学性质也是无法合理预知的。
本发明公开了悬浮液形式的缓释注射制剂及其制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
为了更详细说明本发明。给出下述制备实例。但本发明的范围并非限定于此。
实施例1.式(I)结构化合物的制备
化合物1，庚酸多奈哌齐酯的制备
将多奈哌齐(40.0g,105.4mmol)加入到1000ml三口圆底烧瓶(配备有氩气保护，温度计，机械搅拌，恒压滴液漏斗)中，氮气置换，加入无水四氢呋喃300ml搅拌溶解，然后将体系冷却至-60～-78℃。将双三甲基硅基胺基锂(100ml,1.0mol/L,100mmol)通过双头针加入到恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌15～30分钟后，自然升温到0～10℃。随后将体系温度降至-60～-78℃，然后将庚酸酐(38.82g,242.4mmol)用100ml无水四氢呋喃溶解加入到恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌30分钟后，自然升温至室温(20～30℃)，TLC检测原料反应完全。将反应体系于冰水浴下，滴加250ml饱和氯化铵溶液，滴加完成后，分液，再用20％氯化钠溶液250ml洗涤一遍，用饱和氯化钠溶液250ml洗涤，分液，有机相用无水硫酸钠干燥，减压除去溶剂，得到油状物29.3g(收率:93％)。将油状物用225ml正庚烷加热溶解过滤除去不溶物，然后加入22.5ml乙醇，降温 析晶，在-5～-10℃下保温1h，过滤，用冷的正庚烷/乙醇(10:1)50ml洗涤，抽干，真空干燥得到灰白色固体42.30g(收率:81.7％)。
HPLC(aera):98.2％。
质谱(m/z):[M+H] +＝492.4.
1H-NMR(CDCl 3)δ:7.32-7.31(4H,d),7.26-7.27(1H,m),6.98(1H,s),6.59(1H,s),3.89(3H,s),3.90(3H,s),3.50(2H,s),3.26(2H,s),2.87-2.89(2H,d),2.60-2.64(2H,t),2.27-2.29(2H,d),1.90-1.93(2H,t),1.80-1.83(2H,t),1.65-1.68(2H,t),1.20-1.60(9H,m),0.90-0.96(3H,t).
实施例2.悬浮液的制备
处方
Figure PCTCN2019089370-appb-000012
Figure PCTCN2019089370-appb-000013
X％是指每100ml悬浮液中含有Xg，例如0.5％吐温80是指100ml悬浮液中含有0.5g吐温80。
制备方法
1)将润湿剂，助悬剂，缓冲剂(磷酸氢二钠)等辅料溶解于适量注射用水中，必要时用稀磷酸或氢氧化钠调节PH，过滤除菌；
2)向步骤1所得物料中加入化合物1，分散均匀；
3)将步骤2所得物料处理至(球磨或均质)合适粒径，加入注射用水调节至目标浓度。
实施例3.悬浮液中化合物1粒径的稳定性及再分散性
悬浮液中微粒的大小不仅关系到悬浮液的质量和稳定性，也会影响悬浮液的药效和生物利用度。所以测定悬浮液中微粒大小及其分布，是评定悬浮液质量的重要指标。
优良的悬浮液经过贮存后再振摇，沉降物应能很快重新分散，这样才能保证服用时的均匀性。
使用马尔文3000激光粒度仪测定样品粒径，以体积粒径表示，D10是指样品的累计粒度分布百分数达到10％时所对应的粒径，粒径单位为微米。D50、D90同理。测量前将样品振摇30秒，使悬浮液中颗粒分散均匀，取样加入样品池(分散介质为纯化水)，遮光度稳定后读取数据(D10/D50/D90)。如果样品无法振摇至完全分散，以“聚集”表示。
25℃下，0时、30天时测定的悬浮液中化合物1粒径值
  25℃0时 25℃30天
处方1 0.596/1.46/3.18 NA
处方2 0.596/1.53/3.66 0.574/1.51/3.52
处方3 0.577/1.46/3.27 0.569/1.48/3.36
处方4 0.70/2.24/6.42 0.753/2.26/6.47
处方5 0.70/2.18/6.07 0.769/2.24/6.07
处方6 0.67/2.01/5.53 0.708/2.09/5.87
处方7 0.68/2.24/6.34 0.705/2.20/6.38
处方8 0.67/1.94/5.14 0.730/2.15/5.78
处方13 0.907/3.22/9.06 0.777/2.48/6.88
NA表示未检测
40℃下，0时、10、30天时测定的悬浮液中化合物1粒径值
  40℃0时 40℃10天 40℃30天
处方1 0.596/1.46/3.18 0.606/1.51/4 0.628/1.71/53.2
处方2 0.596/1.53/3.66 0.598/1.53/3.82 0.609/1.64/5.92
处方3 0.577/1.46/3.27 0.612/1.5/3.26 0.633/1.62/4.01
处方4 0.70/2.24/6.42 0.786/2.38/6.93 0.818/2.44/7.17
处方5 0.70/2.18/6.07 0.78/2.27/6.5 聚集
处方6 0.67/2.01/5.53 0.744/2.2/6.46 0.744/2.20/6.46
处方7 0.68/2.24/6.34 0.753/2.22/6.53 0.771/2.42/8.86
处方8 0.67/1.94/5.14 0.768/2.2/6.01 0.811/2.61/8.68
处方13 0.907/3.22/9.06 0.818/2.66/7.36 0.790/2.53/6.94
60℃下，0时、5、10、30天时测定的悬浮液中化合物1粒径值
  60℃0时 60℃10天 60℃30天
处方1 0.596/1.46/3.18 0.620/1.53/3.87 0.703/2.43/166
处方2 0.596/1.53/3.66 0.6/1.5/3.43 0.629/1.79/8.97
处方3 0.577/1.46/3.27 0.698/1.72/3.68 0.732/2/4.58
处方4 0.70/2.24/6.42 0.912/2.82/8.35 1.05/3.95/11
处方5 0.70/2.18/6.07 0.912/2.94/9.49 聚集
处方6 0.67/2.01/5.53 0.956/3.15/7.97 1.19/4.78/15.0
处方7 0.68/2.24/6.34 0.859/2.69/7.91 1.05/4.41/19.1
处方8 0.67/1.94/5.14 0.888/2.68/7.12 1.08/3.75/15.2
处方13 0.907/3.22/9.06 0.890/3.29/9.52 1.39/6.90/17.3
再分散性：由试验结果可知，包括吐温80和CMC-Na的悬浮液易结块形成大颗粒，且震摇后不易分散。
实施例4.药动学研究
实验1
6只雄性SD大鼠(体重220-230g)，随机分成2组，每组3只，其中一组肌肉注射给与30mg/kg剂量的庚酸多奈哌齐酯混悬液(处方14)，另一组皮下注射给予等剂量的庚酸多奈哌齐酯混悬液(处方14)。给药后在大约0.5h、2h、8h、24h(d2)、48h(d3)、72h(d4)、144h(d7)、216h(d10)、312h(d14)和480h(d21)各采集血样约0.3mL至预先制备的氟化钠及草酸钾抗凝的1.5mL离心管中，于冰上暂存至离心。全血经离心后收集血浆，转移血浆至96孔板中，于-20℃保存 至LC-MS/MS检测。通过测定多奈哌齐对照药在血浆中的标准曲线，测定各取样点的药物浓度。
采用WinNonlin 6.3软件，按统计距理论分别求算SD大鼠i.m.和s.c.给予庚酸多奈哌齐酯化合物后各时间点相应化合物浓度的相关药动学参数，详见表-1。
表1.大鼠i.m.与s.c.30mg/kg庚酸多奈哌齐酯混悬注射液后血浆中多奈哌齐的药动学参数
  i.m. s.c.
T 1/2(h) 52.9 53.6
T max(h) 11.3 16.7
C max(ng/mL) 46.9 32.6
AUC last(h*ng/mL) 5270 4146
AUC INF_obs(h*ng/mL) 5467 4437
MRT last(h) 74.8 92
由试验结果可知，本发明注射制剂在相同的剂量条件下，肌肉注射(i.m.)的AUC高于皮下注射(s.c.)的AUC，大约是皮下注射AUC的1.3倍，肌肉注射相比皮下注射具有更好的吸收能力。
试验2
6只雄性SD大鼠(体重220-230g)，随机分成2组，每组3只，其中一组肌肉注射给与90mg/kg剂量的庚酸多奈哌齐酯混悬液，另一组肌肉注射给予等剂量的庚酸多奈哌齐酯油溶液。给药后在大约6h、24h(d2)、48h(d3)、72h(d4)、144h(d7)、216h(d10)和312h(d14)各采集血样约0.3mL至预先制备的氟化钠及草酸钾抗凝的1.5mL离心管中，于冰上暂存至离心。全血经离心后收集血浆，转移血浆至96孔板中，于-20℃保存至LC-MS/MS检测。通过测定多奈哌齐对照药在血浆中的标准曲线，测定各取样点的药物浓度，具体数据见表2，图-2。
表2.大鼠i.m.庚酸多奈哌齐酯混悬液和油溶液后各取样点时血浆中多奈哌齐的药物浓度
Figure PCTCN2019089370-appb-000014
混悬液处方：0.5％CMC-Na，5％Mannitol，0.5％T80，3％PEG4000；油溶液 处方：苯甲酸苄酯/蓖麻油＝36/21(w/w)
由试验结果可知，相比油溶液，本发明的混悬液给药后无突释现象，血药浓度曲线较平稳。
试验3
本实施例中所使用的为6只雄性
Figure PCTCN2019089370-appb-000015
比格犬，体重8.6-10.6kg，购自北京玛斯生物技术有限公司，试验动物皆大于1岁，动物距离上次试验至少有两周以上的间隔。
每组3只试验动物，肌肉注射分别给与辛酸多奈哌齐酯混悬液(18.4mg/kg以多奈哌齐计，辛酸多奈哌齐酯参照实施例1中的庚酸多奈哌齐酯制备)和庚酸多奈哌齐酯混悬液(23.8mg/kg以多奈哌齐计)，给药后在大约2h、6h、10h、24h(d2)、48h(d3)、72h(d4)、144h(d7)、216h(d10)、264h(d12)和336h(d15)各采集血样约0.3mL至预先制备的氟化钠及草酸钾抗凝的1.5mL离心管中，于冰上暂存至离心。全血经离心后收集血浆，转移血浆至96孔板中，于-20℃保存至LC-MS/MS检测。通过测定多奈哌齐对照药在血浆中的标准曲线，测定各取样点的药物浓度，具体数据见表-3，图-3，图-4。
表3.大鼠i.m.庚酸多奈哌齐酯混悬液和辛酸多奈哌齐混悬液后各取样点时血浆中多奈哌齐和前药的药物浓度
Figure PCTCN2019089370-appb-000016
辛酸多奈哌齐酯混悬处方为：1.5％T80，4％PEG4000，4％Mannitol；
庚酸多奈哌齐混悬处方为：0.5％T80，0.5％CMC-Na，5％Mannitol(90mg/ml)。
由试验结果可知，庚酸多奈哌齐酯给药后，可以迅速代谢为原型药，存在前药引起副作用的风险极低。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技 术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (17)

  1. 一种悬浮液形式的缓释注射制剂，包含式(I)结构的化合物，润湿剂和助悬剂，
    Figure PCTCN2019089370-appb-100001
    其中:
    R是C 5-17的烷基。
  2. 如权利要求1所述的缓释注射制剂，其特征在于，所述润湿剂选自聚山梨酯类、聚氧乙烯蓖麻油类、泊洛沙姆类、聚维酮、泰洛沙姆、卵磷脂、聚氧乙烯氢化蓖麻油、胆汁盐或聚氧乙烯聚氧丙烯醚嵌段共聚物中的一种或多种；优选自聚山梨酯20、聚山梨酯40或聚山梨酯80中的一种或多种；更优选聚山梨酯80。
  3. 如权利要求1所述的缓释注射制剂，其特征在于，所述助悬剂选自天然的高分子助悬剂、合成或半合成高分子助悬剂，优选自胶树类、纤维素类、卡波普、聚维酮、葡聚糖或聚乙二醇中的一种或多种，更优选自羧甲基纤维素钠、甲基纤维素、羟丙基纤维素、阿拉伯胶、黄原胶、聚维酮或聚乙二醇中的一种或多种，最优选自聚乙二醇200、聚乙二醇400、聚乙二醇600、聚乙二醇800、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、聚乙二醇6000或聚乙二醇8000中的一种或多种。
  4. 如权利要求1所述的缓释注射制剂，其特征在于，所述润湿剂与助悬剂的配料比(重量)为：1:0.3～1:10，优选自1:0.5～1:6，更优选自1:1、1:3、1:3.75、1:5或1:6。
  5. 如权利要求1所述的缓释注射制剂，其特征在于，式(I)结构的化合物的含量为8～22g/100ml，润湿剂的含量为0.5～1g/100ml，助悬剂的含量为0.3～5g/100ml。
  6. 如权利要求5所述的缓释注射制剂，其特征在于，式(I)结构的化合物的含量为8g/100ml、15g/100ml、17g/100ml、20g/100ml或22g/100ml，润湿剂的含量为0.5g/100ml、0.6g/100ml、0.8g/100ml或1g/100ml，助悬剂的含量为0.3g/100ml、0.5g/100ml或3g/100ml。
  7. 如权利要求1所述的缓释注射制剂，其特征在于，所述缓释注射制剂进一步包含缓冲剂。
  8. 如权利要求7所述的缓释注射制剂，其特征在于，该缓冲剂为磷酸盐，优选地为磷酸氢二钠、磷酸二氢钠。
  9. 如权利要求1所述的缓释注射制剂，其特征在于，R选自正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基、正十一烷基、正十三烷基、正十五烷基或正十七烷基。
  10. 如权利要求1所述的缓释注射制剂，其特征在于，R是C 6烷基。
  11. 如权利要求10所述的缓释注射制剂，其特征在于，R是正己基。
  12. 如权利要求1所述的缓释注射制剂，其特征在于，式(I)结构的化合物选自：
    Figure PCTCN2019089370-appb-100002
    Figure PCTCN2019089370-appb-100003
    优选
    Figure PCTCN2019089370-appb-100004
  13. 如权利要求1所述的缓释注射制剂，其特征在于，所述缓释注射制剂在25℃或40℃存放后不产生颗粒聚集沉降现象的时间至少为1个月；优选至少2-4个月；更优选至少5-6个月；更优选至少6个月。
  14. 权利要求1-13中任意一项所述的缓释注射制剂在制备用于治疗由乙酰胆碱酯酶活性异常引起的疾病的药物中的应用。
  15. 如权利要求14所述的应用，其特征在于，所述疾病是阿尔兹海默症。
  16. 权利要求14所述的应用，其特征在于，所述药物经肌肉内给予或皮下给予；优选肌肉内给予。
  17. 如权利要求1所述的缓释注射制剂，其特征在于，所述缓释注射制剂以 肌肉内或皮下给与的方式给药；优选肌肉内给予的方式。
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