WO2021233402A1 - Brexpiprazole-containing pharmaceutical composition and preparation method therefor - Google Patents

Brexpiprazole-containing pharmaceutical composition and preparation method therefor Download PDF

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WO2021233402A1
WO2021233402A1 PCT/CN2021/095011 CN2021095011W WO2021233402A1 WO 2021233402 A1 WO2021233402 A1 WO 2021233402A1 CN 2021095011 W CN2021095011 W CN 2021095011W WO 2021233402 A1 WO2021233402 A1 WO 2021233402A1
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Prior art keywords
epipiprazole
pharmaceutical composition
sodium
composition containing
cellulose
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PCT/CN2021/095011
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French (fr)
Chinese (zh)
Inventor
王晓洁
刘佳雯
刘艳红
夏金强
任晋生
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江苏先声药业有限公司
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Priority to CN202180035664.XA priority Critical patent/CN115768407A/en
Publication of WO2021233402A1 publication Critical patent/WO2021233402A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K47/36—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
    • A61K9/10—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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition containing epipiprazole and a preparation method thereof
  • Brepiprazole chemical name 7-(4-(4-(benzo[B]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one , Approved for listing in the United States in 2015, trade name It is used for oral treatment of schizophrenia and as an adjuvant treatment of antidepressants for major depression.
  • the marketed dosage form is ordinary oral solid tablets with specifications of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg.
  • Epipiprazole is an atypical antipsychotic. It has partial agonistic activity on serotonin 5-HT1A and dopamine D2 receptors, and has antagonistic activity on serotonin 5-HT2A receptors.
  • Patent JP2012232958 discloses a sustained-release injection preparation of epipiprazole. This patent uses sodium carboxymethyl cellulose as a suspending agent, and the prepared injection has concentrated drug release in the initial stage, which increases the risk of side effects.
  • Patent CN106963746A discloses a slow-release composition of poorly water-soluble/slightly soluble drugs obtained by combining two or more sustained-release microspheres with different release behaviors. Although this method avoids the phenomenon of initial burst release, it has delayed release, is inconvenient for clinical use, has poor patient compliance, and has a complicated preparation process, which is not conducive to industrial production.
  • the purpose of the present invention is to provide a pharmaceutical composition with no obvious sudden release phenomenon after administration, long time of drug effect, stable blood concentration, and small fluctuation range of blood concentration, which has a fast onset of action and good patient compliance. And it has higher bioavailability and better clinical application advantages.
  • another object of the present invention is to provide a method for preparing the pharmaceutical composition.
  • a pharmaceutical composition containing epipiprazole comprising: epipiprazole, a buffer, a pH regulator, water and a dispersing agent, the dispersing agent is selected from gelatin, sodium hyaluronate, hydroxypropyl Cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, sodium lauryl sulfate, poloxamer, span, acacia, tragacanth , Pectin, xanthan gum, guar gum, carrageenan, sodium alginate, agar, starch, corn starch, ⁇ -tocopherol, succinate, maltose, sucrose, trehalose, mannitol, lactose, glucose, malt Dextrin, dextran, sorbitol, pullulan, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, cross-linked polyvinylpyr
  • the dispersant is selected from gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, Sodium lauryl sulfate, poloxamer, span, acacia, tragacanth, pectin, xanthan gum, guar gum, carrageenan, sodium alginate, agar, ⁇ -tocopherol, succinic acid Ester, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, polyoxyethylene castor oil, glycerin, vitamin E polyethylene glycol succinate, polyethylene glycol-polylactic acid, dodecyl two Sodium phenyl ether disulfonate, sodium dioctyl sulfosuccinate, triethanolamine, soy lecithin, egg yolk lecithin, polyvinyl alcohol polyethylene glycol copo
  • the dispersant is selected from gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, One of sodium lauryl sulfate, poloxamer, span, xanthan gum, polyoxyethylene castor oil, glycerin, sodium lauryl diphenyl ether disulfonate, soybean lecithin or egg yolk lecithin or Many kinds.
  • the dispersant is selected from one or more of propylene glycol, hydroxyethyl cellulose, poloxamer, sodium hyaluronate, or gelatin.
  • the dispersant is selected from one or more of propylene glycol, hydroxyethyl cellulose, or poloxamer.
  • the dispersant is selected from one or more of sodium hyaluronate or gelatin.
  • the dispersant is selected from gelatin.
  • the above-mentioned dispersant further comprises Tween, preferably Tween 80.
  • the dispersant is selected from a combination of both poloxamer and Tween, a combination of both propylene glycol and Tween, propylene glycol, hydroxyethyl cellulose, sodium hyaluronate, or gelatin.
  • the amount of the dispersant ranges from 0.001% to 20% by weight of the total amount of the pharmaceutical composition.
  • the amount of the dispersant is 0.005% to 15% by weight of the total amount of the pharmaceutical composition.
  • the amount of the dispersant is 0.005 ⁇ -10wt% of the total amount of the pharmaceutical composition.
  • the amount of the dispersant is 0.5%o-10% by weight of the total amount of the pharmaceutical composition.
  • the amount of the dispersant is 0.5%o-4wt% of the total amount of the pharmaceutical composition.
  • the amount of the dispersant is 0.5%o-0.5wt% of the total amount of the pharmaceutical composition.
  • the amount of epipiprazole is 1-30% by weight of the total amount of the pharmaceutical composition.
  • the amount of epipiprazole is 1-15 wt% of the total amount of the pharmaceutical composition.
  • the amount of epipiprazole is 2-10% by weight of the total amount of the pharmaceutical composition.
  • the amount of epipiprazole is 3-8% by weight of the total amount of the pharmaceutical composition.
  • the amount of epipiprazole is 4-5% by weight of the total amount of the pharmaceutical composition.
  • the buffer is selected from TRIS buffer, phosphate, citrate, acetate.
  • the buffer is selected from TRIS buffer, sodium salt of phosphoric acid.
  • the buffer is sodium dihydrogen phosphate.
  • the buffer is sodium dihydrogen phosphate dihydrate.
  • the amount of the buffer is 0.05-5% by weight of the total amount of the pharmaceutical composition.
  • the amount of the buffer is 0.05-0.5 wt% of the total amount of the pharmaceutical composition.
  • the pH adjuster adjusts the pH of the pharmaceutical composition of the present application to 4.0-9.0, more preferably 6.0-8.0, and most preferably 6.8-7.8.
  • the pH adjusting agent adjusts the pH of the pharmaceutical composition of the present application to 7.0.
  • the pH adjusting agent is selected from hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, magnesium oxide, or magnesium hydroxide.
  • the pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, magnesium oxide, or magnesium hydroxide.
  • the pH adjusting agent is sodium hydroxide.
  • the pharmaceutical composition of the present application further includes a filler.
  • the amount of the filler is 1-20% by weight of the total amount of the pharmaceutical composition.
  • the amount of the filler is 4-5% by weight of the total amount of the pharmaceutical composition.
  • the filler is selected from one or more of mannitol, sucrose, maltose, xylitol, glucose, starch, and sorbitol.
  • the filler is mannitol.
  • the D50 of the epipiprazole is 0.1-50 ⁇ m.
  • the D50 of the epipiprazole is 0.1-30 ⁇ m.
  • the D50 of the epipiprazole is 1.8-21 ⁇ m.
  • the D50 of the epipiprazole is 1.8-10.4 ⁇ m.
  • the D50 of the epipiprazole is 4-6 ⁇ m.
  • the D50 of the epipiprazole is 1-50 ⁇ m.
  • the D50 of the epipiprazole is 1.2-30 ⁇ m.
  • the D50 of the epipiprazole is 1.5-3 ⁇ m.
  • the D50 of the epipiprazole is 1.8 ⁇ m.
  • the pharmaceutical composition of the present application can be prepared as a lyophilized agent, and water for injection is added during use to form the pharmaceutical composition of the present application.
  • the pharmaceutical composition of the present application can be used for injection administration, such as intramuscular injection administration or subcutaneous injection administration, preferably intramuscular injection administration.
  • the plasma concentration of the pharmaceutical composition of the present application is maintained above 5 ng/mL within 0-19 days after administration. In some embodiments, the plasma concentration of the pharmaceutical composition of the present application is maintained above 5 ng/mL within 0 to 26 days after administration.
  • the method further includes a method of preparing a pharmaceutical composition containing epiprazole, wherein the method includes: first pulverizing epiprazole, and then dissolving fillers, buffers, and dispersing agents in water for injection, and then The pH of the solution is adjusted with a pH regulator to obtain an auxiliary material solution, and finally the pulverized epiprazole is added to the above auxiliary material solution to prepare it.
  • the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , The auxiliary material solution is obtained, and finally, epipiprazole is added to the above auxiliary material solution to prepare it.
  • the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , The auxiliary material solution is obtained, and finally epipiprazole is added to the above-mentioned auxiliary material solution, and it is prepared by high-pressure homogenization or micro-jetting.
  • the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , To obtain the auxiliary material solution, and finally prepare by ball milling the epipiprazole and the above-mentioned auxiliary material solution.
  • the solution prepared above is lyophilized to obtain a lyophilized product, and the lyophilized product is re-dissolved with water for injection before use to prepare the pharmaceutical composition containing epipiprazole of the present application.
  • the epipiprazole pharmaceutical composition of the present invention remains in the blood for a long enough time without initial burst release of the drug, has a good drug release curve, has a long drug effect time, stable blood drug concentration, safe drug use, and has a relatively high High bioavailability.
  • the preparation method of the pharmaceutical composition has simple process and convenient operation.
  • Figure 1 shows the average blood concentration-time curve obtained by applying the pharmaceutical composition of epipiprazole prepared in Example 1 to Example 4 of the present invention to rats.
  • the epipiprazole is crushed by a jet mill, where the feeding pressure is 0.8MPa, the crushing pressure is 0.5MPa, and it is crushed until D(50) is about 1.8 ⁇ m.
  • the pulverized epipiprazole is added to the above-mentioned auxiliary material solution, and processed for 5 minutes under high-speed shearing at 15Krpm to obtain an epipiprazole pharmaceutical composition.
  • the average particle size D(50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 21 ⁇ m.
  • epipiprazole Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10Krpm, 2min). After adding epipiprazole, shear evenly (10Krpm, 2min) to obtain epipiprazole.
  • Prazole primary suspension The primary suspension of epipiprazole is passed through a microjet (3W psi, 10 cycles), and the particle size is monitored until it is qualified, and the pharmaceutical composition of epipiprazole is obtained.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 5.9 ⁇ m.
  • the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 0.1 ⁇ m.
  • epipiprazole Slowly add epipiprazole to the above-mentioned auxiliary material solution, and perform high-speed shearing (10Krpm, 10min) for uniform shearing to obtain a primary suspension of epipiprazole.
  • the primary suspension of epiprazole is homogenized under high pressure (80-90 bar, about 8 cycles), and the particle size is monitored until it is qualified to obtain the suspension of epiprazole, 2 g/bottle, aliquoted, and freeze-dried.
  • the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 8.2 ⁇ m.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 27.7 ⁇ m.
  • epipiprazole Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10Krpm, 3min). After adding epipiprazole, shear evenly (10Krpm, 3min) to obtain epipiprazole.
  • Prazole primary suspension The primary suspension of epiprazole is homogenized under high pressure (50-55 bar, about 4 cycles), and the particle size is monitored until it is qualified to obtain the suspension of epiprazole, 2 g/bottle, aliquoted, and freeze-dried. Before use, the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 13.5 ⁇ m.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 4.9 ⁇ m.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 4.9 ⁇ m.
  • a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1.
  • the average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 ⁇ m.
  • the pharmacokinetic test of the drug composition of epiprazole prepared in Example 1 to Example 4 of the present invention corresponds to the corresponding curve in Figure 1, and the pharmacokinetic test of Example 2 in the patent JP2012232958 is used for the pharmacokinetic test. Contrast.
  • the administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration.
  • blood was collected from the jugular vein at 0.167, 1, 2, 5, 6, 7, 8, 12, 13, 16, 19, 22, 26, 28, 30, 33, 36, and 45 days. Not less than 100 ⁇ L, frozen at -80°C.
  • the rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. The concentration of epipiprazole in the blood of each sample was determined, and the results are shown in Table 1.
  • Figure 1 shows that the pharmaceutical composition containing epipiprazole of the present application can still maintain the plasma concentration above 5 ng/mL after 19 days.
  • the pharmaceutical composition of the present application has a good and stable drug release curve. Compared with JP2012232958, it shows a stable drug release curve at various particle sizes without obvious burst release. Compared with JP2012232958 in Example 5 and Example 6, the relative bioavailability is 1.6-2.2 times the same under the same particle size and the same dosage.
  • Example 7 of the present invention The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 7 of the present invention was used, and the pharmacokinetic test of Example 7 in the patent JP2012232958 was used for comparison.
  • Example 7 of the present application is about 1.6 times that of Example 7 (particle size 16 ⁇ m) of JP2012232958.
  • Example 8 of the present invention The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 8 of the present invention was used, and the pharmacokinetic test of Example 4 in the patent JP2012232958 was used for comparison.
  • Example 8 of the present application is about 1.6 times that of Example 4 of JP2012232958 (with a particle size of 3.5 ⁇ m).
  • Example 9 of the present invention The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 9 of the present invention was used, and the pharmacokinetic test of Example 4 in the patent JP2012232958 was used for comparison.
  • the administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration.
  • the rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis.
  • the relative bioavailability of Example 9 of the present application is about 1.6 times that of Example 4 of JP2012232958 (with a particle size of 3.5 ⁇ m).
  • the administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration.
  • the administration method is intramuscular injection, single administration.
  • the rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. Determine the concentration of epipiprazole in the blood of each sample to obtain:
  • Example 11 AUC(0-t)(day*ng/mL) 636.7 ⁇ 105.4 574.7 ⁇ 126.5
  • Example 10 of the present application is about 1.8 times that of Example 4 of JP2012232958 (with a particle size of 3.5 ⁇ m).
  • the relative bioavailability of Example 11 of the present application is about 1.8 times that of Example 6 (particle size 10.2 ⁇ m) of JP2012232958.

Abstract

A brexpiprazole-containing pharmaceutical composition and a preparation method therefor. The pharmaceutical composition comprises brexpiprazole and one or more dispersants. The pharmaceutical composition has no obvious burst release phenomenon after administration, long effective time, stable plasma-drug concentration, small plasma-drug concentration fluctuation amplitude and fast onset of action speed, and the preparation process is simple and convenient to operate.

Description

一种含依匹哌唑药物组合物及其制备方法Medicinal composition containing epipiprazole and preparation method thereof
本申请要求年2020年5月21日向中国国家知识产权局提交的，专利申请号为202010436814.5，发明名称为“一种含依匹哌唑药物组合物及其制备方法”的在先申请的优先权。上述在先申请的全文通过引用的方式结合于本申请中。This application claims the priority of the earlier application filed with the State Intellectual Property Office of China on May 21, 2020, the patent application number is 202010436814.5, and the invention title is "a pharmaceutical composition containing epiprazole and its preparation method" . The full text of the aforementioned prior application is incorporated into this application by reference.
技术领域Technical field
本发明属于医药技术领域，具体涉及一种含依匹哌唑药物组合物及其制备方法The invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition containing epipiprazole and a preparation method thereof
背景技术Background technique
依匹哌唑(brexpiprazole)，化学名7-(4-(4-(苯并[B]噻吩-4-基-哌嗪-1-基)丁氧基)-1H-喹啉-2-酮，于2015年在美国批准上市，商品名
Figure PCTCN2021095011-appb-000001
用于精神分裂症的口服治疗以及作为重度抑郁症的抗抑郁药的辅助治疗，上市剂型为普通的口服固体片剂，其规格有0.25mg，0.5mg，1mg，2mg，3mg，4mg。依匹哌唑是一种非典型抗精神病药，对血清素5-HT1A和多巴胺D2受体具有部分激动活性，对5-羟色胺5-HT2A受体具有拮抗活性。 Brepiprazole, chemical name 7-(4-(4-(benzo[B]thiophen-4-yl-piperazin-1-yl)butoxy)-1H-quinolin-2-one , Approved for listing in the United States in 2015, trade name
Figure PCTCN2021095011-appb-000001
It is used for oral treatment of schizophrenia and as an adjuvant treatment of antidepressants for major depression. The marketed dosage form is ordinary oral solid tablets with specifications of 0.25mg, 0.5mg, 1mg, 2mg, 3mg, 4mg. Epipiprazole is an atypical antipsychotic. It has partial agonistic activity on serotonin 5-HT1A and dopamine D2 receptors, and has antagonistic activity on serotonin 5-HT2A receptors.
Figure PCTCN2021095011-appb-000002
Figure PCTCN2021095011-appb-000002
专利JP2012232958中公开了一种依匹哌唑的持续释放注射制剂，该专利采用羧甲基纤维素钠作为悬浮剂，制备的注射液在初期出现药物集中释放，增加副作用风险。Patent JP2012232958 discloses a sustained-release injection preparation of epipiprazole. This patent uses sodium carboxymethyl cellulose as a suspending agent, and the prepared injection has concentrated drug release in the initial stage, which increases the risk of side effects.
专利CN106963746A公开了一种将两种以上释放行为不同的缓释微球组合在一起，得到的水难溶/微溶性药物的缓释组合物。此方法虽然避免了初期突释现象，但存在延迟释放，临床使用不方便，患者依从性差，且制备工艺复杂，不利于工业化生产。Patent CN106963746A discloses a slow-release composition of poorly water-soluble/slightly soluble drugs obtained by combining two or more sustained-release microspheres with different release behaviors. Although this method avoids the phenomenon of initial burst release, it has delayed release, is inconvenient for clinical use, has poor patient compliance, and has a complicated preparation process, which is not conducive to industrial production.
发明内容Summary of the invention
本发明的目的在于提供一种给药后无明显突释现象、药效时间长，血药浓度稳定、血药浓度波动幅度较小的药物组合物，其起效速度快、患者顺应性好，以及具有较高的生物利用度和更好的临床应用优势。同时，本发明的另一目的在于提供所述药物组合物的制备方法。The purpose of the present invention is to provide a pharmaceutical composition with no obvious sudden release phenomenon after administration, long time of drug effect, stable blood concentration, and small fluctuation range of blood concentration, which has a fast onset of action and good patient compliance. And it has higher bioavailability and better clinical application advantages. At the same time, another object of the present invention is to provide a method for preparing the pharmaceutical composition.
本发明的目的可以通过以下技术方案实现：The purpose of the present invention can be achieved through the following technical solutions:
一种含依匹哌唑的药物组合物，该组合物包括：依匹哌唑、缓冲剂、pH调节剂、水和分散剂，所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、阿拉伯胶、西黄蓍胶、果胶、黄原胶、瓜尔胶、卡拉胶、海藻酸钠、琼脂、淀粉、玉米淀粉、α-生育酚、琥 珀酸酯、麦芽糖、蔗糖、海藻糖、甘露醇、乳糖、葡萄糖、麦芽糊精、葡聚糖、山梨糖醇、普鲁兰多糖、微晶纤维素、微晶纤维素-羧甲基纤维素钠、交联聚乙烯吡咯烷酮、聚氧乙烯蓖麻油、甘油、维生素E聚乙二醇琥珀酸酯、鲸蜡硬脂基葡糖苷、聚乙二醇-聚乳酸、羟丙基-β-环糊精、β-乳球蛋白、大豆分离蛋白、乳清分离蛋白、酪蛋白、胆固醇、脱氧胆酸钠、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、十二烷基二苯醚二磺酸钠、磺基琥珀酸钠二辛酯、三乙醇胺、大豆卵磷脂、蛋黄卵磷脂、聚乙烯醇聚乙二醇共聚物、聚乙烯醇、三醋酸甘油酯、多库酯钠、聚丙烯酸树脂、甘草酸、乙烯吡咯烷酮-醋酸乙烯酯、氢化蓖麻油聚氧乙烯醚、柚皮素或齐墩果酸的一种或多种。A pharmaceutical composition containing epipiprazole, the composition comprising: epipiprazole, a buffer, a pH regulator, water and a dispersing agent, the dispersing agent is selected from gelatin, sodium hyaluronate, hydroxypropyl Cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, sodium lauryl sulfate, poloxamer, span, acacia, tragacanth , Pectin, xanthan gum, guar gum, carrageenan, sodium alginate, agar, starch, corn starch, α-tocopherol, succinate, maltose, sucrose, trehalose, mannitol, lactose, glucose, malt Dextrin, dextran, sorbitol, pullulan, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, polyoxyethylene castor oil, glycerin, vitamin E poly Ethylene glycol succinate, cetearyl glucoside, polyethylene glycol-polylactic acid, hydroxypropyl-β-cyclodextrin, β-lactoglobulin, soy protein isolate, whey protein isolate, casein , Cholesterol, sodium deoxycholate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, sodium dodecyl diphenyl ether disulfonate, sodium sulfosuccinate dioctyl ester, triethanolamine, Soy lecithin, egg yolk lecithin, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, triacetin, sodium docusate, polyacrylic resin, glycyrrhizic acid, vinylpyrrolidone-vinyl acetate, hydrogenated castor oil poly One or more of oxyethylene ether, naringenin or oleanolic acid.
在一些实施方案中，所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、阿拉伯胶、西黄蓍胶、果胶、黄原胶、瓜尔胶、卡拉胶、海藻酸钠、琼脂、α-生育酚、琥珀酸酯、微晶纤维素、微晶纤维素-羧甲基纤维素钠、聚氧乙烯蓖麻油、甘油、维生素E聚乙二醇琥珀酸酯、聚乙二醇-聚乳酸、十二烷基二苯醚二磺酸钠、磺基琥珀酸钠二辛酯、三乙醇胺、大豆卵磷脂、蛋黄卵磷脂、聚乙烯醇聚乙二醇共聚物、聚乙烯醇、乙烯吡咯烷酮-醋酸乙烯酯或氢化蓖麻油聚氧乙烯醚的一种或多种。In some embodiments, the dispersant is selected from gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, Sodium lauryl sulfate, poloxamer, span, acacia, tragacanth, pectin, xanthan gum, guar gum, carrageenan, sodium alginate, agar, α-tocopherol, succinic acid Ester, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, polyoxyethylene castor oil, glycerin, vitamin E polyethylene glycol succinate, polyethylene glycol-polylactic acid, dodecyl two Sodium phenyl ether disulfonate, sodium dioctyl sulfosuccinate, triethanolamine, soy lecithin, egg yolk lecithin, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate or hydrogenated castor One or more of sesame oil polyoxyethylene ether.
在一些实施方案中，所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、黄原胶、聚氧乙烯蓖麻油、甘油、十二烷基二苯醚二磺酸钠、大豆卵磷脂或蛋黄卵磷脂的一种或多种。In some embodiments, the dispersant is selected from gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, One of sodium lauryl sulfate, poloxamer, span, xanthan gum, polyoxyethylene castor oil, glycerin, sodium lauryl diphenyl ether disulfonate, soybean lecithin or egg yolk lecithin or Many kinds.
在一些实施方案中，所述分散剂选自丙二醇、羟乙基纤维素、泊洛沙姆、透明质酸钠或明胶的一种或多种。In some embodiments, the dispersant is selected from one or more of propylene glycol, hydroxyethyl cellulose, poloxamer, sodium hyaluronate, or gelatin.
在一些实施方案中，所述分散剂选自丙二醇、羟乙基纤维素或泊洛沙姆的一种或多种。In some embodiments, the dispersant is selected from one or more of propylene glycol, hydroxyethyl cellulose, or poloxamer.
在一些实施方案中，所述分散剂选自透明质酸钠或明胶的一种或多种。In some embodiments, the dispersant is selected from one or more of sodium hyaluronate or gelatin.
在一些实施方案中，所述分散剂选自明胶。In some embodiments, the dispersant is selected from gelatin.
在一些实施方案中，上述分散剂进一步包含吐温，优选吐温80。In some embodiments, the above-mentioned dispersant further comprises Tween, preferably Tween 80.
在一些实施方案中，所述分散剂选自泊洛沙姆和吐温两者的组合、丙二醇和吐温两者的组合、丙二醇、羟乙基纤维素、透明质酸钠或明胶。In some embodiments, the dispersant is selected from a combination of both poloxamer and Tween, a combination of both propylene glycol and Tween, propylene glycol, hydroxyethyl cellulose, sodium hyaluronate, or gelatin.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.001‰-20wt％。In some embodiments, the amount of the dispersant ranges from 0.001% to 20% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.005‰-15wt％。In some embodiments, the amount of the dispersant is 0.005% to 15% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.005‰-10wt％。In some embodiments, the amount of the dispersant is 0.005‰-10wt% of the total amount of the pharmaceutical composition.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.5‰-10wt％。In some embodiments, the amount of the dispersant is 0.5%o-10% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.5‰-4wt％。In some embodiments, the amount of the dispersant is 0.5%o-4wt% of the total amount of the pharmaceutical composition.
在一些实施方案中，所述分散剂的量为药物组合物总量的0.5‰-0.5wt％。In some embodiments, the amount of the dispersant is 0.5%o-0.5wt% of the total amount of the pharmaceutical composition.
在一些实施方案中，所述依匹哌唑的量为药物组合物总量的1-30wt％。In some embodiments, the amount of epipiprazole is 1-30% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述依匹哌唑的量为药物组合物总量的1-15wt％。In some embodiments, the amount of epipiprazole is 1-15 wt% of the total amount of the pharmaceutical composition.
在一些实施方案中，所述依匹哌唑的量为药物组合物总量的2-10wt％。In some embodiments, the amount of epipiprazole is 2-10% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述依匹哌唑的量为药物组合物总量的3-8wt％。In some embodiments, the amount of epipiprazole is 3-8% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述依匹哌唑的量为药物组合物总量的4-5wt％。In some embodiments, the amount of epipiprazole is 4-5% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述缓冲剂选自TRIS缓冲剂、磷酸盐、柠檬酸盐、乙酸盐。In some embodiments, the buffer is selected from TRIS buffer, phosphate, citrate, acetate.
在一些实施方案中，所述缓冲剂选自TRIS缓冲剂、磷酸的钠盐。In some embodiments, the buffer is selected from TRIS buffer, sodium salt of phosphoric acid.
在一些实施方案中，所述缓冲剂为磷酸二氢钠。In some embodiments, the buffer is sodium dihydrogen phosphate.
在一些实施方案中，所述缓冲剂为二水合磷酸二氢钠。In some embodiments, the buffer is sodium dihydrogen phosphate dihydrate.
在一些实施方案中，所述缓冲剂的量为药物组合物总量的0.05-5wt％。In some embodiments, the amount of the buffer is 0.05-5% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述缓冲剂的量为药物组合物总量的0.05-0.5wt％。In some embodiments, the amount of the buffer is 0.05-0.5 wt% of the total amount of the pharmaceutical composition.
pH调节剂是将本申请药物组合物的pH调节至4.0-9.0，更优选为6.0-8.0，最优选为6.8-7.8。The pH adjuster adjusts the pH of the pharmaceutical composition of the present application to 4.0-9.0, more preferably 6.0-8.0, and most preferably 6.8-7.8.
在一些实施方案中，pH调节剂是将本申请药物组合物的pH调节至7.0。In some embodiments, the pH adjusting agent adjusts the pH of the pharmaceutical composition of the present application to 7.0.
在一些实施方案中，所述pH调节剂选自盐酸、乙酸、氢氧化钠、氢氧化钾、碳酸钙、碳酸氢钠、氧化镁或氢氧化镁。In some embodiments, the pH adjusting agent is selected from hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, magnesium oxide, or magnesium hydroxide.
在一些实施方案中，所述pH调节剂选自氢氧化钠、氢氧化钾、碳酸钙、碳酸氢钠、氧化镁或氢氧化镁。In some embodiments, the pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, magnesium oxide, or magnesium hydroxide.
在一些实施方案中，所述pH调节剂为氢氧化钠。In some embodiments, the pH adjusting agent is sodium hydroxide.
在一些实施方案中，本申请的药物组合物还包括填充剂。In some embodiments, the pharmaceutical composition of the present application further includes a filler.
在一些实施方案中，所述填充剂的量为药物组合物总量的1-20wt％。In some embodiments, the amount of the filler is 1-20% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述填充剂的量为药物组合物总量的4-5wt％。In some embodiments, the amount of the filler is 4-5% by weight of the total amount of the pharmaceutical composition.
在一些实施方案中，所述填充剂选自甘露醇，蔗糖，麦芽糖，木糖醇，葡萄糖，淀粉，山梨糖醇中的一种或多种。In some embodiments, the filler is selected from one or more of mannitol, sucrose, maltose, xylitol, glucose, starch, and sorbitol.
在一些实施方案中，所述填充剂为甘露醇。In some embodiments, the filler is mannitol.
在一些实施方案中，所述依匹哌唑的粉末x-射线衍射光谱具有如下特征峰：2θ＝6.4、13.5、14.1、14.5、17.0、18.8、19.9、21.0和22.9。In some embodiments, the powder X-ray diffraction spectrum of epipiprazole has the following characteristic peaks: 2θ=6.4, 13.5, 14.1, 14.5, 17.0, 18.8, 19.9, 21.0, and 22.9.
在一些实施方案中，所述依匹哌唑的D50为0.1-50μm。In some embodiments, the D50 of the epipiprazole is 0.1-50 μm.
在一些实施方案中，所述依匹哌唑的D50为0.1-30μm。In some embodiments, the D50 of the epipiprazole is 0.1-30 μm.
在一些实施方案中，所述依匹哌唑的D50为1.8-21μm。In some embodiments, the D50 of the epipiprazole is 1.8-21 μm.
在一些实施方案中，所述依匹哌唑的D50为1.8-10.4μm。In some embodiments, the D50 of the epipiprazole is 1.8-10.4 μm.
在一些实施方案中，所述依匹哌唑的D50为4-6μm。In some embodiments, the D50 of the epipiprazole is 4-6 μm.
在一些实施方案中，所述依匹哌唑的D50为1-50μm。In some embodiments, the D50 of the epipiprazole is 1-50 μm.
在一些实施方案中，所述依匹哌唑的D50为1.2-30μm。In some embodiments, the D50 of the epipiprazole is 1.2-30 μm.
在一些实施方案中，所述依匹哌唑的D50为1.5-3μm。In some embodiments, the D50 of the epipiprazole is 1.5-3 μm.
在一些实施方案中，所述依匹哌唑的D50为1.8μm。In some embodiments, the D50 of the epipiprazole is 1.8 μm.
本申请的药物组合物可制备成冻干剂，使用时加入注射用水形成本申请的药物组合物。The pharmaceutical composition of the present application can be prepared as a lyophilized agent, and water for injection is added during use to form the pharmaceutical composition of the present application.
本申请的药物组合物可用于注射给药，例如肌肉内注射给药、或皮下注射给药，优选肌肉内注射给药。The pharmaceutical composition of the present application can be used for injection administration, such as intramuscular injection administration or subcutaneous injection administration, preferably intramuscular injection administration.
在一些实施方案中，本申请的药物组合物在给药后0～19天内，血药浓度维持在5ng/mL以上。在一些实施方案中，本申请的药物组合物在给药后0～26天内，血药浓度维持在5ng/mL以上。In some embodiments, the plasma concentration of the pharmaceutical composition of the present application is maintained above 5 ng/mL within 0-19 days after administration. In some embodiments, the plasma concentration of the pharmaceutical composition of the present application is maintained above 5 ng/mL within 0 to 26 days after administration.
在一些实施方案中，还包括制备含依匹哌唑的药物组合物的方法，其中该方法包括：先粉碎依匹哌唑，再将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将经粉碎后的依匹哌唑加入上述辅料溶液中制备得到。In some embodiments, the method further includes a method of preparing a pharmaceutical composition containing epiprazole, wherein the method includes: first pulverizing epiprazole, and then dissolving fillers, buffers, and dispersing agents in water for injection, and then The pH of the solution is adjusted with a pH regulator to obtain an auxiliary material solution, and finally the pulverized epiprazole is added to the above auxiliary material solution to prepare it.
在一些实施方案中，还包括制备含依匹哌唑的药物组合物的方法，其中该方法包括：先将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将依匹哌唑加入上述辅料溶液制备得到。In some embodiments, the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , The auxiliary material solution is obtained, and finally, epipiprazole is added to the above auxiliary material solution to prepare it.
在一些实施方案中，还包括制备含依匹哌唑的药物组合物的方法，其中该方法包括：先将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将依匹哌唑加入上述辅料溶液中，经高压均质或微射流制备得到。In some embodiments, the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , The auxiliary material solution is obtained, and finally epipiprazole is added to the above-mentioned auxiliary material solution, and it is prepared by high-pressure homogenization or micro-jetting.
在一些实施方案中，还包括制备含依匹哌唑的药物组合物的方法，其中该方法包括：先将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将依匹哌唑与上述辅料溶液球磨制备得到。In some embodiments, the method further includes a method of preparing a pharmaceutical composition containing epipiprazole, wherein the method includes: first dissolving a filler, a buffer, and a dispersing agent in water for injection, and then adjusting the pH of the solution with a pH adjusting agent , To obtain the auxiliary material solution, and finally prepare by ball milling the epipiprazole and the above-mentioned auxiliary material solution.
可选地，冻干上文制得的溶液得到冻干产品，在使用前加注射用水复溶冻干产品制得本申请的含依匹哌唑的药物组合物。Optionally, the solution prepared above is lyophilized to obtain a lyophilized product, and the lyophilized product is re-dissolved with water for injection before use to prepare the pharmaceutical composition containing epipiprazole of the present application.
本发明的依匹哌唑药物组合物在血液中保持足够长的时间，而无药物的初始突释，有良好的释药曲线，药效时间长，血药浓度稳定，用药安全，以及具有较高的生物利用度。其次，该药物组合物的制备方法，工艺简单，操作方便。The epipiprazole pharmaceutical composition of the present invention remains in the blood for a long enough time without initial burst release of the drug, has a good drug release curve, has a long drug effect time, stable blood drug concentration, safe drug use, and has a relatively high High bioavailability. Secondly, the preparation method of the pharmaceutical composition has simple process and convenient operation.
附图说明Description of the drawings
图1：显示了本发明实施例1-实施例4中制备的依匹哌唑药物组合物施加给大鼠而得到的平均血药浓度-时间曲线图。Figure 1: shows the average blood concentration-time curve obtained by applying the pharmaceutical composition of epipiprazole prepared in Example 1 to Example 4 of the present invention to rats.
具体实施方式Detailed ways
本发明将于下文通过实施例更加详细的描述，这些实施例示例性地用于进一步说明，可以更好理解本发明的内容，但不应当视为对本发明的限制。实施例中的依匹哌唑原料根据文献CN101155804A制备。The present invention will be described in more detail below through examples. These examples are exemplarily used for further explanation to better understand the content of the present invention, but should not be regarded as a limitation of the present invention. The raw materials of epipiprazole in the examples are prepared according to document CN101155804A.
实施例1含依匹哌唑药物组合物的制备Example 1 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
丙二醇Propylene Glycol 200mg200mg
注射用水Water for Injection 加至2gAdd to 2g
1、将依匹哌唑通过气流粉碎机粉碎，其中送料压力0.8MPa，粉碎压力0.5MPa，粉碎至D(50)在1.8μm左右。1. The epipiprazole is crushed by a jet mill, where the feeding pressure is 0.8MPa, the crushing pressure is 0.5MPa, and it is crushed until D(50) is about 1.8μm.
2、在室温条件下，将除了依匹哌唑外的上述成分溶解在注射用水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。2. At room temperature, dissolve the above-mentioned components except epipiprazole in water for injection, adjust the pH of the solution to 7.0 with 1 mol/L sodium hydroxide aqueous solution, and filter through a 0.22 μm filter membrane to obtain an auxiliary material solution.
3、将粉碎后的依匹哌唑加入上述辅料溶液中，在15Krpm高速剪切下，处理5min，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)为1.8μm左右。3. The pulverized epipiprazole is added to the above-mentioned auxiliary material solution, and processed for 5 minutes under high-speed shearing at 15Krpm to obtain an epipiprazole pharmaceutical composition. The average particle size D(50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8μm.
实施例2含依匹哌唑药物组合物的制备Example 2 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
泊洛沙姆188Poloxamer 188 1.546mg1.546mg
Tween 80Tween 80 0.0145mg0.0145mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
实施例3含依匹哌唑药物组合物的制备Example 3 Preparation of a pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
丙二醇Propylene Glycol 200mg200mg
Tween 80Tween 80 0.0145mg0.0145mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
实施例4含依匹哌唑药物组合物的制备Example 4 Preparation of a pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
羟乙基纤维素Hydroxyethyl cellulose 64mg64mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
实施例5含依匹哌唑药物组合物的制备Example 5 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 80mg80mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
实施例6含依匹哌唑药物组合物的制备Example 6 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
透明质酸钠Sodium hyaluronate 2mg2mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
实施例7含依匹哌唑药物组合物的制备Example 7 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将处方量的依匹哌唑与辅料溶液，置于球磨机中，15:1的球料比(5mm玛瑙球)对混悬体系进行高效研磨。研磨参数：提前开启冷却设备预冷20min，使用500rpm中高转速对样品进行研磨粉碎，转5min暂停5min为一个周期，每个研磨周期结束后，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为21μm。2. Put the prescription amount of epiprazole and auxiliary material solution in a ball mill, and efficiently grind the suspension system with a ball-to-material ratio of 15:1 (5mm agate ball). Grinding parameters: turn on the cooling equipment in advance to pre-cool for 20 minutes, use 500 rpm medium and high speed to grind and grind the sample, rotate for 5 minutes and pause for 5 minutes as a cycle. After each grinding cycle, monitor the particle size until it is qualified, and obtain the epipiprazole drug combination Things. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 21 μm.
实施例8含依匹哌唑药物组合物的制备Example 8 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(3.5Krpm，5min； 6Krpm，5min)，加完依匹哌唑，继续剪切4min至均匀，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(200～230bar，8个循环)，监测粒径，直至合格，得到依匹哌唑混悬液，2g/瓶，分装，冻干。使用前，使用注射用水复溶冻干产品，得到2g依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为4.3μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (3.5Krpm, 5min; 6Krpm, 5min). After adding epipiprazole, continue to shear for 4 minutes until uniform. A primary suspension of epipiprazole is obtained. The primary suspension of epipiprazole is homogenized by high pressure (200-230 bar, 8 cycles), and the particle size is monitored until it is qualified to obtain the suspension of epiprazole, 2 g/bottle, aliquoted, and freeze-dried. Before use, the freeze-dried product is re-dissolved with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 4.3 μm.
实施例9含依匹哌唑药物组合物的制备Example 9 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(10Krpm，5min)，加完依匹哌唑，剪切均匀(10Krpm，5min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(280～300bar，约2个循环；180～200bar约1.5个循环；90～100bar约2个循环)，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为5.7μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10Krpm, 5min). After adding epipiprazole, shear evenly (10Krpm, 5min) to obtain epipiprazole. Prazole primary suspension. The primary suspension of epipiprazole was homogenized by high pressure (280-300 bar, about 2 cycles; 180-200 bar about 1.5 cycles; 90-100 bar about 2 cycles), and the particle size was monitored until it was qualified. Prazole pharmaceutical composition. The average particle size D(50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 5.7μm.
实施例10含依匹哌唑药物组合物的制备Example 10 Preparation of a pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 1mg1mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(10Krpm，2min)，加完依匹哌唑，剪切均匀(10Krpm，2min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经微射流(3W psi，10个循环)，监测粒径，直至合格，得到依匹哌唑药物组合物。使用 马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为5.9μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10Krpm, 2min). After adding epipiprazole, shear evenly (10Krpm, 2min) to obtain epipiprazole. Prazole primary suspension. The primary suspension of epipiprazole is passed through a microjet (3W psi, 10 cycles), and the particle size is monitored until it is qualified, and the pharmaceutical composition of epipiprazole is obtained. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 5.9 μm.
实施例11含依匹哌唑药物组合物的制备Example 11 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
透明质酸钠Sodium hyaluronate 2mg2mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(10K rpm，2min)，加完依匹哌唑，剪切均匀(10Krpm，2min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经微射流(1.5W psi，2个循环)，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为10.4μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10K rpm, 2min). After adding epipiprazole, shear evenly (10Krpm, 2min) to obtain the Primary suspension of piperazole. The primary suspension of epipiprazole is passed through a microjet (1.5W psi, 2 cycles), and the particle size is monitored until it is qualified to obtain a pharmaceutical composition of epipiprazole. The average particle size D(50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 10.4μm.
实施例12含依匹哌唑药物组合物的制备Example 12 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(3.5Krpm，5min；6Krpm，5min)，加完依匹哌唑，剪切均匀(6Krpm，4min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(400～420bar，3个循环；640～670bar，4个循环；1280～1310bar，33个循环)，监测粒径，直至合格，得到依匹哌唑混悬液，2g/瓶，分装，冻干。使用前将冻干产品用注射用水复溶，得到2g依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为0.1μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (3.5Krpm, 5min; 6Krpm, 5min). After adding epipiprazole, shear evenly (6Krpm, 4min). ) To obtain a primary suspension of epipiprazole. The primary suspension of epipiprazole was homogenized by high pressure (400～420bar, 3 cycles; 640～670bar, 4 cycles; 1280～1310bar, 33 cycles), and the particle size was monitored until it was qualified. Azole suspension, 2g/bottle, aliquoted and freeze-dried. Before use, the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 0.1 μm.
实施例13含依匹哌唑药物组合物的制备Example 13 Preparation of a pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切(10Krpm，10min)，剪切均匀，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(80～90bar，约8个循环)，监测粒径，直至合格，得到依匹哌唑混悬液，2g/瓶，分装，冻干。使用前将冻干产品用注射用水复溶，得到2g依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为8.2μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution, and perform high-speed shearing (10Krpm, 10min) for uniform shearing to obtain a primary suspension of epipiprazole. The primary suspension of epiprazole is homogenized under high pressure (80-90 bar, about 8 cycles), and the particle size is monitored until it is qualified to obtain the suspension of epiprazole, 2 g/bottle, aliquoted, and freeze-dried. Before use, the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 8.2 μm.
实施例14含依匹哌唑药物组合物的制备Example 14 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将处方量的依匹哌唑与辅料溶液，置于球磨机中，15:1的球料比(5mm玛瑙球)对混悬体系进行高效研磨。研磨参数：提前开启冷却设备预冷20min，使用500rpm中高转速对样品进行研磨粉碎，转5min暂停5min为一个周期，每个研磨周期结束后，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为27.7μm。2. Put the prescription amount of epiprazole and auxiliary material solution in a ball mill, and efficiently grind the suspension system with a ball-to-material ratio of 15:1 (5mm agate ball). Grinding parameters: turn on the cooling equipment in advance to pre-cool for 20 minutes, use 500 rpm medium and high speed to grind and grind the sample, rotate for 5 minutes and pause for 5 minutes as a cycle. After each grinding cycle, monitor the particle size until it is qualified, and obtain the epipiprazole drug combination Things. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 27.7 μm.
实施例15含依匹哌唑药物组合物的制备Example 15 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(10Krpm，3min)，加完依匹哌唑，剪切均匀(10Krpm，3min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(50～55bar，约4个循环)，监测粒径，直至合格，得到依匹哌唑混悬液，2g/瓶，分装，冻干。使用前将冻干产品用注射用水复溶，得到2g依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为13.5μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (10Krpm, 3min). After adding epipiprazole, shear evenly (10Krpm, 3min) to obtain epipiprazole. Prazole primary suspension. The primary suspension of epiprazole is homogenized under high pressure (50-55 bar, about 4 cycles), and the particle size is monitored until it is qualified to obtain the suspension of epiprazole, 2 g/bottle, aliquoted, and freeze-dried. Before use, the lyophilized product is reconstituted with water for injection to obtain 2 g of the epipiprazole pharmaceutical composition. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 13.5 μm.
实施例16含依匹哌唑药物组合物的制备Example 16 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 1mg1mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将处方量的依匹哌唑与辅料溶液置于球磨机中，15:1的球料比(5mm玛瑙球)对混悬体系进行高效研磨。研磨参数：提前开启冷却设备预冷20min，使用500rpm中高转速对样品进行研磨粉碎，转5min暂停5min为一个周期，每个研磨周期结束后，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为4.9μm。2. Put the prescription amount of epiprazole and the auxiliary material solution in a ball mill, and the suspension system is efficiently ground with a ball-to-material ratio of 15:1 (5mm agate ball). Grinding parameters: turn on the cooling equipment in advance to pre-cool for 20 minutes, use 500 rpm medium and high speed to grind and grind the sample, rotate for 5 minutes and pause for 5 minutes as a cycle. After each grinding cycle, monitor the particle size until it is qualified, and obtain the epipiprazole drug combination Things. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 4.9 μm.
实施例17含依匹哌唑药物组合物的制备Example 17 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 2mg2mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将处方量的依匹哌唑与辅料溶液置于球磨机中，15:1的球料比(5mm玛瑙球)对混悬体系进行高效研磨。研磨参数：提前开启冷却设备预冷20min，使用500rpm中高转速对样品进行研磨粉碎，转5min暂停5min为一个周期，每个研磨周期结束后，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为4.9μm。2. Put the prescription amount of epiprazole and the auxiliary material solution in a ball mill, and the suspension system is efficiently ground with a ball-to-material ratio of 15:1 (5mm agate ball). Grinding parameters: turn on the cooling equipment in advance to pre-cool for 20 minutes, use 500 rpm medium and high speed to grind and grind the sample, rotate for 5 minutes and pause for 5 minutes as a cycle. After each grinding cycle, monitor the particle size until it is qualified, and obtain the epipiprazole drug combination Things. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 4.9 μm.
实施例18含依匹哌唑药物组合物的制备Example 18 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
明胶gelatin 10mg10mg
注射用水Water for Injection 加至2gAdd to 2g
1、将除了依匹哌唑外的上述成分在55℃水浴条件下，溶解在超纯水中，用1mol/L氢氧化钠水溶液调节溶液pH为7.0，并经0.22μm滤膜过滤，得到辅料溶液。1. Dissolve the above-mentioned ingredients except epipiprazole in ultrapure water at 55℃ in a water bath, adjust the pH of the solution to 7.0 with 1mol/L sodium hydroxide aqueous solution, and filter through a 0.22μm filter membrane to obtain auxiliary materials Solution.
2、将依匹哌唑缓慢加入上述辅料溶液中，经高速剪切，边加边剪切搅拌(3.5Krpm，5min)，加完依匹哌唑，剪切均匀(3.5Krpm，5min)，得到依匹哌唑初级混悬液。将依匹哌唑初级混悬液经高压均质(400～420bar，3个循环；640～670bar，4个循环)，监测粒径，直至合格，得到依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.2μm。2. Slowly add epipiprazole to the above-mentioned auxiliary material solution. After high-speed shearing, shear and stir while adding (3.5Krpm, 5min). After adding epipiprazole, shear evenly (3.5Krpm, 5min) to obtain Primary suspension of epipiprazole. The primary suspension of epipiprazole is homogenized under high pressure (400-420 bar, 3 cycles; 640-670 bar, 4 cycles), and the particle size is monitored until it is qualified to obtain an epipiprazole pharmaceutical composition. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.2 μm.
实施例19含依匹哌唑药物组合物的制备Example 19 Preparation of pharmaceutical composition containing epipiprazole
依匹哌唑Epipiprazole 90mg90mg
甘露醇Mannitol 90mg90mg
二水合磷酸二氢钠Sodium Dihydrogen Phosphate Dihydrate 1.48mg1.48mg
1mol/L氢氧化钠1mol/L sodium hydroxide 调节至pH 7.0Adjust to pH 7.0
甲基纤维素Methylcellulose 1mg1mg
注射用水Water for Injection 加至2gAdd to 2g
根据上表的处方采用实施例1的制备方法制得含依匹哌唑药物组合物。使用马尔文3000湿法粒径仪测得依匹哌唑的平均粒径D(50)约为1.8μm。According to the prescription in the above table, a pharmaceutical composition containing epipiprazole was prepared using the preparation method of Example 1. The average particle size D (50) of the epipiprazole measured by the Malvern 3000 wet particle size analyzer is about 1.8 μm.
试验例1大鼠体内药代动力学试验Test Example 1 In vivo pharmacokinetic test in rats
使用本发明实施例1-实施例4中制备的依匹哌唑药物组合物进行药代动力学试验即对应图1中相应的曲线，同时以专利JP2012232958中的实施例2药代动力学试验进行对照。The pharmacokinetic test of the drug composition of epiprazole prepared in Example 1 to Example 4 of the present invention corresponds to the corresponding curve in Figure 1, and the pharmacokinetic test of Example 2 in the patent JP2012232958 is used for the pharmacokinetic test. Contrast.
每组试验采用SD全雄、SPF级大鼠3只，无需禁食，自由饮水。给药体积为0.5ml/kg，给药方式为肌肉注射，单次给药。给药后，分别于0.167、1、2、5、6、7、8、12、13、16、19、22、26、28、30、33、36、45天进行颈静脉采血，每次采血不少于100μL，-80℃冻存。大鼠血浆样品室温融解，涡旋，离心，取上清液进样分析。测定各样品的依匹哌唑在血液中的浓度，结果见表1所示。Each group of experiments used SD males and 3 SPF rats without fasting and drinking water freely. The administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration. After administration, blood was collected from the jugular vein at 0.167, 1, 2, 5, 6, 7, 8, 12, 13, 16, 19, 22, 26, 28, 30, 33, 36, and 45 days. Not less than 100μL, frozen at -80℃. The rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. The concentration of epipiprazole in the blood of each sample was determined, and the results are shown in Table 1.
表1含依匹哌唑药物组合物给药后血药浓度(ng/mL)Table 1 Plasma concentration (ng/mL) of the drug composition containing epipiprazole after administration
Figure PCTCN2021095011-appb-000003
Figure PCTCN2021095011-appb-000003
NA表示未检测。NA means not detected.
图1显示本申请的含依匹哌唑药物组合物在19天后血药浓度仍能维持在5ng/mL以上。Figure 1 shows that the pharmaceutical composition containing epipiprazole of the present application can still maintain the plasma concentration above 5 ng/mL after 19 days.
此外，本申请的药物组合物具有很好的平稳的释药曲线，与JP2012232958相比，在各种粒径下均显示释药曲线平稳，无明显突释。实施例5和实施例6相比于JP2012232958，在相同粒径，相同给药剂量下，相对生物利用度是其1.6～2.2倍。In addition, the pharmaceutical composition of the present application has a good and stable drug release curve. Compared with JP2012232958, it shows a stable drug release curve at various particle sizes without obvious burst release. Compared with JP2012232958 in Example 5 and Example 6, the relative bioavailability is 1.6-2.2 times the same under the same particle size and the same dosage.
试验例2大鼠体内药代动力学试验Test Example 2 In vivo pharmacokinetic test in rats
使用本发明实施例7中制备的依匹哌唑药物组合物进行药代动力学试验，同时以专利 JP2012232958中的实施例7药代动力学试验进行对照。The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 7 of the present invention was used, and the pharmacokinetic test of Example 7 in the patent JP2012232958 was used for comparison.
每组试验采用SD全雄、SPF级大鼠3只，无需禁食，自由饮水。给药体积为0.5ml/kg，给药方式为肌肉注射，单次给药。给药后，分别于0.083、1、3、4、5、6、7、10、14、17、20、24天进行颈静脉采血，每次采血不少于100μL，-80℃冻存。大鼠血浆样品室温融解，涡旋，离心，取上清液进样分析。测定各样品的依匹哌唑在血液中的浓度，得到：AUC(0-t)(day*ng/mL)＝409.1±34.2。本申请实施例7相对生物利用度是JP2012232958的实施例7(粒径16μm)的约1.6倍。Each group of experiments used SD males and 3 SPF rats without fasting and drinking water freely. The administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration. After administration, the jugular venous blood was collected at 0.083, 1, 3, 4, 5, 6, 7, 10, 14, 17, 20, and 24 days, with no less than 100 μL of blood taken each time, and frozen at -80°C. The rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. The concentration of epipiprazole in the blood of each sample was measured, and the result was: AUC(0-t)(day*ng/mL)=409.1±34.2. The relative bioavailability of Example 7 of the present application is about 1.6 times that of Example 7 (particle size 16 μm) of JP2012232958.
试验例3大鼠体内药代动力学试验Test Example 3 In vivo pharmacokinetic test in rats
使用本发明实施例8中制备的依匹哌唑药物组合物进行药代动力学试验，同时以专利JP2012232958中的实施例4药代动力学试验进行对照。The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 8 of the present invention was used, and the pharmacokinetic test of Example 4 in the patent JP2012232958 was used for comparison.
每组试验采用SD全雄、SPF级大鼠3只，无需禁食，自由饮水。给药体积为0.5ml/kg，给药方式为肌肉注射，单次给药。给药后，分别于0.083、1、2、3、4、6、7、10、14、17、21、24、28、35天进行颈静脉采血，每次采血不少于100μL，-80℃冻存。大鼠血浆样品室温融解，涡旋，离心，取上清液进样分析。测定各样品的依匹哌唑在血液中的浓度，得到：AUC(0-t)(day*ng/mL)＝601.92±45.12。本申请实施例8的相对生物利用度是JP2012232958的实施例4(粒径3.5μm)的约1.6倍。Each group of experiments used SD males and 3 SPF rats without fasting and drinking water freely. The administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration. After administration, take blood from the jugular vein at 0.083, 1, 2, 3, 4, 6, 7, 10, 14, 17, 21, 24, 28, and 35 days, with no less than 100μL each time, -80℃ Freeze storage. The rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. The concentration of epipiprazole in the blood of each sample was measured to obtain: AUC(0-t)(day*ng/mL)=601.92±45.12. The relative bioavailability of Example 8 of the present application is about 1.6 times that of Example 4 of JP2012232958 (with a particle size of 3.5 μm).
试验例4大鼠体内药代动力学试验Test Example 4 In vivo pharmacokinetic test in rats
使用本发明实施例9中制备的依匹哌唑药物组合物进行药代动力学试验，同时以专利JP2012232958中的实施例4药代动力学试验进行对照。The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Example 9 of the present invention was used, and the pharmacokinetic test of Example 4 in the patent JP2012232958 was used for comparison.
每组试验采用SD全雄、SPF级大鼠3只，无需禁食，自由饮水。给药体积为0.5ml/kg，给药方式为肌肉注射，单次给药。给药后，分别于0.083、1、2、3、5、6、8、12、15、19、22、26、29天进行颈静脉采血，每次采血不少于100μL，-80℃冻存。大鼠血浆样品室温融解，涡旋，离心，取上清液进样分析。测定各样品的依匹哌唑在血液中的浓度，得到：AUC(0-t)(day*ng/mL)＝602.23±53.90。本申请实施例9的相对生物利用度是JP2012232958的实施例4(粒径3.5μm)的约1.6倍。Each group of experiments used SD males and 3 SPF rats without fasting and drinking water freely. The administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration. After administration, take blood from the jugular vein at 0.083, 1, 2, 3, 5, 6, 8, 12, 15, 19, 22, 26, and 29 days, with no less than 100 μL of blood taken each time, and cryopreserved at -80°C . The rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. The concentration of epipiprazole in the blood of each sample was determined to obtain: AUC(0-t)(day*ng/mL)=602.23±53.90. The relative bioavailability of Example 9 of the present application is about 1.6 times that of Example 4 of JP2012232958 (with a particle size of 3.5 μm).
试验例5大鼠体内药代动力学试验Test Example 5 In vivo pharmacokinetic test in rats
使用本发明实施例10和11中制备的依匹哌唑药物组合物进行药代动力学试验，同时以专利JP2012232958中的实施例4和6药代动力学试验进行对照。The pharmacokinetic test of the epiprazole pharmaceutical composition prepared in Examples 10 and 11 of the present invention was used, and the pharmacokinetic test of Examples 4 and 6 in the patent JP2012232958 were used for comparison.
每组试验采用SD全雄、SPF级大鼠3只，无需禁食，自由饮水。给药体积为0.5ml/kg，给药方式为肌肉注射，单次给药。给药后，分别于0.083、1、2、3、4、7、10、14、16、21、24、28、31天进行颈静脉采血，每次采血不少于100μL，-80℃冻存。大鼠血浆样品室温融 解，涡旋，离心，取上清液进样分析。测定各样品的依匹哌唑在血液中的浓度，得到：Each group of experiments used SD males and 3 SPF rats without fasting and drinking water freely. The administration volume is 0.5ml/kg, and the administration method is intramuscular injection, single administration. After administration, take blood from the jugular vein at 0.083, 1, 2, 3, 4, 7, 10, 14, 16, 21, 24, 28, and 31 days, with no less than 100 μL of blood taken each time, and cryopreserved at -80°C . The rat plasma samples were thawed at room temperature, vortexed, centrifuged, and the supernatant was taken for analysis. Determine the concentration of epipiprazole in the blood of each sample to obtain:
 To 实施例10Example 10 实施例11Example 11
AUC(0-t)(day*ng/mL)AUC(0-t)(day*ng/mL) 636.7±105.4636.7±105.4 574.7±126.5574.7±126.5
本申请实施例10的相对生物利用度是JP2012232958的实施例4(粒径3.5μm)的约1.8倍。本申请实施例11的相对生物利用度是JP2012232958的实施例6(粒径10.2μm)的约1.8倍。The relative bioavailability of Example 10 of the present application is about 1.8 times that of Example 4 of JP2012232958 (with a particle size of 3.5 μm). The relative bioavailability of Example 11 of the present application is about 1.8 times that of Example 6 (particle size 10.2 μm) of JP2012232958.

Claims (24)

  1. 一种含依匹哌唑的药物组合物，其特征在于所述组合物包括：依匹哌唑、缓冲剂、pH调节剂、水和分散剂，所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、阿拉伯胶、西黄蓍胶、果胶、黄原胶、瓜尔胶、卡拉胶、海藻酸钠、琼脂、淀粉、玉米淀粉、α-生育酚、琥珀酸酯、麦芽糖、蔗糖、海藻糖、甘露醇、乳糖、葡萄糖、麦芽糊精、葡聚糖、山梨糖醇、普鲁兰多糖、微晶纤维素、微晶纤维素-羧甲基纤维素钠、交联聚乙烯吡咯烷酮、聚氧乙烯蓖麻油、甘油、维生素E聚乙二醇琥珀酸酯、鲸蜡硬脂基葡糖苷、聚乙二醇-聚乳酸、羟丙基-β-环糊精、β-乳球蛋白、大豆分离蛋白、乳清分离蛋白、酪蛋白、胆固醇、脱氧胆酸钠、聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、十二烷基二苯醚二磺酸钠、磺基琥珀酸钠二辛酯、三乙醇胺、大豆卵磷脂、蛋黄卵磷脂、聚乙烯醇聚乙二醇共聚物、聚乙烯醇、三醋酸甘油酯、多库酯钠、聚丙烯酸树脂、甘草酸、乙烯吡咯烷酮-醋酸乙烯酯、氢化蓖麻油聚氧乙烯醚、柚皮素或齐墩果酸的一种或多种。A pharmaceutical composition containing epipiprazole, characterized in that the composition comprises: epipiprazole, a buffer, a pH regulator, water and a dispersing agent, and the dispersing agent is selected from the group consisting of gelatin and sodium hyaluronate , Hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, sodium lauryl sulfate, poloxamer, span, gum arabic, Tragacanth, pectin, xanthan gum, guar gum, carrageenan, sodium alginate, agar, starch, corn starch, α-tocopherol, succinate, maltose, sucrose, trehalose, mannitol, lactose , Glucose, maltodextrin, dextran, sorbitol, pullulan, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, polyoxyethylene castor oil, glycerin , Vitamin E polyethylene glycol succinate, cetearyl glucoside, polyethylene glycol-polylactic acid, hydroxypropyl-β-cyclodextrin, β-lactoglobulin, soy protein isolate, whey isolate Protein, casein, cholesterol, sodium deoxycholate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, sodium lauryl diphenyl ether disulfonate, sodium dioctyl sulfosuccinate , Triethanolamine, soy lecithin, egg yolk lecithin, polyvinyl alcohol polyethylene glycol copolymer, polyvinyl alcohol, triacetin, docusate sodium, polyacrylic resin, glycyrrhizic acid, vinylpyrrolidone-vinyl acetate, One or more of hydrogenated castor oil polyoxyethylene ether, naringenin or oleanolic acid.
  2. 权利要求1所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、阿拉伯胶、西黄蓍胶、果胶、黄原胶、瓜尔胶、卡拉胶、海藻酸钠、琼脂、α-生育酚、琥珀酸酯、微晶纤维素、微晶纤维素-羧甲基纤维素钠、聚氧乙烯蓖麻油、甘油、维生素E聚乙二醇琥珀酸酯、聚乙二醇-聚乳酸、十二烷基二苯醚二磺酸钠、磺基琥珀酸钠二辛酯、三乙醇胺、大豆卵磷脂、蛋黄卵磷脂、聚乙烯醇聚乙二醇共聚物、聚乙烯醇、乙烯吡咯烷酮-醋酸乙烯酯或氢化蓖麻油聚氧乙烯醚的一种或多种。The pharmaceutical composition containing epipiprazole according to claim 1, wherein the dispersant is selected from the group consisting of gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, Hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, sodium lauryl sulfate, poloxamer, span, acacia, tragacanth, pectin, xanthan gum, guar gum, carrageenan , Sodium alginate, agar, α-tocopherol, succinate, microcrystalline cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, polyoxyethylene castor oil, glycerin, vitamin E polyethylene glycol succinate , Polyethylene glycol-polylactic acid, sodium lauryl diphenyl ether disulfonate, sodium dioctyl sulfosuccinate, triethanolamine, soy lecithin, egg yolk lecithin, polyvinyl alcohol polyethylene glycol copolymer , Polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate or hydrogenated castor oil polyoxyethylene ether one or more.
  3. 权利要求2所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自明胶、透明质酸钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、羧甲基淀粉钠、丙二醇、十二烷基硫酸钠、泊洛沙姆、司盘、黄原胶、聚氧乙烯蓖麻油、甘油、十二烷基二苯醚二磺酸钠、大豆卵磷脂或蛋黄卵磷脂的一种或多种。The pharmaceutical composition containing epipiprazole according to claim 2, wherein the dispersing agent is selected from the group consisting of gelatin, sodium hyaluronate, hydroxypropyl cellulose, hypromellose, methyl cellulose, Hydroxyethyl cellulose, sodium carboxymethyl starch, propylene glycol, sodium lauryl sulfate, poloxamer, span, xanthan gum, polyoxyethylene castor oil, glycerin, dodecyl diphenyl ether disulfonate One or more of sodium, soybean lecithin or egg yolk lecithin.
  4. 权利要求3所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自丙二醇、羟乙基纤维素、泊洛沙姆、透明质酸钠或明胶的一种或多种。The pharmaceutical composition containing epipiprazole according to claim 3, wherein the dispersing agent is selected from one or more of propylene glycol, hydroxyethyl cellulose, poloxamer, sodium hyaluronate or gelatin. kind.
  5. 权利要求4所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自丙二醇、羟乙基纤维素或泊洛沙姆的一种或多种。The pharmaceutical composition containing epipiprazole according to claim 4, wherein the dispersant is selected from one or more of propylene glycol, hydroxyethyl cellulose or poloxamer.
  6. 权利要求4所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自透明质酸钠或明胶的一种或多种，优选明胶。The pharmaceutical composition containing epipiprazole according to claim 4, characterized in that the dispersant is selected from one or more of sodium hyaluronate or gelatin, preferably gelatin.
  7. 权利要求1-6任一项所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂进一步包含吐温，优选吐温80。The pharmaceutical composition containing epipiprazole according to any one of claims 1 to 6, wherein the dispersant further comprises Tween, preferably Tween 80.
  8. 权利要求1所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂选自泊洛沙姆和吐温两者的组合、丙二醇和吐温两者的组合、丙二醇、羟乙基纤维素、透明质酸钠或明胶。The pharmaceutical composition containing epipiprazole according to claim 1, wherein the dispersant is selected from the group consisting of a combination of poloxamer and Tween, a combination of both propylene glycol and Tween, propylene glycol, hydroxy Ethyl cellulose, sodium hyaluronate or gelatin.
  9. 权利要求1-8任一项所述的含依匹哌唑的药物组合物，其特征在于：所述分散剂的量为药物组合物总量的0.001‰-20wt％，优选0.005‰-15wt％，更优选0.005‰-10wt％，进一步优选0.5‰-10wt％，更进一步优选0.5‰-4wt％。The pharmaceutical composition containing epipiprazole according to any one of claims 1-8, wherein the amount of the dispersant is 0.001‰-20wt% of the total amount of the pharmaceutical composition, preferably 0.005‰-15wt% , More preferably 0.005‰-10wt%, still more preferably 0.5‰-10wt%, still more preferably 0.5‰-4wt%.
  10. 权利要求1-9任一项所述的含依匹哌唑的药物组合物，其特征在于：所述依匹哌唑的量为药物组合物总量的1-30wt％，优选1-15wt％，更优选2-10wt％，进一步优选3-8wt％，更进一步优选4-5wt％。The pharmaceutical composition containing epipiprazole according to any one of claims 1-9, characterized in that the amount of the epipiprazole is 1-30% by weight of the total pharmaceutical composition, preferably 1-15% by weight , More preferably 2-10% by weight, still more preferably 3-8% by weight, still more preferably 4-5% by weight.
  11. 权利要求1-10任一项所述的含依匹哌唑的药物组合物，其特征在于：所述缓冲剂选自TRIS缓冲剂、磷酸盐、柠檬酸盐、乙酸盐，优选TRIS缓冲剂、磷酸的钠盐，更优选磷酸二氢钠。The pharmaceutical composition containing epipiprazole according to any one of claims 1-10, wherein the buffer is selected from the group consisting of TRIS buffer, phosphate, citrate, and acetate, preferably TRIS buffer , Sodium salt of phosphoric acid, more preferably sodium dihydrogen phosphate.
  12. 权利要求1-11任一项所述的含依匹哌唑的药物组合物，其特征在于：所述缓冲剂的量为药物组合物总量的0.05-5wt％，优选0.05-0.5wt％。The pharmaceutical composition containing epipiprazole according to any one of claims 1-11, wherein the amount of the buffer is 0.05-5 wt% of the total amount of the pharmaceutical composition, preferably 0.05-0.5 wt%.
  13. 权利要求1-12任一项所述的含依匹哌唑的药物组合物，其特征在于：pH调节剂是将药物组合物的pH调节至4.0-9.0，优选6.0-8.0，更优选6.8-7.8，进一步优选7.0。The pharmaceutical composition containing epipiprazole according to any one of claims 1-12, wherein the pH adjuster adjusts the pH of the pharmaceutical composition to 4.0-9.0, preferably 6.0-8.0, more preferably 6.8- 7.8, more preferably 7.0.
  14. 权利要求1-13任一项所述的含依匹哌唑的药物组合物，其特征在于：所述pH调节剂选自盐酸、乙酸、氢氧化钠、氢氧化钾、碳酸钙、碳酸氢钠、氧化镁或氢氧化镁，优选氢氧化钠、氢氧化钾、碳酸钙、碳酸氢钠、氧化镁或氢氧化镁，更优选氢氧化钠。The pharmaceutical composition containing epipiprazole according to any one of claims 1-13, wherein the pH adjusting agent is selected from the group consisting of hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium carbonate, and sodium bicarbonate , Magnesium oxide or magnesium hydroxide, preferably sodium hydroxide, potassium hydroxide, calcium carbonate, sodium bicarbonate, magnesium oxide or magnesium hydroxide, more preferably sodium hydroxide.
  15. 权利要求1-14任一项所述的含依匹哌唑的药物组合物，其特征在于：所述药物组合物还包括填充剂。The pharmaceutical composition containing epipiprazole according to any one of claims 1-14, wherein the pharmaceutical composition further comprises a filler.
  16. 权利要求15所述的含依匹哌唑的药物组合物，其特征在于：所述填充剂的量为药物组合物总量的1-20wt％，优选4-5wt％。The pharmaceutical composition containing epipiprazole according to claim 15, wherein the amount of the filler is 1-20% by weight of the total pharmaceutical composition, preferably 4-5% by weight.
  17. 权利要求15-16任一项所述的含依匹哌唑的药物组合物，其特征在于：所述填充剂选自甘露醇，蔗糖，麦芽糖，木糖醇，葡萄糖，淀粉，山梨糖醇中的一种或多种，优选甘露醇。The pharmaceutical composition containing epipiprazole according to any one of claims 15-16, wherein the filler is selected from the group consisting of mannitol, sucrose, maltose, xylitol, glucose, starch, and sorbitol One or more of, preferably mannitol.
  18. 权利要求1-17任一项所述的含依匹哌唑的药物组合物，其特征在于：所述依匹哌唑的粉末x-射线衍射光谱具有如下特征峰：2θ＝6.4、13.5、14.1、14.5、17.0、18.8、19.9、21.0和22.9。The pharmaceutical composition containing epipiprazole according to any one of claims 1-17, wherein the powder X-ray diffraction spectrum of the epipiprazole has the following characteristic peaks: 2θ=6.4, 13.5, 14.1 , 14.5, 17.0, 18.8, 19.9, 21.0 and 22.9.
  19. 权利要求1-18任一项所述的含依匹哌唑的药物组合物，其特征在于：所述依匹哌唑的D50为0.1-50μm，优选0.1-30μm，更优选1.8-21μm，进一步优选1.8-10.4μm，更进一步优选4-6μm。The pharmaceutical composition containing epipiprazole according to any one of claims 1-18, wherein the D50 of the epipiprazole is 0.1-50 μm, preferably 0.1-30 μm, more preferably 1.8-21 μm, and further It is preferably 1.8-10.4 μm, and more preferably 4-6 μm.
  20. 权利要求1-18任一项所述的含依匹哌唑的药物组合物，其特征在于：所述依匹哌唑的D50为1-50μm，优选1.2-30μm，更优选1.5-3μm，进一步优选1.8μm。The pharmaceutical composition containing epipiprazole according to any one of claims 1-18, wherein the D50 of the epipiprazole is 1-50 μm, preferably 1.2-30 μm, more preferably 1.5-3 μm, and further It is preferably 1.8 μm.
  21. 权利要求1-20任一项所述的含依匹哌唑的药物组合物，其特征在于：所述药物组合物用于注射给药，包括肌肉内注射给药或皮下注射给药，优选肌肉内注射给药。The pharmaceutical composition containing epipiprazole according to any one of claims 1-20, characterized in that: the pharmaceutical composition is used for injection administration, including intramuscular injection or subcutaneous injection, preferably intramuscular Administration by injection.
  22. 权利要求1-21任一项所述的含依匹哌唑的药物组合物，其特征在于：所述药物组合物在给药后0～19天内，血药浓度维持在5ng/mL以上，优选所述药物组合物在给药后0～26天内，血药浓度维持在5ng/mL以上。The pharmaceutical composition containing epipiprazole according to any one of claims 1-21, characterized in that the blood concentration of the pharmaceutical composition is maintained above 5 ng/mL within 0-19 days after administration, preferably The blood concentration of the pharmaceutical composition is maintained above 5 ng/mL within 0 to 26 days after administration.
  23. 权利要求1-22任一项所述的含依匹哌唑的药物组合物的制备方法，包括：先粉碎依匹哌唑，再将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将经粉碎后的依匹哌唑加入上述辅料溶液中制备得到。The preparation method of the pharmaceutical composition containing epipiprazole according to any one of claims 1-22, comprising: first pulverizing epipiprazole, and then dissolving filler, buffer and dispersant in water for injection, and then The pH of the solution is adjusted with a pH regulator to obtain an auxiliary material solution, and finally the pulverized epiprazole is added to the above auxiliary material solution to prepare it.
  24. 权利要求1-22任一项所述的含依匹哌唑的药物组合物的制备方法，包括：先将填充剂、缓冲剂和分散剂溶解在注射用水中，然后用pH调节剂调节溶液pH，得到辅料溶液，最后将依匹哌唑加入所述辅料溶液制备得到。The preparation method of the pharmaceutical composition containing epipiprazole according to any one of claims 1-22, comprising: first dissolving the filler, buffer and dispersant in water for injection, and then adjusting the pH of the solution with a pH regulator , The auxiliary material solution is obtained, and finally epipiprazole is added to the auxiliary material solution to prepare it.
PCT/CN2021/095011 2020-05-21 2021-05-21 Brexpiprazole-containing pharmaceutical composition and preparation method therefor WO2021233402A1 (en)

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WO2023083212A1 (en) * 2021-11-10 2023-05-19 广东东阳光药业有限公司 Quinoline pharmaceutical composition

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CN106389357A (en) * 2011-06-07 2017-02-15 大塚制药株式会社 Freeze-dried aripiprazole formulation

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WO2023083212A1 (en) * 2021-11-10 2023-05-19 广东东阳光药业有限公司 Quinoline pharmaceutical composition
CN114767663A (en) * 2022-04-19 2022-07-22 浙江和泽医药科技股份有限公司 Orally dissolving film agent and preparation method thereof

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