CN110327296A - 一种阿立哌唑长效注射制剂及其制备方法 - Google Patents
一种阿立哌唑长效注射制剂及其制备方法 Download PDFInfo
- Publication number
- CN110327296A CN110327296A CN201910722417.1A CN201910722417A CN110327296A CN 110327296 A CN110327296 A CN 110327296A CN 201910722417 A CN201910722417 A CN 201910722417A CN 110327296 A CN110327296 A CN 110327296A
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- Prior art keywords
- aripiprazole
- powder
- acid
- preparation
- long acting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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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 abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 238000002347 injection Methods 0.000 title claims abstract description 35
- 239000007924 injection Substances 0.000 title claims abstract description 35
- 239000000843 powder Substances 0.000 claims abstract description 35
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 25
- 239000000375 suspending agent Substances 0.000 claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003381 stabilizer Substances 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000006172 buffering agent Substances 0.000 claims abstract description 3
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- 239000000872 buffer Substances 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 14
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- 238000003756 stirring Methods 0.000 claims description 11
- 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 9
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
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- 239000001488 sodium phosphate Substances 0.000 claims description 2
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims 1
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- 235000011083 sodium citrates Nutrition 0.000 claims 1
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- 239000012730 sustained-release form Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
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- QPUMEZIFDXYGPG-UHFFFAOYSA-N piperazine 1H-pyrrole Chemical class N1CCNCC1.N1C=CC=C1 QPUMEZIFDXYGPG-UHFFFAOYSA-N 0.000 description 2
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- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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 or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
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Abstract
本发明属于医药制剂技术领域,具体涉及一种阿立哌唑长效注射制剂及其制备方法,所述制剂包括阿立哌唑粉末、稳定剂、助悬剂、缓冲剂和pH调节剂,其中,阿立哌唑粉末的D90为0.01μm‑0.1μm,且通过研磨和水飞的方法制备得到。所得制剂具有良好的稳定性,利于储藏和运输,阿立哌唑以溶解度低的难溶性颗粒存在,粒度较小,且分布均匀,具有良好的可注射性,有利于提高其生物利用度。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及一种阿立哌唑长效注射制剂及其制备方法。
背景技术
阿立哌唑,英文名:Aripiprazole,7-[4-[4-(2,3-二氯苯基)-l-呢嗪基]丁氧基]-3,4-二氢喹诺酮,化学分子式为:C23H27C12N3O2,分子量为448.39,本品在三氯甲烷中易溶,在甲醇、丙酮或乙腈中微溶,在水、0.lmol/L盐酸溶液或0.lmol/L氢氧化钠溶液中几乎不溶。其化学结构式如下:
CN1870980B公开了一种控释阿立哌唑注射剂,主要涉及一种含有无菌冻干阿立哌唑的注射剂,在使用时,将该控释制剂与注射用水组合用于注射,在至少大约1周、多达大约8周内释放阿立哌唑。
CN103596557A公开了阿立哌唑的冻干制剂,该专利发明了一种表现出良好分散性、且当用水复配时容易分散成均匀的悬浮液的阿立哌唑的冻干粉末制剂。
CN105012236A提供了一种长效非水载体注射液,其特征在于,包括精神类药物和非水性载体,其可以在至少4周内持续释放:其中,所述精神类药物为月桂酰阿立哌唑、或帕潘立酮棕榈酸酯。该技术方案依赖于特定的设备实现,同时,在保存过程中,药物离子的均匀性和稳定性还有待进一步提高。
CN105078898A提供了一种阿立哌唑长效缓释微粒注射剂及其制备方法,所述阿立哌唑长效缓释微粒,包括如下重量百分比的组分:阿立哌唑1~50%,高分子聚合物48~97%,释药特性调控剂1~5%,乳化剂0.01~0.5%,其采用苯甲醇作为溶剂。
CN103301461A提供了一种长效注射制剂,包括精神类药物和药学上可接受的非水性载体,所述制剂可以至少2周持续释放,所述精神类药物均匀的溶解在非水性载体中,所述的精神类药物选自阿立哌唑或其药学上可接受的盐;所述非水性载体为药学上可接受的非水性酯溶剂和非水性赋形剂,所述非水性酯溶剂选自苯甲酸苄酯、油酸乙酯、十四酸异丙酯或棕榈酸异丙酯中的一种或多种;所述非水性赋形剂为药学上可接受的醇和注射用油;所述药学上可接受的醇选自苯甲醇或乙醇中的一种或两种;所述注射用油选自蓖麻油、芝麻油、花生油、大豆油或茶油中的一种或多种。然而,CN105078898A和CN103301461A由于处方中加入大量的苯甲醇,可能导致过敏或者麻醉等副作用。
发明内容
鉴于现有技术存在的问题,本发明提供了一种阿立哌唑长效注射制剂及其制备方法,该制剂可以是混悬液的形式,也可以是冻干粉的形式。
本发明得到的混悬液或者经冻干制剂,均具有良好的稳定性,利于储藏和运输。阿立哌唑以溶解度低的难溶性颗粒存在,粒度较小,且分布均匀,具有良好的可注射性,有利于提高其生物利用度。
本发明具体通过以下技术方案来实现:
一种阿立哌唑长效注射制剂及其制备方法,包括阿立哌唑粉末、稳定剂、助悬剂、缓冲剂和pH调节剂,其中,阿立哌唑粉末的D90为0.01μm-0.1μm,且通过研磨和水飞的方法制备得到。
通过大量的实验研究发现,所述方法获得阿立哌唑不仅均有优异微米粒径,且粉末间的差异小,是实现本发明分布均匀和提高其生物利用度关键,然而,采用常规过筛或者机械研磨获得阿立哌唑粉末,难以达到这样的效果。
作为本发明的一种实施方案,阿立哌唑的粉末的获得方法具体地包括:
(1)以粉碎至粒度在80~100目得粗阿立哌唑粉;
(2)将上述粗阿立哌唑粉,加入适量清水,研磨成糊状,再加多量的水搅拌,立即倾出混悬液,如此反复进行多次,将不能混悬的部分弃去;待多次倾出的混悬液静置、沉淀后,倾出上面的清水,将沉淀物干燥即得。
作为本发明的一种实施方案,所述稳定剂的浓度范围为10.0mg/mL-40.0mg/mL。在一些实施例中,所述稳定剂的浓度为4.0mg/mL,6.0mg/mL,10.0mg/mL,18.0mg/mL,20.0mg/mL,40.0mg/mL。
所述稳定剂包含选自聚乙二醇1000维生素E琥珀酸酯、聚氧乙烯氢化蓖麻油RH40、酸酯聚乙二醇-15-羟基硬脂酸酯中的至少一种。
通过大量的实验研究发现,采用所述组成和比例的稳定剂,可以更好的保证注射剂的稳定性。
所述助悬剂的浓度范围为0.2mg/mL-2.0mg/mL。在一些实施例中,所述助悬剂的浓度为0.5mg/mL,1.0mg/mL。
所述助悬剂包含选自羧甲基纤维素钠、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶中的至少一种。在一些实施例中,所述助悬剂为羧甲基纤维素钠。
通过大量的实验研究发现,采用所述组成和比例的助悬剂,可以更好的保证注射剂的分散效果,以及在存储过程中的均一性。
所述缓冲剂包含选自磷酸氢二钠、乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸中的至少一种。所述缓冲剂的浓度范围为0.2mg/mL-2.0mg/mL。在一些实施例中,所述缓冲剂的浓度为0.5mg/mL,1.0mg/mL。
所述pH调节剂选自酸性pH调节剂或者碱性pH调节剂,所述酸性pH调节剂选自盐酸、乙酸、磷酸中的至少一种,所述碱性pH调节剂选自氢氧化钠、磷酸氢钠、碳酸钙、氢氧化镁中的至少一种。以调节pH值为6.0至7.0。
通过大量的实验研究发现,采用所述组成和比例的缓冲剂,pH调节剂,可以更好的保证注射剂的溶解效果,降低给药的刺激性,提高顺应性。
本发明所述的阿立哌唑注射制剂,可为即用型液体注射剂或冻干制剂。在一些实施例中为即用型液体注射剂,在一些实施例中为冻干粉针剂。
在一些实施方式中,所述的阿立哌唑注射制剂为冻干制剂,所述冻干制剂是饼块的形式。
另一方面,本发明提供一种制备上述的一种阿立哌唑注长效注射制剂的方法,包括下列步骤:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值为6.0至7.0,定容。
作为本发明的一种实施方案,所述的制备方法,还可包括制备成冻干制剂的步骤,所述制备成冻干制剂的步骤包括:将所述最终混悬液冷冻干燥。在一些实施例中,所述冷冻干燥包括通过冷却所述最终混悬液至-30℃以下,并在低于0℃干燥所述冷却的最终混悬液;在一些实施例中,所述最终混悬液冷冻干燥是以三个阶段实施的:
(l)预冻阶段,包括在-45℃冷却最终混悬液;
(2)初步干燥阶段,在低于0℃干燥冷却的最终混悬液;和
(3)二次干燥阶段,在高于0℃干燥冷却的最终混悬液,从而得到阿立哌唑冻干制剂。
本发明所述的阿立哌唑注射制剂,在与水混合后,形成混悬液形式的注射剂,其中,存在于混悬液中的阿立哌唑的浓度范围为40.0mg/mL-400.0mg/mL,阿立哌唑的D90范围为0.01μm-0.1μm,所述制剂注射后,在多达4周的时间,或者更长时间例如多达9周的时间期间持续释放阿立哌唑。所述药物可经肌肉内注射或者皮下注射。
本发明相对于现有技术的优势包括:
(1)该混悬液中阿立哌唑以溶解度低的难溶性颗粒存在,注射后能够缓慢持续释放药物,可明显降低给药次数,避免峰谷波动,从而提高患者的治疗依从性和安全性;
(2)本制剂载药量较高,可获得至少2周或更长时间的持续释放;
(3)该混悬液中阿立哌唑粒度较小,且分布均匀,具有良好的可注射性,有利于提高其生物利用度。
附图说明
图1本发明样品与对比例的药物的释放曲线;;
图2为本发明阿立哌唑注射制剂在动物实验中血药浓度测定结果。
具体实施方式
以下结合附图和具体实施例,对本发明进一步说明。
实施例1:
(1)以粉碎至粒度在80~100目得粗阿立哌唑粉100g;
(2)将上述粗阿立哌唑粉,加入清水100mL,研磨成糊状,再加多量的水搅拌,立即倾出混悬液,如此反复进行20次,将不能混悬的部分弃去;待多次倾出的混悬液静置、沉淀后,倾出上面的清水,将沉淀物干燥即得;过筛取D90为0.01μm-0.1μm的部分代用。
实施例2:
将实施例1获得阿立哌唑粉末,按照浓度为200mg/mL;稳定剂聚乙二醇1000维生素E琥珀酸酯,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;缓冲剂磷酸二氢钠0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为6.5。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容。
实施例3:
将实施例1获得阿立哌唑粉末,按照浓度为200mg/mL;稳定剂聚氧乙烯氢化蓖麻油RH40,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;缓冲剂磷酸二氢钠0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为7.0。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容。
实施例4:
将实施例1获得阿立哌唑粉末,按照浓度为150mg/mL;稳定剂酸酯聚乙二醇-15-羟基硬脂酸酯,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;缓冲剂磷酸二氢钠0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为7.0。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容。
实施例5:
将实施例2-4的溶液分别进行灌装,采用以下冻干工艺,制备成冻干粉末样品A、B和C。
对比实施例1:
将阿立哌唑粉末(由过80目筛获得,D90约为180μm),按照浓度为150mg/mL;稳定剂酸酯聚乙二醇-15-羟基硬脂酸酯,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;缓冲剂磷酸二氢钠0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为7.0。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容,采用实施例5的冻干工艺制备冻干样品。
对比实施例2:
将阿立哌唑粉末(由过80目筛获得,D90约为180μm),按照浓度为150mg/mL;稳定剂吐温80,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;缓冲剂磷酸二氢钠0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为7.0。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容,采用实施例5的冻干工艺制备冻干样品。
对比实施例3:
将阿立哌唑粉末(由过80目筛获得,D90约为180μm),按照浓度为150mg/mL;稳定剂吐温80,浓度为10.0mg/mL;助悬剂羧甲基纤维素钠,浓度为0.5mg/mL;包含pH调节剂氢氧化钠,以调节pH值为7.0。
按照以下方法制备:
(a)分别将稳定剂、和缓冲剂依次溶解于水中,
(b)加入助悬剂至上述溶液中,搅拌至完全溶解,
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值,定容,采用实施例5的冻干工艺制备冻干样品。
对比实施例4:
采用CN1870980B实施例1的技术方案。
对比实施例5:
采用CN105012236A实施例1的技术方案。
以下为测试结果:
稳定性考察
将实施例2、3、4与对比例1、2、3、4和5制得的冻干粉末/注射剂进行压盖,放置于60℃、40℃/75%RH下放置6个月,测定有关物质,结果如下表。
从上述实验结果可见,本发明实施例2(样品A)、3(样品B)、4(样品C)相对于对比例1、2、3、4和5方案具有更好的稳定性,有关物质的含量更低。
释放效果测定考察
将适量样品A和B以及对比例1、2、3、4和5制得的注射剂(n=6)置于50mL pH7.4磷酸盐缓冲液中,50r/min,37℃摇床中震摇,分别于1h,6h,24h及2~60天每隔一天取样一次,并补充等量缓冲液。高效液相色谱法测定药物的释放曲线如图1所示。
具体地,部分时间的释放数据的偏差结果如下:
结果显示,本发明实施例方案所得注射液具有稳定的长期释放效果,长达60天,各释放点数据的相对标准偏差RSD%,有利于保证用药的准确性和均一性。
体内药效考察
选用8只购自广州试验动物中心的普通比格犬,雌雄各半,分为两组,试验开始时动物月龄约12个月,试验开始动物体重约8.5kg-9.0kg。
分为两组,雌雄各2只,给药前禁食12小时,注射方式为后腿肌注,前肢头静脉预埋针采集全血,每个时间点2ml,依诺肝素抗凝,采集时间点为给药前0小时,给药后1小时,4小时,8小时,12小时,24小时,2天,4天,6天,8天,10天,15天,20天,25天,30天,35天,40天,45天,60天。分离血浆,分析前保存于Thermo超低温冰箱中(-80℃)。
结果显示,所得注射液具有稳定的长期释放效果,从图2中看出阿立哌唑注射制剂表现出了近9周的稳定血药浓度。然而,对比例根据其体外溶出效果,难以达到本发明如此长的体内释放效果。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种阿立哌唑长效注射制剂,其特征在于,包括阿立哌唑粉末、稳定剂、助悬剂、缓冲剂和pH调节剂,所述稳定剂包含选自聚乙二醇1000维生素E琥珀酸酯、聚氧乙烯氢化蓖麻油RH40、酸酯聚乙二醇-15-羟基硬脂酸酯中的至少一种,其中,阿立哌唑粉末的D90为0.01μm-0.1μm,且通过研磨和水飞的方法制备得到。
2.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,阿立哌唑粉末经由以下方式获得:
(1)以粉碎至粒度在80~100目得粗阿立哌唑粉;
(2)将上述粗阿立哌唑粉,加入适量清水,研磨成糊状,再加多量的水搅拌,立即倾出混悬液,如此反复进行多次,将不能混悬的部分弃去;待多次倾出的混悬液静置、沉淀后,倾出上面的清水,将沉淀物干燥即得。
3.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述稳定剂的浓度范围为10.0mg/mL-40.0mg/mL。
4.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述助悬剂的浓度范围为0.2-2.0mg/mL。
5.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述助悬剂包含选自羧甲基纤维素钠、明胶、聚乙烯吡咯烷酮、甲基纤维素、阿拉伯胶中的至少一种。
6.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述缓冲剂包含选自磷酸氢二钠、乙酸、柠檬酸、柠檬酸钠、琥珀酸、己二酸、酒石酸、抗坏血酸、苯甲酸、苹果酸中的至少一种,浓度范围为0.2mg/mL-2.0mg/mL。
7.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述pH调节剂选自酸性pH调节剂或者碱性pH调节剂,所述酸性pH调节剂选自盐酸、乙酸、磷酸中的至少一种,所述碱性pH调节剂选自氢氧化钠、磷酸氢钠、碳酸钙、氢氧化镁中的至少一种;以调节pH值为6.0至7.0。
8.根据权利要求1所述的阿立哌唑长效注射制剂,其特征在于,所述注射制剂为注射剂或冻干制剂。
9.一种制备上述权利要求1-8任一项所述的阿立哌唑长效注射制剂的制备方法,包括下列步骤:
(a)分别将稳定剂、和缓冲剂依次溶解于水中;
(b)加入助悬剂至上述溶液中,搅拌至完全溶解;
(c)加入阿立哌唑粉末,得混悬液,用pH调节剂调节pH值为6.0至7.0,定容。
10.根据权利要求9所述的制备方法,其特征在于,该制备方法还包括将所述定容后的最终混悬液进行冷冻干燥步骤,具体包括下列步骤:
(l)预冻阶段,包括在-45℃冷却最终混悬液;
(2)初步干燥阶段,在低于0℃干燥冷却的最终混悬液;和
(3)二次干燥阶段,在高于0℃干燥冷却的最终混悬液,从而得到阿立哌唑冻干制剂。
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