TWI584823B - Aripiprazole suspension formulation with prolonged shelf life - Google Patents
Aripiprazole suspension formulation with prolonged shelf life Download PDFInfo
- Publication number
- TWI584823B TWI584823B TW104128608A TW104128608A TWI584823B TW I584823 B TWI584823 B TW I584823B TW 104128608 A TW104128608 A TW 104128608A TW 104128608 A TW104128608 A TW 104128608A TW I584823 B TWI584823 B TW I584823B
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- TW
- Taiwan
- Prior art keywords
- aripiprazole
- suspension
- sorbitan monooleate
- polyoxyethylene
- cellulosic
- Prior art date
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims description 75
- 229960004372 aripiprazole Drugs 0.000 title claims description 70
- 239000000725 suspension Substances 0.000 title claims description 40
- 239000000203 mixture Substances 0.000 title claims description 24
- 238000009472 formulation Methods 0.000 title claims description 23
- 230000002035 prolonged effect Effects 0.000 title 1
- 229940102213 injectable suspension Drugs 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 28
- 229920000053 polysorbate 80 Polymers 0.000 claims description 27
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 15
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 12
- 239000000375 suspending agent Substances 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000000337 buffer salt Substances 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 10
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 10
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 7
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 7
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 3
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- 239000001913 cellulose Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000001593 sorbitan monooleate Substances 0.000 claims description 3
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 3
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 125000006353 oxyethylene group Chemical group 0.000 claims 2
- 239000004721 Polyphenylene oxide Substances 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
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- 239000007927 intramuscular injection Substances 0.000 description 2
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- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
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- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
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- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
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- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
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Description
本發明屬於藥物製劑領域，具體係關於一種具有延長的保存期限的阿立哌唑可注射懸浮液製劑，及應用所述製劑治療精神***症以及相關疾病的方法。另一方面，本發明亦關於一種延長阿立哌唑可注射懸浮液製劑的保存期限的方法。The present invention belongs to the field of pharmaceutical preparations, and in particular to an aripiprazole injectable suspension preparation having an extended shelf life, and a method of using the preparation for treating schizophrenia and related diseases. In another aspect, the invention is also directed to a method of extending the shelf life of an aripiprazole injectable suspension formulation.
阿立哌唑作為多巴胺神經元神經傳導物質拮抗劑，用於治療精神***症及其他精神病及中樞神經系統方面的紊亂。在精神***症的治療中，長效阿立哌唑注射製劑可以增加患者的依從性從而降低復發率、有效提高患者的社交能力及生活品質。Aripiprazole is a neurotransmitter antagonist of dopamine neurons for the treatment of schizophrenia and other disorders of the mental and central nervous system. In the treatment of schizophrenia, long-acting aripiprazole injection preparation can increase patient compliance, reduce the recurrence rate, and effectively improve the social ability and quality of life of patients.
Abilify Maintena作為一種長效注射製劑，已經FDA核准上市。但原研發公司指出阿立哌唑懸浮液長期存放後顆粒聚集沉降，難以再分散，所以Abilify Maintena使用凍乾技術形成凍乾粉（參見CN 101801342 B），使用時以注射用水再分散後注射。此外，CN 102133171 A雖然亦揭示一種阿立哌唑的長效注射製劑，但並未提及阿立哌唑懸浮液長期存放後顆粒聚集沉降、難以再分散的問題。Abilify Maintena is a long-acting injection formulation that has been approved for FDA marketing. However, the original research and development company pointed out that the aripiprazole suspension accumulated and settled after long-term storage, and it is difficult to redisperse. Therefore, Abilify Maintena uses freeze-drying technology to form lyophilized powder (see CN 101801342 B), and then re-dispersed with water for injection after injection. In addition, although CN 102133171 A also discloses a long-acting injection preparation of aripiprazole, there is no mention of the problem of aggregation and sedimentation of the aripiprazole suspension after long-term storage and difficulty in redispersion.
為了降低生產成本，簡化生產製程，便於患者使用，本發明克服了「阿立哌唑懸浮液長期存放後顆粒聚集沉降，難以再分散」的缺陷，提供了一種延長阿立哌唑可注射懸浮液製劑的保存期限的方法，以及一種穩定的、具有延長的保存期限的阿立哌唑可注射懸浮液製劑。In order to reduce the production cost, simplify the production process and facilitate the use of the patient, the present invention overcomes the defect that "the aripiprazole suspension is aggregated and settled after long-term storage and is difficult to redisperse", and provides an extended aripiprazole injectable suspension. A method of shelf life of the formulation, and a stable aripiprazole injectable suspension formulation having an extended shelf life.
本發明之目的為提供一種穩定的、具有延長的保存期限的阿立哌唑可注射懸浮液製劑，且保有與現有的製劑類似的長效、緩釋特性。It is an object of the present invention to provide a stable aripiprazole injectable suspension formulation having an extended shelf life and which retains long-lasting, sustained release properties similar to existing formulations.
本發明是通過以下技術方案實現的：The invention is achieved by the following technical solutions:
本發明提供一種具有延長的保存期限的阿立哌唑可注射懸浮液製劑，其特徵在於，包含纖維素類助懸劑及聚氧乙烯(20)山梨醇酐單油酸酯（polyoxyethylene (20) sorbitan monooleate）。The present invention provides an aripiprazole injectable suspension preparation having an extended shelf life, comprising a cellulosic suspending agent and polyoxyethylene (20) sorbitan monooleate (polyoxyethylene (20)) Sorbitan monooleate).
根據本發明，纖維素類助懸劑與聚氧乙烯(20)山梨醇酐單油酸酯的組合，特別適於製備阿立哌唑的懸浮注射製劑，能夠克服其長期存放後顆粒聚集沉降、難以再分散的缺陷。本發明中使用的纖維素類助懸劑包括但不限於：甲基纖維素、羧甲基纖維素、羥丙甲基纖維素及羥丙基纖維素。According to the present invention, the combination of the cellulosic suspending agent and the polyoxyethylene (20) sorbitan monooleate is particularly suitable for preparing a suspension injection preparation of aripiprazole, which can overcome the aggregation and sedimentation of the particles after long-term storage. Defects that are difficult to redistribute. Cellulosic suspending agents for use in the present invention include, but are not limited to, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑中纖維素類助懸劑與聚氧乙烯(20)山梨醇酐單油酸酯的配料比(重量)為：1:0.5~1:6，較佳為1:0.5~1:3，更佳為1:0.5、1:1、1:2或1:3。In a specific embodiment, the ratio (weight) of the cellulosic suspension to the polyoxyethylene (20) sorbitan monooleate in the aripiprazole injectable suspension formulation of the present invention is: 1: 0.5 to 1:6, preferably 1:0.5 to 1:3, more preferably 1:0.5, 1:1, 1:2 or 1:3.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑更包含甘露醇。In a specific embodiment, the aripiprazole injectable suspension formulation of the present invention further comprises mannitol.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑為水懸浮液形式的緩釋無菌注射製劑。該注射製劑用於注射後，在至少1周的時間期間，較佳在2周、3周或4周，多達6周的時間期間或更長的時間期間持續釋放出治療量的阿立哌唑。所述注射包括肌肉注射或皮下注射。In a specific embodiment, the aripiprazole injectable suspension formulation of the invention is a sustained release sterile injectable formulation in the form of an aqueous suspension. The injectable preparation is used for sustained release of a therapeutic amount of aripipide during the period of at least one week, preferably at 2 weeks, 3 weeks or 4 weeks, for a period of up to 6 weeks or longer, after the injection. Oxazole. The injection includes intramuscular or subcutaneous injection.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑更包含一緩衝鹽，所述緩衝鹽可為磷酸鹽，較佳為磷酸氫二鈉、磷酸二氫鈉，更優選為磷酸二氫鈉。In a specific embodiment, the aripiprazole injectable suspension preparation of the present invention further comprises a buffer salt, and the buffer salt may be a phosphate, preferably disodium hydrogen phosphate, sodium dihydrogen phosphate, more preferably Sodium dihydrogen phosphate.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑可包含阿立哌唑，纖維素類助懸劑，聚氧乙烯(20)山梨坦單油酸酯，注射用水，並調整至適當的pH值；亦可進一步包含緩衝鹽。In a specific embodiment, the aripiprazole injectable suspension formulation of the present invention may comprise aripiprazole, a cellulosic suspension, polyoxyethylene (20) sorbitan monooleate, water for injection, and Adjusted to an appropriate pH; it may further comprise a buffer salt.
在一具體實施例中，本發明的阿立哌唑可注射懸浮液製劑包含：50~300mg/mL的阿立哌唑，2~10mg/mL的纖維素類助懸劑及4~48mg/mL的聚氧乙烯(20)山梨醇酐單油酸酯，其中，纖維素類助懸劑與聚氧乙烯(20)山梨醇酐單油酸酯的配料比(重量)為：1:0.5~1:6。In a specific embodiment, the aripiprazole injectable suspension preparation of the present invention comprises: 50 to 300 mg/mL of aripiprazole, 2 to 10 mg/mL of a cellulosic suspension, and 4 to 48 mg/mL. Polyoxyethylene (20) sorbitan monooleate, wherein the ratio of the cellulosic suspension to the polyoxyethylene (20) sorbitan monooleate (weight) is 1:0.5~1 :6.
在另一具體實施例中，阿立哌唑存在的量在50~200mg/mL範圍內，纖維素類助懸劑存在的量在4~8mg/mL範圍內，甘露醇存在的量在30-45mg/mL範圍內，聚氧乙烯(20)山梨坦單油酸酯存在的量在4~24mg/mL範圍內，磷酸二氫鈉存在的量在0.4~4mg/mL範圍內，纖維素類助懸劑與聚氧乙烯(20)山梨坦單油酸酯的配料比(重量)為：1:0.5~1:3。In another embodiment, the amount of aripiprazole is in the range of 50 to 200 mg/mL, the amount of the cellulosic suspension is in the range of 4 to 8 mg/mL, and the amount of mannitol is 30- In the range of 45mg/mL, the amount of polyoxyethylene (20) sorbitan monooleate is in the range of 4~24mg/mL, and the amount of sodium dihydrogen phosphate is in the range of 0.4~4mg/mL. The ratio (weight) of the suspension to the polyoxyethylene (20) sorbitan monooleate is 1:0.5~1:3.
在一具體實施例中，每1mL可注射懸浮液製劑中，阿立哌唑的量為200mg，纖維素類助懸劑的量選自4mg或8mg，甘露醇的量為40mg，聚氧乙烯(20)山梨坦單油酸酯的量選自4mg，8mg或24mg，磷酸二氫鈉的量為0.6mg，纖維素類助懸劑與聚氧乙烯(20)山梨坦單油酸酯的配料比(重量)為：1:0.5~1:3，優選自1:0.5、1:1、1:2、1:3、1:6。In one embodiment, the amount of aripiprazole is 200 mg per 1 mL of the injectable suspension formulation, the amount of cellulosic suspension is selected from 4 mg or 8 mg, and the amount of mannitol is 40 mg, polyoxyethylene ( 20) The amount of sorbitan monooleate is selected from 4 mg, 8 mg or 24 mg, the amount of sodium dihydrogen phosphate is 0.6 mg, and the ratio of cellulose suspension to polyoxyethylene (20) sorbitan monooleate (Weight): 1:0.5~1:3, preferably from 1:0.5, 1:1, 1:2, 1:3, 1:6.
本文中所使用的術語「治療量」指導致任何參數或者臨床症狀改進的數量。實際的劑量可能隨著每個患者的不同而變化，並且不一定指消除所有疾病症狀的總量。The term "therapeutic amount" as used herein refers to an amount that results in any parameter or improvement in clinical symptoms. The actual dose may vary from patient to patient and does not necessarily mean eliminating the total amount of symptoms of all diseases.
本發明的阿立哌唑藥物組合物可包括阿立哌唑的晶體（晶體B、C、D、E、F、G等）或者無定型、阿立哌唑的鹽、阿立哌唑的無水合物或水合物，尤其是一水合物，包括常規水合物，或水合物A、阿立哌唑的溶劑化物（如乙醇合物）、或者阿立哌唑的前藥、或者阿立哌唑的代謝物、所有的形式都可以用於本發明製劑。The aripiprazole pharmaceutical composition of the present invention may comprise crystals of aripiprazole (crystals B, C, D, E, F, G, etc.) or amorphous, aripiprazole salts, aripiprazole a hydrate or hydrate, especially a monohydrate, including a conventional hydrate, or a hydrate A, a solvate of aripiprazole (such as an ethanolate), or a prodrug of aripiprazole, or aripiprazole Metabolites, all forms can be used in the formulations of the invention.
本發明中阿立哌唑的鹽表示保留母體化合物的生物有效性及性質的該等鹽類。其中酸加成鹽是指，通過母體化合物的游離鹹與無機酸或有機酸的反應而得。無機酸包括但不限於鹽酸、氫溴酸、硝酸、磷酸、偏磷酸、硫酸、亞硫酸及過氯酸等。有機酸包括但不限於甲酸、乙酸、丙酸、丙烯酸、草酸、（D）或（L）蘋果酸、富馬酸、馬來酸、羥基苯甲酸、γ-羥基丁酸、甲氧基苯甲酸、鄰苯二甲酸、苯甲酸、吡啶甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、對甲苯磺酸、三氟甲磺酸、四氟硼酸、六氟磷酸、水楊酸、酒石酸、檸檬酸、乳酸、杏仁酸、琥珀酸或丙二酸等。The salts of aripiprazole in the present invention represent such salts which retain the biological effectiveness and properties of the parent compound. The acid addition salt is obtained by reacting free salt of the parent compound with an inorganic acid or an organic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like. Organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid , phthalic acid, benzoic acid, picolinic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, tetrafluoroboric acid, six Fluorophosphoric acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid.
本發明中阿立哌唑的前藥是阿立哌唑的沒有活性的衍生物，它們在體內會輕易地轉變為所需的化合物。The prodrug of aripiprazole in the present invention is an inactive derivative of aripiprazole which is readily converted into the desired compound in vivo.
本發明中的磷酸二氫鈉包括無水磷酸二氫鈉、磷酸二氫鈉一水合物、磷酸二氫鈉二水合物，所有的形式都可以用於本發明之製劑。The sodium dihydrogen phosphate in the present invention includes anhydrous sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium dihydrogen phosphate dihydrate, and all forms can be used in the preparation of the present invention.
本發明亦提供阿立哌唑注射製劑用於治療精神***症及相關疾病（如雙相性精神障礙及癡呆）的方法，包括將治療量的上述阿立哌唑注射劑投予需要治療的患者的步驟，可以經肌肉內投予或皮下投予。The present invention also provides a method for the treatment of schizophrenia and related diseases (such as bipolar disorder and dementia) by aripiprazole injection preparation, comprising the step of administering a therapeutic amount of the above aripiprazole injection to a patient in need of treatment. It can be administered intramuscularly or subcutaneously.
另一方面，本發明提供一種延長阿立哌唑可注射懸浮液製劑的保存期限的方法，其特徵在於，使用纖維素類助懸劑及聚氧乙烯(20)山梨坦單油酸酯來配製注射用媒介物。In another aspect, the present invention provides a method of extending the shelf life of an aripiprazole injectable suspension formulation, characterized in that it is formulated using a cellulosic suspending agent and polyoxyethylene (20) sorbitan monooleate. Injectable vehicle.
一般阿立哌唑可注射懸浮液製劑的製備方法包括以下步驟：將阿立哌唑分散於一注射用媒介物中。該注射用媒介物可含有助懸劑及緩衝鹽等。The preparation of a typical aripiprazole injectable suspension formulation comprises the steps of dispersing aripiprazole in an injectable vehicle. The vehicle for injection may contain a suspending agent, a buffer salt or the like.
本發明的方法特徵在於，使用纖維素類助懸劑及聚氧乙烯(20)山梨坦單油酸酯來配製注射用媒介物。本所述纖維素類助懸劑包括但不限於：甲基纖維素、羧甲基纖維素、羥丙甲基纖維素及羥丙基纖維素。The method of the present invention is characterized in that a vehicle for injection is prepared using a cellulosic suspending agent and polyoxyethylene (20) sorbitan monooleate. Cellulosic suspending agents described herein include, but are not limited to, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, and hydroxypropylcellulose.
在一具體實施例中，纖維素類助懸劑與聚氧乙烯(20)山梨醇酐單油酸酯的配料比(重量)為：1:0.5~1:6，較佳為1:0.5~1:3，更佳為1:0.5、1:1、1:2或1:3。In one embodiment, the ratio (weight) of the cellulosic suspension to the polyoxyethylene (20) sorbitan monooleate is from 1:0.5 to 1:6, preferably 1:0.5. 1:3, more preferably 1:0.5, 1:1, 1:2 or 1:3.
本文中所描述的「延長保存期限」係指延長阿立哌唑懸浮液在常溫（例如，25℃）或高溫（例如，40℃或以上）存放後不會產生顆粒聚集沉降現象的期間。該延長的保存期限至少為1個月，優選為至少2-4個月，更優選為至少5-6個月，又更優選為至少6個月。As used herein, "extended shelf life" refers to a period in which the aripiprazole suspension does not undergo particle aggregation and sedimentation after storage at normal temperature (for example, 25 ° C) or high temperature (for example, 40 ° C or above). The extended shelf life is at least one month, preferably at least 2-4 months, more preferably at least 5-6 months, still more preferably at least 6 months.
下面結合實例對本發明作進一步詳細說明，但不限制本發明。The invention will be further illustrated in detail below with reference to examples without restricting the invention.
實例Instance 11 ：: 阿立哌唑懸浮液的製備Preparation of aripiprazole suspension
配方formula
表 1
- 成分配比
製備方法Preparation
配方1-5：Formula 1-5:
方法1： （1） 將羧甲基纖維素鈉、甘露醇、聚氧乙烯(20)山梨坦單油酸酯、緩衝鹽溶解於適量注射用水中，用0.22μm濾膜除菌過濾； （2）向步驟1所得物料中加入無菌阿立哌唑，分散均勻； （3） 將步驟2物料處理至合適粒徑，加入注射用水調節至目標濃度，分裝。Method 1: (1) Dissolve sodium carboxymethyl cellulose, mannitol, polyoxyethylene (20) sorbitan monooleate, buffer salt in an appropriate amount of water for injection, and sterilize and filter with a 0.22 μm filter; (2) Adding sterile aripiprazole to the material obtained in step 1 and dispersing uniformly; (3) treating the material of step 2 to a suitable particle size, adding water for injection to the target concentration, and dispensing.
方法2： （1）將無菌阿立哌唑處理至合適粒徑； （2）製備含有羧甲基纖維素鈉、甘露醇、聚氧乙烯(20)山梨坦單油酸酯及緩衝鹽的水溶液，0.22μm濾膜除菌過濾； （3）將步驟1、2物料混合，加入注射用水調整至目標濃度，分裝。Method 2: (1) Treating sterile aripiprazole to a suitable particle size; (2) preparing an aqueous solution containing sodium carboxymethylcellulose, mannitol, polyoxyethylene (20) sorbitan monooleate and a buffer salt 0.22μm filter membrane sterilization filtration; (3) Mix the materials of steps 1 and 2, add water for injection to the target concentration, and dispense.
比較例1： （1）將甘露醇、聚氧乙烯(20)山梨坦單油酸酯、緩衝鹽溶解於適量注射用水中，用0.22μm濾膜除菌過濾； （2）向步驟1物料中加入無菌阿立哌唑，分散均勻； （3）將步驟2物料處理至合適粒徑，加入注射用水調節至目標濃度，分裝。Comparative Example 1: (1) Dissolving mannitol, polyoxyethylene (20) sorbitan monooleate, buffer salt in an appropriate amount of water for injection, sterilizing and filtering with a 0.22 μm filter; (2) in the material of step 1. Add sterile aripiprazole and disperse evenly; (3) Treat the material of step 2 to a suitable particle size, add water for injection to the target concentration, and dispense.
比較例2： （1）將羧甲基纖維素鈉、甘露醇、聚氧乙烯(20)山梨坦單月桂酸酯、緩衝鹽溶解於適量注射用水中，用0.22μm濾膜除菌過濾； （2）向步驟1物料中加入無菌阿立哌唑，分散均勻； （3）將步驟2物料處理至合適粒徑，加入注射用水調節至目標濃度，分裝。Comparative Example 2: (1) Dissolving sodium carboxymethylcellulose, mannitol, polyoxyethylene (20) sorbitan monolaurate, and buffer salt in an appropriate amount of water for injection, and sterilizing and filtering with a 0.22 μm filter; 2) Add sterile aripiprazole to the material of step 1 and disperse evenly; (3) Treat the material of step 2 to a suitable particle size, add water for injection to the target concentration, and dispense.
實例Instance 22 ：懸浮液中阿立哌唑粒徑的穩定性: Stability of aripiprazole particle size in suspension
使用馬爾文3000雷射粒徑分佈分析儀測定樣品粒徑，以體積徑表示，D10是指樣品的累計粒徑分佈百分數達到10%時所對應的粒徑，粒徑單位為微米。D50、D90同理。測量前將樣品振搖30秒，使懸浮液中顆粒分散均勻，取樣加入樣品池（分散介質為純化水），遮光度穩定後讀取資料(D10/D50/D90)。如果樣品無法振搖至完全分散，以「聚集」表示。The particle size of the sample was measured using a Malvern 3000 laser particle size distribution analyzer, expressed as a volumetric diameter. D10 is the particle size corresponding to the cumulative particle size distribution percentage of the sample of 10%, and the particle size is in microns. D50, D90 are the same. The sample was shaken for 30 seconds before measurement, and the particles in the suspension were uniformly dispersed. The sample was added to the sample cell (the dispersion medium was purified water), and the data was read after the opacity was stabilized (D10/D50/D90). If the sample cannot be shaken to complete dispersion, it is indicated by "aggregation".
表 2
- 25℃下懸浮液中阿立哌唑粒徑值
表 3
- 40℃下懸浮液中阿立哌唑粒徑值
表 4
- 60℃下懸浮液中阿立哌唑粒徑值
結論：表2~4結果顯示，本發明的阿立哌唑懸浮液長期存放後顆粒不易聚集沉降，可以再分散，克服了先前技術中存在的問題。Conclusion: The results of Tables 2-4 show that after long-term storage of the aripiprazole suspension of the present invention, the particles are less likely to aggregate and settle, and can be redispersed, overcoming the problems in the prior art.
實例Instance 33 ：: SDSD 大鼠藥動力學分析Pharmacokinetic analysis of rats
本發明阿立哌唑懸浮液經SD大鼠大腿肌注射，檢驗藥物在SD大鼠體內的藥動力學，並與經由商業管道獲得的Abilify Maintena比較，評估本發明阿立哌唑懸浮液的緩釋效果。The aripiprazole suspension of the present invention is injected into the thigh muscle of SD rats to test the pharmacokinetics of the drug in SD rats, and the relaxation of the aripiprazole suspension of the present invention is evaluated in comparison with Abilify Maintena obtained through a commercial pipeline. Release effect.
本實例中所使用的為雄性SD大鼠（SPF級），體重230~250g，購自上海斯萊克實驗動物有限公司。整個試驗過程中，大鼠自由飲水。Male Sprague-Dawley rats (SPF grade), weighing 230-250 g, were purchased from Shanghai Slack Laboratory Animal Co., Ltd. in this example. Rats were given free access to water throughout the trial.
對試驗用SD大鼠隨機分組，分為試驗組，及對照組（即Abilify Maintena組），各組以肌肉注射（i.m.）的方式給藥，給藥劑量設為25mg/kg。試驗組的配方及製備方法與實例1相同，阿立哌唑的D90不大於30μm。SD rats for the test were randomly divided into a test group and a control group (i.e., Abilify Maintena group), and each group was administered by intramuscular injection (i.m.) at a dose of 25 mg/kg. The formulation and preparation method of the test group were the same as in Example 1, and the D90 of aripiprazole was not more than 30 μm.
SD大鼠禁食12 小時(h)後給藥，給藥後4 h提供食物。給藥後分別於6，24，72，144，216，336，504，672，840，1008h，從眼底靜脈採集靜脈血0.5ml置於預先標號的EDTA(4mM)抗凝的離心管中，全血採集後放置在冰上，隨即在4℃、8000rpm、5min條件下離心收集血漿，轉移至96孔盤中，於-20℃保存至LC-MS/MS檢測。使用LC/MS/MS(Agilent6460)方法測定EDTA(4mM)抗凝的SD大鼠血漿中的藥物濃度，試驗組及對照組的濃度時間曲線如圖1所示。SD rats were fasted for 12 hours (h) and food was provided 4 hours after administration. After administration, 0.5 ml of venous blood was collected from the fundus vein at 6, 24, 72, 144, 216, 336, 504, 672, 840, 1008 h, respectively, and placed in a pre-labeled EDTA (4 mM) anticoagulated centrifuge tube. The blood was collected and placed on ice, and then the plasma was collected by centrifugation at 4 ° C, 8000 rpm, 5 min, transferred to a 96-well plate, and stored at -20 ° C until LC-MS/MS detection. The concentration of the drug in the plasma of EDTA (4 mM) anticoagulated SD rats was determined by LC/MS/MS (Agilent 6460) method, and the concentration time curves of the test group and the control group are shown in Fig. 1.
結論：大鼠單次給藥後監測至1008h，本發明懸浮液具有與市售產品（Abilify Maintena）相似的緩釋效果。Conclusion: The rats were monitored to 1008 h after a single administration, and the suspension of the present invention has a sustained release effect similar to that of a commercially available product (Abilify Maintena).
咸相信本發明所屬領域中具通常知識者基於本文之描述，無須進一步之說明，可最大限度利用本發明。因此，所提供之說明及申請專利範圍應理解為例示之目的，而非以任何方式限制本發明之範圍。It is believed that those of ordinary skill in the art to which this invention pertains are based on the description herein. The scope of the invention is to be construed as being limited by the scope of the invention.
圖1為給藥後1008小時內，試驗組及對照組SD大鼠體內的藥動力學曲線。Figure 1 is a pharmacokinetic profile of the test group and the control group of SD rats within 1008 hours after administration.
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