WO2018153315A1 - 一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 - Google Patents

一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法 Download PDF

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WO2018153315A1
WO2018153315A1 PCT/CN2018/076599 CN2018076599W WO2018153315A1 WO 2018153315 A1 WO2018153315 A1 WO 2018153315A1 CN 2018076599 W CN2018076599 W CN 2018076599W WO 2018153315 A1 WO2018153315 A1 WO 2018153315A1
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donepezil
hemi
pamoate
powder
agent
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PCT/CN2018/076599
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English (en)
French (fr)
Inventor
葛建
李云飞
林丽红
孙登学
王佳苗
王艺瑾
王志云
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上海华汇拓医药科技有限公司
浙江华海药业股份有限公司
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Priority to CN201880003588.2A priority Critical patent/CN109803654B/zh
Priority to US16/465,116 priority patent/US11197850B2/en
Publication of WO2018153315A1 publication Critical patent/WO2018153315A1/zh
Priority to US17/523,229 priority patent/US11801239B2/en

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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
    • 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
    • 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
    • A61K47/26—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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms

Definitions

  • the invention belongs to the technical field of pharmaceutical preparation, and in particular relates to a preparation method of donepezil hemi-pamoate powder injection.
  • AD Alzheimer disease
  • a ⁇ beta amyloid
  • FDA US Food and Drug Administration
  • Tacrine has been basically abandoned due to the need to take 4 times a day and potentially severe hepatotoxicity.
  • the other four drugs are currently the first-line drugs for the treatment of AD, which can moderately improve the cognitive ability, daily living ability, mental behavior and overall function of AD patients, and have good safety and tolerance.
  • Donepezil, rivastigmine and galantamine are equally effective, but donepezil is safer and more tolerant and patient-adhered.
  • AD treatments huperzine A, donepezil, piracetam, oxiracetam, pyrithione, nimodipine, citicoline, ginkgo extract, dihydro ergot Alkali, memantine, acetylglutamine and idebenone.
  • Donepezil is a highly effective AD treatment in both domestic and foreign markets. It is highly selective and reversible in the treatment of Alzheimer's disease. However, conventional preparations require daily medication, and patients with dementia have poor compliance, resulting in patients not being able to get on time. Taking the medicine according to the amount seriously affects the treatment effect. In order to solve the problems caused by the conventional preparation of donepezil, domestic and foreign scholars have made various attempts on the long-acting preparation of donepezil.
  • the present invention first provides a donepezil hemi-pamoate powder injection comprising donepezil hemi-pamoate crystals having an average particle size (D 50 ) of from 0.5 to 200 ⁇ m, or a plurality of At 180 ⁇ m, or not less than 160 ⁇ m, or not less than 140 ⁇ m, or not less than 120 ⁇ m, or not less than 100 ⁇ m, or not less than 80 ⁇ m, or not less than 60 ⁇ m, or not less than 30 ⁇ m, or not less than 10 ⁇ m, preferably 0.5 to 52 ⁇ m, more preferably 2 to 32 ⁇ m, still more preferably 4 to 15 ⁇ m.
  • D 50 average particle size
  • the donepezil hemi-pamoate crystals have an angle of repose of from 25 to 46 degrees; preferably from 32 to 43 degrees.
  • the invention provides a preparation method of donepezil hemi-pamoate powder injection, comprising: crystallization of donepezil hemi-pamoate, followed by dry powdering, optionally into a sterilization container, and then sterilized Process prepared.
  • the preparation method of the aforementioned donepezil hemi-pamoate powder injection may include the following steps:
  • Step 1 Donepezil hydrochloride was dissolved in purified water, stirred, filtered, and the filtrate was used.
  • Step 2 Disodium penic acid disodium salt is dissolved in purified water, stirred, filtered, and the filtrate is ready for use.
  • Step 3 Donetiperzil semi-pamoate seed crystals are added to the filtrate obtained in step 1, and then the filtrate obtained in step 2 is dropped into the above solution, stirred for 1-2 hours, filtered, and the obtained filter cake is washed with purified water, dried, and then subjected to Dry method powder, prepared by sterilization process.
  • the dry pulverization is selected from the group consisting of sieve pulverization, ball milling pulverization and/or jet pulverization;
  • the sterilization process in the above preparation method is ⁇ -ray irradiation sterilization, electron beam irradiation sterilization or microwave irradiation sterilization, preferably electron beam irradiation sterilization, and the irradiation dose of electron beam irradiation sterilization is 25 kGy ⁇ 60kGy;
  • the sterilization container can be made of borosilicate glass with pyrogen.
  • the dry pulverization may be performed by pulverizing with a screen pulverizer equipped with a 10-mesh-20 mesh screen.
  • the present invention also provides a composition comprising donepezil hemi-pamoate comprising the aforementioned donepezil hemi-pamoate powder injection or the donepezil hemi-pamoate powder injection prepared by the aforementioned method.
  • the content of the donepezil hemi-pamoate powder injection is from 13% to 24%, based on the total mass of the composition.
  • the composition further comprises a diluent; preferably, the diluent comprises from 0.03% to 3% of a suspending agent, by mass fraction, based on the total mass of the diluent, 3% to 6% of the tonicity agent, and 0.03% to 2% of the wetting agent.
  • the suspending agent is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginate, chitosan, One or more compositions of dextran, gelatin, polyethylene glycol, polyoxyethylene ether, polyoxypropylene ether, preferably sodium carboxymethylcellulose (CMC-Na);
  • the tonicity agent is selected from the group consisting of One or more compositions of sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate, preferably mannitol or sodium chloride;
  • the wetting agent is selected from the group consisting of polysorbate 80, One or more compositions of polysorbate 20, poloxamer, lecithin, polyoxyethylene ether, polyoxypropylene ether, sodium deoxycholate, preferably poloxamer 188 or Tween 80.
  • the suspending agent may also range from 0.5% to 1.5%, preferably from 0.75% to 1.5%, and the wetting agent may also range from 0.05% to 0.5%, preferably 0.05. % ⁇ 0.2%, the range of tonicity agent can also be between 4.5%-5% and 4.5%-6%;
  • the present invention still further provides a method for preparing a donepezil hemi-pamoate injection, which is characterized by the following steps:
  • a nafezipine hemi-pamoate injection is prepared, wherein the diluent comprises 0.03% by mass based on the total mass of the diluent.
  • the suspending agent may also range from 0.5% to 1.5%, preferably from 0.75% to 1.5%, and the wetting agent may also range from 0.05% to 0.5%, preferably 0.05. % ⁇ 0.2%, the tonicity agent may also be in the range of 4.5% to 6%; the suspending agent is preferably CMC-Na, the tonicity agent is preferably mannitol or sodium chloride, and the wetting agent is preferably poloxamer 188. Or Tween 80.
  • the donepezil hemi-pamoate drug powder injection provided by the invention reduces the irritation of the drug by controlling the particle size of the drug; further, the flowability of the donepezil hemi-pamoate drug powder of the invention is good, More conducive to dispensing.
  • any of the products of the present invention necessarily does not necessarily require all of the advantages described above to be achieved at the same time.
  • Step 1 6.6 g of donepezil hydrochloride was dissolved in 250 ml of purified water. After stirring, 0.34 g of activated carbon was added, and the mixture was stirred at a temperature of 40-60 ° C for 1-2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was used.
  • Step 2 3.7 g of disodium salt of palmitic acid is dissolved in 250 ml of purified water. After stirring, 0.18 g of activated carbon is added, and the mixture is stirred at a temperature of 40-60 ° C for 1-2 hours. The reaction solution is cooled to room temperature, filtered, and the filtrate is filtered. stand-by.
  • Step 3 0.2 g of donepezil hemi-pamoate seed crystal (preparation method reference patent WO2013078608, example 4) is added to the filtrate obtained in step 1, and then the filtrate obtained in step 2 is slowly dropped into the above solution at room temperature for 1 hour. After the dropwise addition, the mixture was slowly stirred for 5-10 hours with an anchor stir bar, and the resulting filter cake was washed with purified water and dried to finally obtain 9.6 g of solid particles of donepezil hemi-pamoate. The obtained particles had an average particle diameter D 50 of 90 ⁇ 17 ⁇ M as measured by a laser granulometer.
  • Step 1 and step 2 are the same as the step of powder 1#, step 3: 0.2 g of donepezil hemi-pamoate seed crystal (preparation method is the same as above) is added to the filtrate obtained in step 1, and then the step 2 is obtained at a temperature of 4-10 ° C.
  • the filtrate was slowly dropped into the above solution, and the mixture was dropped in 1 hour. At room temperature, it was stirred for 1-2 hours, and filtered.
  • the obtained filter cake was washed with purified water, dried, and then put into a pulverizer equipped with a 10-mesh sieve one by one.
  • the solid particles of 8.1 g of donepezil hemi-pamoate were obtained, and the obtained particles had an average particle diameter D 50 of 42 ⁇ 10 ⁇ M as measured by a laser gravimeter.
  • Step 1 and Step 2 are the same as the step of powder 1#, step 3: 0.2 g of donepezil hemi-pamoate seed crystal (preparation method reference patent WO 2013078608) is added to the filtrate obtained in step 1, and then the temperature of the obtained solution is raised to 50-60 ° C. Then, the filtrate obtained in the step 2 is slowly dropped into the above solution, and the reaction solution is cooled to room temperature, stirred for 1-2 hours, filtered, and the obtained filter cake is washed with purified water, dried, and then placed into a 20-mesh sieve one by one.
  • step 3 0.2 g of donepezil hemi-pamoate seed crystal (preparation method reference patent WO 2013078608) is added to the filtrate obtained in step 1, and then the temperature of the obtained solution is raised to 50-60 ° C. Then, the filtrate obtained in the step 2 is slowly dropped into the above solution, and the reaction solution is cooled to room temperature, stirred for 1-2 hours, filtered
  • the sieve pulverizer finally obtained 8.9 g of solid particles of donepezil hemi-pamoate (yield 91%), and the obtained particles had an average particle diameter D 50 of 13 ⁇ 2 ⁇ M as measured by a laser granulometer.
  • the powder 3# prepared above is further subjected to ultrafine pulverization by a jet mill;
  • the obtained particles had an average particle diameter D 50 of 3 ⁇ 1 ⁇ M as measured by a laser gravimeter.
  • the powder 4# prepared above was again subjected to ultrafine pulverization by a jet mill;
  • the obtained particles had an average particle diameter D 50 of 0.9 ⁇ 0.4 ⁇ M as measured by a laser granulometer.
  • Example 1 The powder 3# prepared in Example 1 was placed at 160 ° C for 2 hours, and its appearance change and weight loss were recorded. The results showed that after 2 hours, the powder sample gradually changed from light yellow to bright brown, and finally coagulated and melted. A weight loss of about 5.14% was observed, and these results indicate that donepezil hemi-pamoate powder cannot withstand dry heat sterilization conditions of 160 °C.
  • the powder 3# prepared in Example 1 was dispensed into a 6 ml borosilicate glass container containing pyrogen, and then irradiated with different surface irradiation doses of 20 kGy, 30 kGy, 40 kGy, 50 kGy or 60 kGy, respectively, and then the powder bottle was irradiated. Accelerated stability studies were carried out under storage conditions of 40 ° C and a relative humidity of 75%, and samples were taken at time points after sterilization, 1 month, 2 months, 3 months, and 6 months, respectively.
  • the test results show that the drug powder can be further extended under the accelerated stability condition after being sterilized by electron beam irradiation with a sterilization dose of 60 kGy, and the total impurities are not more than 0.3%, and the unknown impurities are not more than 0.1%.
  • E-beam sterilization having a sterilization dose of 60 kGy or less does not adversely affect the basic properties of the drug.
  • the best sterilization method is irradiation sterilization, including gamma ray electron beam irradiation and microwave irradiation.
  • Example 2 Appearance and fluidity test of donepezil hemi-pamoate powder injection
  • the angle of repose is a common index for evaluating the fluidity of dry powder.
  • the funnel is fixed at a suitable height H.
  • the general rule is that when the powder angle of repose is ⁇ 9°, it is very free flowing; when the powder angle of repose is at 20-29°, it is free flowing; when the powder angle of repose is at 30-39°, it is a general flow; when the powder angle of repose is ⁇ 40°, for slow flow.
  • the powder 3# prepared in Example 1 was placed in a different diluent to prepare a suspension having a concentration of 230 mg/mL to obtain different formulation formulations; wherein the diluent contained 0.75%-1.5% carboxymethyl fiber.
  • Sodium (CMC-Na) and 0.05%-0.20% poloxamer 188 or Tween 80 then shake for 5 minutes and let stand for 30 minutes, respectively, take 4ml of the upper layer, the middle layer and the bottom layer of the suspension to prepare 12mL
  • the solution was used to determine the content of donepezil hemi-pamoate, and the inter-layer relative concentration difference (RCD) of donepezil hemi-pamoate was calculated to evaluate the suspension of the different formulations.
  • the results are shown in Table 2.
  • the optimized dosage range of CMC-Na is 0.75 to 1.0%.
  • Example 5 Irritation test of donepezil hemi-pamoate injection on rabbit muscle
  • Group 1 was a vehicle control group, and the excipient diluent of Sample 1 in which no drug powder was added in Example 4 was administered;
  • Group 2 - Group 6 was a test group, and Group 2 animals were given Powder 1 in Example 1, a group.
  • Example 1 5# At the time of administration, the drug powder of Group 2 - Group 6 was dispersed in the adjuvant diluent used in Group 1, and the drug dose was adjusted to 85.1 mg per animal (based on donepezil). Each group of animals was administered at a volume of 1 mL per mouse, and was administered by a single injection through the left quadriceps muscle.
  • the injection site and surrounding tissues were visually observed for redness, congestion, and other irritations. Observe once a day for the corresponding time after administration.
  • test group 4 One animal in the test group 4 was observed to have slight redness at the administration site on the 2nd to 4th day of the test, and the animals in the other groups had no obvious symptoms at the administration site on the 2nd to 4th day after administration;
  • the vehicle control group, the test group 3 and the group 5 tested animals showed no histopathological abnormalities; one of the two animals tested in the test group 4 and group 6 was Mononuclear cells were slightly infiltrated on both sides of the skeletal muscle at the administration site, and no symptoms were observed in the other animal.
  • the test group 2 was moderately infiltrated with muscle mononuclear cells at the site of administration of the test animals, and slightly subcutaneous hemorrhage. Mild hemorrhage and moderate edema were seen in the skeletal muscle.
  • the scores of muscle stimulation response are shown in Table 6.
  • the powder 1# prepared in Example 1 can cause a local irritating reaction in the muscle of the administration site, and the powder 2#, powder 3#, powder 4# and powder 5# prepared in Example 1 It only causes mild irritation of the muscle at the site of administration. It is thus seen that the powder 2#-5# is relatively safe in drug safety relative to the powder 1.

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Abstract

一种多奈哌齐半帕莫酸盐的粉针剂及其制备方法，以及含有该粉针剂的组合物及其制备方法。所述粉针剂包含多奈哌齐半帕莫酸盐晶体，晶体的平均粒径为0.5-100μm。

Description

一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法
本申请要求于2017年02月23日提交中国专利局、申请号为201710099184.5发明名称为“一种注射用多奈哌齐半帕莫酸盐的粉针剂及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物制备技术领域，具体涉及一种多奈哌齐半帕莫酸盐粉针剂的制备方法。
背景技术
阿尔茨海默病(Alzheimer disease,AD)发病机制复杂，是多因素相互作用的结果，目前普遍接受的假说有：胆碱能损伤假说、兴奋性氨基酸毒性假说、β淀粉样蛋白(Aβ)级联假说、Tau蛋白过磷酸化假说以及氧化应激假说等。美国食品药品管理局(FDA)目前只批准了5种治疗AD的药物：4种为乙酰胆碱酯酶抑制剂(AChEI)，即他克林(1993)、多奈哌齐(1996)、卡巴拉汀(2000)和加兰他敏(2001)，还有一种为N-甲基-D-天冬氨酸(NMDA)受体拮抗剂，即美金刚(2003)。其中，他克林由于需一日服药4次及潜在的严重肝毒性已基本弃用。另外四个药物是目前治疗AD的一线药物，均能适度改善AD患者的认知能力、日常生活能力、精神行为和总体功能，且安全性和耐受性良好。多奈哌齐、卡巴拉汀和加兰他敏三者疗效相当，但多奈哌齐安全性和耐受性以及患者依从性更优。在中国，常用AD治疗药物有以下几个品种：石杉碱甲、多奈哌齐、吡拉西坦、奥拉西坦、吡硫醇、尼莫地平、胞磷胆碱、银杏提取物、双氢麦角碱、美金刚、乙酰谷酰胺和艾地苯醌等。
多奈哌齐是一个在国内外市场均表现较佳的AD治疗药物，其具有高度选择性、能够可逆性治疗阿尔茨海默病，但常规制剂需每天服药，而老年痴呆患者依从性差，导致患者不能按时按量服药，严重影响治疗效果。为解决多奈哌齐常规制剂带来的问题，国内外学者对多奈哌齐的长效制剂做了多种尝试，目前已有很多多奈哌齐长效制剂技术被公开：如在专利US2011/0218216、WO2010/039381、CN101167697、CN1602867、CN103316974 等专利中均有所描述，然而这些长效制剂还存在制造成本高、难以商业规模进行生产的问题。目前仍需改进多奈哌齐的制剂工艺，从而充分发挥多奈哌齐的疗效，使其医疗效益最大化。
发明内容
本发明的目的在于提供一种多奈哌齐半帕莫酸盐的粉针剂、包含其的组合物及它们的制备方法；本发明的目的通过以下技术方案实现：
本发明首先提供了一多奈哌齐半帕莫酸盐粉针剂，包含多奈哌齐半帕莫酸盐晶体，所述多奈哌齐半帕莫酸盐晶体的平均粒径(D 50)为0.5～200μm，或是不少于180μm，或是不少于160μm，或是不少于140μm，或是不少于120μm，或是不少于100μm，或是不少于80μm，或是不少于60μm，或是不少于30μm，或是不少于10μm，优选为0.5～52μm，更优选为2～32μm，更优选为4～15μm。
在本发明的一些实施方式中，所述多奈哌齐半帕莫酸盐晶体的休止角是25～46度；优选为32～43度。
本发明提供了一种多奈哌齐半帕莫酸盐粉针剂的制备方法，包括：将多奈哌齐半帕莫酸盐结晶后，进行干法粉粹，任选地装入灭菌容器中，再经灭菌工艺制备而成。
在本发明的一些具体实施方式中，前述的多奈哌齐半帕莫酸盐粉针剂的制备方法，可以包括以下步骤：
步骤1：盐酸多奈哌齐溶解于纯化水中，搅拌后，过滤，滤液待用。
步骤2：帕莫酸二钠盐溶解于纯化水中，搅拌后，过滤，滤液待用。
步骤3：多奈哌齐半帕莫酸盐晶种加入步骤1所得滤液，然后将步骤2所得滤液滴入上述溶液，搅拌1-2小时，过滤，所得滤饼用纯化水洗涤后烘干后，再进行干法粉粹，经灭菌工艺制备而成。
所述的干法粉碎选自筛网粉粹、球磨粉碎和/或气流粉碎；
以上制备方法中的灭菌工艺为γ射线辐照灭菌，电子束辐照灭菌或微波辐照灭菌，优选电子束辐照灭菌，电子束辐照灭菌的辐照剂量为 25kGy～60kGy；所述的灭菌容器可以由除热原的硼硅类玻璃制成。
在本发明的一些具体实施方式中，所述的干法粉碎具体可以为：用安装有10目-20目筛网的筛网粉碎机进行粉碎。
本发明还提供了一种含有多奈哌齐半帕莫酸盐的组合物，其包前述的多奈哌齐半帕莫酸盐粉针剂或由前述的方法制备的多奈哌齐半帕莫酸盐粉针剂。
在本发明的一些实施方式中，基于所述组合物的总质量，所述多奈哌齐半帕莫酸盐粉针剂的质量分数为13％～24％。
在本发明的一些实施方式中，所述组合物还包含稀释剂；优选地，基于所述稀释剂的总质量，按质量分数计，所述稀释剂包含0.03％～3％的助悬剂、3％～6％的张力剂、及0.03％～2％的润湿剂。
在本发明的一些实施方式中，其中所述的助悬剂选自甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素，聚乙烯吡咯烷酮、海藻酸盐、壳聚糖、葡聚糖、明胶、聚乙二醇、聚氧乙烯醚、聚氧丙烯醚中的一种或多种组合物，优选羧甲基纤维素钠(CMC-Na)；所述的张力剂选自氯化钠、右旋糖、甘露醇、山梨醇、乳糖、硫酸钠中的一种或多种组合物，优选甘露醇或氯化钠；所述的润湿剂选自聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆、卵磷脂、聚氧乙烯醚、聚氧丙烯醚、脱氧胆酸钠中的一种或多种组合物，优选泊洛沙姆188或吐温80。
在本发明的一些实施方式中，助悬剂的范围还可以在0.5％～1.5％之间，优选0.75％～1.5％，润湿剂的范围还可以在0.05％～0.5％之间，优选0.05％～0.2％，张力剂的范围还可以在4.5％～5％、4.5％～6％之间；
本发明还进一步提供了一种多奈哌齐半帕莫酸盐注射剂的制备方法，其特征在于其按照下列步骤：
(1)获得前述的多奈哌齐半帕莫酸盐粉针剂，或由前述的任一项所述的方法制备的多奈哌齐半帕莫酸盐粉针剂；
(2)将步骤(1)的粉针剂与稀释剂混合后，制得多奈哌齐半帕莫酸盐 注射剂，其中基于所述稀释剂的总质量，按质量分数计，所述稀释剂包含0.03％～3％的助悬剂、3％～6％的张力剂、0.03％～2％的润湿剂及注射用水组成。
在本发明的一些实施方式中，助悬剂的范围还可以在0.5％～1.5％之间，优选0.75％～1.5％，润湿剂的范围还可以在0.05％～0.5％之间，优选0.05％～0.2％，张力剂的范围还可以在4.5％～6％之间；所述的助悬剂优选CMC-Na，张力剂优选甘露醇或氯化钠，润湿剂优选泊洛沙姆188或吐温80。
本发明提供的多奈哌齐半帕莫酸盐药物粉针剂，通过对药物粒径的控制，减少了药物的刺激性；更进一步地，本发明的多奈哌齐半帕莫酸盐药物粉针剂的流动性好，更有利于分装。当然，实施本发明的任一产品必不一定需要同时达到以上所述的所有优点。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例一：多奈哌齐半帕莫酸盐粉针剂的制备
1、不同粒径药物粉末的制备
(1)粉末1#的制备
步骤1：6.6g盐酸多奈哌齐溶解于250ml纯化水中，搅拌后，加入0.34g活性碳，在40-60℃温度条件下，搅拌1-2小时，反应液降温至室温，过滤，滤液待用。
步骤2：3.7g帕莫酸二钠盐溶解于250ml纯化水中，搅拌后，加入0.18g活性碳，在40-60℃温度条件下，搅拌1-2小时，反应液降温至室温，过滤，滤液待用。
步骤3：0.2g多奈哌齐半帕莫酸盐晶种(制备方法参考专利WO2013078608，实施例4)加入步骤1所得滤液，然后在室温条件下，将步骤2 所得滤液缓慢滴入上述溶液，1小时内滴毕，用锚式搅拌杆，缓慢搅拌5-10小时，过滤，所得滤饼用纯化水洗涤后烘干后，最终得到9.6g多奈哌齐半帕莫酸盐的固体颗粒。经激光颗粒度仪检测，所得颗粒的平均粒径D 50：90±17μM。
(2)粉末2#的制备
步骤1和步骤2同粉末1#的步骤，步骤3：0.2g多奈哌齐半帕莫酸盐晶种(制备方法同上)加入步骤1所得滤液，然后在4-10℃温度条件下，将步骤2所得滤液缓慢滴入上述溶液，1小时内滴毕，室温条件下，搅拌1-2小时，过滤，所得滤饼用纯化水洗涤后烘干后，逐一投入安装有10目筛网的粉碎机，最终得到8.1g多奈哌齐半帕莫酸盐的固体颗粒，经激光颗粒度仪检测，所得颗粒的平均粒径D 50：42±10μM。
(3)粉末3#的制备：
步骤1和步骤2同粉末1#的步骤，步骤3：0.2g多奈哌齐半帕莫酸盐晶种(制备方法参考专利WO 2013078608)加入步骤1所得滤液，然后将所得溶液温度升至50-60℃，再将步骤2所得滤液缓慢滴入上述溶液，滴毕，反应液降温至室温，搅拌1-2小时，过滤，所得滤饼用纯化水洗涤后烘干后，逐一投入安装有20目筛网的筛网粉碎机，最终得到8.9g多奈哌齐半帕莫酸盐的固体颗粒(收率91％)，经激光颗粒度仪检测，所得颗粒的平均粒径D 50：13±2μM。
(4)粉末4#的制备
采用气流粉碎机对上述所制备的粉末3#进行进一步地超微粉碎；
粉碎条件：注入超微粉碎机时压力位0.8-1.15MP，超微粉碎机的工作压力位0.7-1.2MP，粉碎时间为30分钟；
经激光颗粒度仪检测，所得颗粒的平均粒径D 50：3±1μM。
(5)粉末5#的制备
采用气流粉碎机对上述所制备的粉末4#再次进行超微粉碎；
粉碎条件：注入超微粉碎机时压力位0.8-1.15MP，超微粉碎机的工作压力位0.7-1.2MP，粉碎时间为90分钟；
经激光颗粒度仪检测，所得颗粒的平均粒径D 50：0.9±0.4μM。
2、多奈哌齐半帕莫酸盐粉针剂灭菌条件研究
(1)评估药物粉末在干热灭菌条件下的稳定性
将实施例一所制备的粉末3#置于160℃下2小时，记录其外观变化和重量损失，结果显示，2小时后，药粉样品由淡黄色逐渐变成亮褐色，最终凝聚并融化，另外，观察到重量损失约5.14％，这些结果表明多奈哌齐半帕莫酸盐粉剂不能耐受160℃的干热灭菌条件。
(2)评估药物粉末在电子束辐照(E-beam)灭菌条件下的稳定性
将实施例一所制备粉末3#分装至除热原的6ml硼硅类玻璃容器中，然后以20kGy、30kGy、40kGy、50kGy或60kGy的不同表面照射剂量分别对其进行照射，然后将粉末瓶置于40℃、相对湿度为75％的储存条件下进行加速稳定性研究，分别在灭菌后、1个月、2个月、3个月及6个月的时间点取样进行测试。
检测结果表明，药物粉末经灭菌剂量达到60kGy的电子束辐照灭菌后，在加速稳定性条件下进一步延长贮存，能够保持稳定，总杂质未超过0.3％，未知杂质未超过0.1％。在加速试验期间，外观、鉴别、杂质、含水量和粒度分布等关键理化性质没有显著变化。因此，可以确认灭菌剂量为60kGy及以下的E-beam灭菌不会对药物的基本性质产生不利影响。
因此对于上述药物粉末，最佳的灭菌方法是辐照灭菌，包括γ射线电子束辐照及微波辐照。
实施例二：多奈哌齐半帕莫酸盐粉针剂的外观及流动性检测
休止角是评价干粉流动性的常用指标，测定时，将漏斗固定在适宜高度H，将实施例一所制备干粉置漏斗中，自然漏下成堆，直到圆锥体的尖端将要接触到漏斗的出口为止，然后测出圆锥底面的半径r，休止角＝arctg(H/r)。
观察实施例一所制备的各药物粉末的外观并检测休止角值，如表1所示：
表1
样品 外观观察 休止角(°)
粉末1# 均一的固态颗粒 28±4
粉末2# 均一的固态颗粒 35±3
粉末3# 均一的固态颗粒 42±1
粉末4# 均一的固态颗粒 38±3
粉末5# 静电明显，团聚严重 50±4
一般规则认为当粉末休止角≤9°，为很自由流动；当粉末休止角在20-29°，为自由流动；当粉末休止角在30-39°，为一般流动；当粉末休止角在≥40°，为迟缓流动。
由上表可看出，5种不同粒径的粉末中，粉末5#的流动性较差，且静电明显，团聚严重，而粉末1#、2#、4#及3#均具有一定的流动性。
实施例三：多奈哌齐半帕莫酸盐注射剂处方研究
1、悬浮性研究
将实施例1所制备的粉末3#入到不同的稀释剂中，配制成浓度为230mg/mL的混悬液，得到不同的制剂处方；其中，稀释剂含有0.75％-1.5％羧甲基纤维素钠(CMC-Na)和0.05％-0.20％泊洛沙姆188或吐温80，然后振荡5分钟并静置30分钟，分别取4ml的上层，中层和底层的混悬液制备成12mL的溶液，用于测定多奈哌齐半帕莫酸盐的含量，计算多奈哌齐半帕莫酸盐的层间相对浓度差(RCD)以评估不同制剂处方的悬浮性，评估结果件表2。
表2
Figure PCTCN2018076599-appb-000001
Figure PCTCN2018076599-appb-000002
如表2所示，CMC-Na(0.75～1.5％)和泊洛沙姆188或吐温80(0.05％～0.20％)的各浓度下多奈哌齐半帕莫酸盐含量的层间相对标准偏差均小于2％。这些结果表明，上述处方对多奈哌齐半帕莫酸盐粉末具有良好的悬浮作用。
2、注射能力研究
制备含有不同浓度的CMC-Na、泊洛沙姆188或吐温80的稀释剂，加入实施例1所制备的粉末2#或粉末3#，并使粉末2#或粉末3#的浓度均为230mg/mL，然后振荡数分钟直至形成均匀的混悬液。通过使用不同大小针头的注射器注射混悬液，进行注射能力研究。手动可注射性分为3个等级：+，++，+++，分别为注射简单，注射中等困难，注射较困难，结果见表3。
表3
Figure PCTCN2018076599-appb-000003
Figure PCTCN2018076599-appb-000004
手动测试结果(表3)显示，通过22G针头注射任何一种混悬液处方都较困难，CMC-Na达到最高浓度(1.5％)时，只能通过18G针头注射，且注射中等困难；而样品处方中的CMC-Na含量≤1.0％，吐温80浓度<2.0％时，样品可通过18G针头。
基于上述的悬浮试验及注射能力研究的综合结果，CMC-Na的优化用量范围为0.75～1.0％。
3、渗透压研究
将不同量的甘露醇添加到上述稀释剂中，其中CMC-Na和泊洛沙姆188的浓度分别固定为1％和0.05％，并利用该稀释剂将粉末3#配制成浓度为230mg/mL的混悬液，测定渗透压。
结果(表4)显示，当甘露醇的含量为4.5～5.80％时，渗透压的范围为285～330mOsmol/kg。
表4.不同含量的甘露醇稀释剂的渗透压
处方批号 甘露醇浓度 渗透压(mOsmol/Kg)
处方0111 4.5％ 285
处方0211 4.8％ 292
处方0311 5.0％ 310
处方0411 5.2％ 318
处方0511 5.4％ 323
处方0611 5.6％ 326
处方0711 5.8％ 330
实施例四：多奈哌齐半帕莫酸盐注射剂的制备
根据表5处方中各辅料量制备不同处方的7个注射剂样品，具体制备步骤：将80％的注射用水和张力剂在50～60℃下混合搅拌，完全溶解后，缓慢加入CMC-Na，搅拌后再加入润湿剂，再加入注射用水，最终配制为3ml稀释液，稀释液经0.22μm的滤膜过滤，无菌分装至除热原的硼硅类西林瓶中，临用前，将实施例1所制备粉针剂416mg溶解于稀释液中，制得多奈哌齐半帕莫酸盐注射剂。
表5
Figure PCTCN2018076599-appb-000005
参照《中华人民共和国药典》2015版，对上述注射液的外观性状，微粒大小，沉降体积比，重新分散性，通针性等项目进行检测，结果外观性状，重新分散试验，通针试验等各项指标均符合要求，沉降体积比接近1，粉针剂的粒度分布均匀。
实施例五：多奈哌齐半帕莫酸盐注射剂对兔肌肉的刺激性试验
观察兔肌肉单次注射多奈哌齐半帕莫酸盐注射剂后给药部位的局部反应，初步评价该制剂的安全性。
方法：12只清洁级新西兰兔按性别和体重大小通过随机化分组方式分为6组，每组使用2只动物评价。组1为溶媒对照组，给予实施例4中不添加药物粉末的样品1的辅料稀释剂；组2-组6均为供试品组，组2动物给予实施例1中的粉末1#，组3动物给予实施例1中的粉末2#，组4动物给予实施例1中的粉末3#，组5动物给予实施例1中的粉末4#，组6动物给予实施例1中的粉末5#；给药时，组2-组6的药物粉末分散于组1所用的辅料稀释液中，药物剂量调整为每只动物85.1mg(按多奈哌齐计)。各组动物给药体积均为1mL/只，单次经左侧股四头肌肉缓慢注射给药。
试验过程中肉眼观察注射部位及周围组织是否有红肿、充血等刺激现象。给药后每天对应时间观察一次。
单次给药14天后，所有试验动物执行安乐死后，纵向切开兔左侧股四头肌，以注射时标记的进针点为界，观察其附近肌肉并按照下表6所列标准进行评分，最后根据肉眼观察和组织病理学检查的结果进行综合判断。
给药部位观察结果：
肉眼观察结果显示，溶媒对照组中有1只动物给药部位于试验第2天见轻度充血，第2-4天见红斑，而另一只动物给药部位无明显症状；
供试品组2两只动物于试验第2～4天观察到给药部位红肿；
供试品组4有1只动物于试验第2～4天观察给药部位轻微红肿，其余组别的动物在给药第2～4天，给药部位无明显症状；
单次给药后14天，溶媒对照组、供试品组3和组5受检测动物未见任何组织病理学异常；供试品组4和组6受检测的2只动物中有1只在给药部位骨骼肌两侧分别见单核细胞轻度浸润，另一只动物给药部位无明显症状；供试品组2受检测动物给药部位肌肉单核细胞中度浸润、轻微皮下出血，骨骼肌可见轻微出血和中度水肿。
肌肉刺激性评价：
肌肉刺激反应评分见表6，本实验检查结果见表7，由表7可看出，供试品组2药物可以引起给药部位中度充血和水肿(分值＝2)，而供试品组3-组6药物能引起给药部位轻微充血(分值＝1)。
上述观察结果表明实施例1所制备的粉末1#注射后，对给药部位肌肉的刺激性较大，而实施例1所制备的粉末2#、粉末3#、粉末4#及粉末5#，注射给药后对肌肉刺激性较小。
表6
Figure PCTCN2018076599-appb-000006
表7
Figure PCTCN2018076599-appb-000007
结论：
由该实验可看出，实施例1所制备的粉末1#可以引起给药部位肌肉出现局部刺激性反应，而实施例1所制备的粉末2#、粉末3#、粉末4#及粉末5#仅会引起给药部位肌肉轻度刺激性反应。由此看出粉末2#-5#相对于粉末1的药物安全性较高。
众所周知，对长效注射混悬剂而言，给药剂量及辅料成分不变，药物粉末粒径越大，药物给药后对给药部位所产生的刺激性越大，但本发明出人预料地发现了大粒径的药物粉末2#、粉末3#及4#，相比于更小粒径的粉末5#，药物刺激性均不大。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (13)

  1. 一种多奈哌齐半帕莫酸盐粉针剂，其特征在于，包含多奈哌齐半帕莫酸盐晶体，所述多奈哌齐半帕莫酸盐晶体的平均粒径为0.5～100μm，优选为0.5～52μm，更优选为2～32μm，更优选为4～15μm。
  2. 如权利要求1所述的多奈哌齐半帕莫酸盐粉针剂，其特征在于，所述多奈哌齐半帕莫酸盐晶体的休止角是25～46度；优选为32～43度。
  3. 如权利要求1或2所述的一种多奈哌齐半帕莫酸盐粉针剂的制备方法，其特征在于，包括：
    将多奈哌齐半帕莫酸盐结晶后，进行干法粉粹，再经灭菌工艺制备而成，优选地，所述干法粉粹选自筛网粉粹、球磨粉碎和/或气流粉碎。
  4. 如权利要求3所述的一种多奈哌齐半帕莫酸盐粉针剂的制备方法，其特征在于，包括以下步骤：
    步骤1：盐酸多奈哌齐溶解于纯化水中，搅拌后，过滤，滤液待用。
    步骤2：帕莫酸二钠盐溶解于纯化水中，搅拌后，过滤，滤液待用。
    步骤3：多奈哌齐半帕莫酸盐晶种加入步骤1所得滤液，然后将步骤2所得滤液滴入上述溶液，搅拌1-2小时，过滤，所得滤饼用纯化水洗涤后烘干后，再进行干法粉粹，经灭菌工艺制备而成。
  5. 根据权利要求4的制备方法，其特征在于，所述灭菌工艺为γ射线辐照灭菌，电子束辐照灭菌或微波辐照灭菌；所述辐照灭菌的辐照剂量为25kGy～60kGy。
  6. 根据权利要求3～5中任一项所述的制备方法，其特征在于，所述的干法粉碎具体为：用安装有10-20目筛网的筛网粉碎机进行粉碎。
  7. 一种含有多奈哌齐半帕莫酸盐的组合物，其特征在于，包含权利要求1-2中任一项所述的多奈哌齐半帕莫酸盐粉针剂或由权利要求3-6所述的方法制备的多奈哌齐半帕莫酸盐粉针剂，优选地，基于所述组合物的总质量，所述多奈哌齐半帕莫酸盐粉针剂的质量分数为13％～24％。
  8. 根据权利要求7所述的组合物，其特征在于，所述组合物还包含稀释剂；优选地，基于所述稀释剂的总质量，按质量分数计，所述稀释剂包含0.03％～3％的助悬剂、3％～6％的张力剂、及0.03％～2％的润湿剂；更优选地，其中所述的助悬剂选自甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素，聚乙烯吡咯烷酮、海藻酸盐、壳聚糖、葡聚糖、明胶、聚乙二醇、聚氧乙烯醚、及聚氧丙烯醚中的一种或多种组合物；所述的张力剂选自氯化钠、右旋糖、甘露醇、山梨醇、乳糖、及硫酸钠中的一种或多种组合物；所述的润湿剂选自聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆、卵磷脂、聚氧乙烯醚、聚氧丙烯醚、及脱氧胆酸钠中的一种或多种组合物。
  9. 根据权利要求8的组合物，其特征在于，所述稀释剂包含0.75％～1.5％的助悬剂、4.5％～6％的张力剂及0.05％～0.2％的润湿剂，优选地，所述稀释剂包含0.75％～1.0％的助悬剂、4.5％～5.8％的张力剂及0.05％～0.2％的润湿剂。
  10. 根据权利要求8或9的组合物，其特征在于，所述的助悬剂为羧甲基纤维素钠，张力剂为甘露醇或氯化钠，润湿剂为泊洛沙姆188或吐温80。
  11. 一种多奈哌齐半帕莫酸盐注射剂的制备方法，其特征在于包含下列步骤：
    (1)获得权利要求1或2所述的多奈哌齐半帕莫酸盐粉针剂，或由权利要求3-6中任一项所述的方法制备的多奈哌齐半帕莫酸盐粉针剂；
    (2)将步骤(1)的粉针剂与稀释剂混合，制得多奈哌齐半帕莫酸盐注射剂，其中基于所述稀释剂的总质量，按质量分数计，所述稀释剂包含0.03％～3％的助悬剂、3％～6％的张力剂、0.03％～2％的润湿剂及注射用水。
  12. 根据权利要求11的制备方法，其特征在于，所述的稀释剂包含0.75％～1.5％的助悬剂、4.5％～6％的张力剂、0.05％～0.2％的润湿剂及注射用水优选地，所述稀释剂包含0.75％～1.0％的助悬剂、4.5％～5.8％的张力剂及0.05％～0.2％的润湿剂。
  13. 根据权利要求11或12的制备方法，其特征在于，所述的助悬剂为羧甲基纤维素钠，张力剂为甘露醇或氯化钠，润湿剂为泊洛沙姆188或吐温80。
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