CN113069419A - 一种伊万卡塞药物组合物及其制备方法 - Google Patents
一种伊万卡塞药物组合物及其制备方法 Download PDFInfo
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- CN113069419A CN113069419A CN201911310445.9A CN201911310445A CN113069419A CN 113069419 A CN113069419 A CN 113069419A CN 201911310445 A CN201911310445 A CN 201911310445A CN 113069419 A CN113069419 A CN 113069419A
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- pharmaceutical composition
- injection
- yiwan
- avancin
- polysorbate
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 48
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- 240000009305 Pometia pinnata Species 0.000 title claims abstract description 21
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- 238000002347 injection Methods 0.000 claims abstract description 39
- 239000007924 injection Substances 0.000 claims abstract description 39
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 23
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- 235000019438 castor oil Nutrition 0.000 claims abstract description 15
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 15
- -1 polyoxyethylene Polymers 0.000 claims abstract description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 14
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- 150000003839 salts Chemical class 0.000 claims abstract description 11
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229920001983 poloxamer Polymers 0.000 claims abstract description 3
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- 238000002156 mixing Methods 0.000 claims description 13
- 229960000987 paricalcitol Drugs 0.000 claims description 11
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 claims description 11
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- 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 8
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 claims description 4
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- 239000003963 antioxidant agent Substances 0.000 claims description 3
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- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims 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 claims 2
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- 235000019333 sodium laurylsulphate Nutrition 0.000 abstract description 2
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- 239000012490 blank solution Substances 0.000 description 18
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- 230000000052 comparative effect Effects 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 10
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- 240000007653 Pometia tomentosa Species 0.000 description 4
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
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- 229940067596 butylparaben Drugs 0.000 description 4
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000000849 parathyroid Effects 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 201000002980 Hyperparathyroidism Diseases 0.000 description 2
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
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- 238000000502 dialysis Methods 0.000 description 2
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- 230000000144 pharmacologic effect Effects 0.000 description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
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- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- RZNUIYPHQFXBAN-XLIONFOSSA-N 2-[4-[(3s)-3-[[(1r)-1-naphthalen-1-ylethyl]amino]pyrrolidin-1-yl]phenyl]acetic acid Chemical compound C([C@@H](C1)N[C@H](C)C=2C3=CC=CC=C3C=CC=2)CN1C1=CC=C(CC(O)=O)C=C1 RZNUIYPHQFXBAN-XLIONFOSSA-N 0.000 description 1
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- 239000004471 Glycine Substances 0.000 description 1
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- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
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- 239000000556 agonist Substances 0.000 description 1
- 229960002233 benzalkonium bromide Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
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- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
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- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
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Classifications
-
- 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
-
- 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
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Abstract
本发明公开了一种伊万卡塞药物组合物及其制备方法。一种注射用伊万卡塞药物组合物,包含伊万卡塞或其可药用盐,载体和注射用水,所述载体选自乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、十二烷基硫酸钠、聚山梨酯、泊洛沙姆、聚维酮中的一种或多种。本发明提供的伊万卡塞组合物,稳定性良好,制备方法简单可行,工艺可控,工业化可操作性强,这为开发伊万卡塞注射液奠定了良好的基础。
Description
技术领域
本发明涉及药物制剂领域,涉及一种伊万卡塞药物组合物及其制备方法。
背景技术
继发性甲状旁腺功能亢进症是慢性肾脏病(CKD)常见的并发症之一,主要是由于慢性肾脏病发展过程中维生素D激活受损,使血钙减少,进而导致的甲状旁腺激素(PTH)过量分泌。
伊万卡塞,是一种芳基烷基胺化合物的新型CaR激动剂,化学名为(4-{(3S)-3-[(1R)-1-(萘-1-基)乙基氨基]吡咯烷-1-基}苯基)乙酸〔4-{(3S)-3-[(1R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl}phenyl acetic acid〕,化学结构如下。伊万卡塞作用于甲状旁腺细胞表面的Ca受体,抑制PTH分泌,降低血液中PTH的浓度,进而缓解症状,此外,伊万卡塞还能调节PTH的生物合成和甲状旁腺细胞增殖,控制PTH的生成。
伊万卡塞水溶性较差,口服生物利用度较低,目前主要通过添加赋形剂,提高药物的溶解度,改善药物的稳定性。CN108135883是日本协和发酵麒麟株式会社的伊万卡塞药物组合物专利,公开了含有芳基烷基胺化合物的药物组合物,该药物组合物主要为口服固体制剂,可作为甲状旁腺功能亢进症等的预防或治疗药有用的芳基烷基胺化合物、且可被允许作为药品的稳定的药物组合物。
目前用于透析患者的甲状旁腺功能亢进症治疗主要为口服制剂,如伊万卡塞药物组合物专利(CN108135883)主要公开了一种口服固体制剂,西那卡塞口服片剂,CN1946382是安进公司已上市的药物Sensipar的制剂专利,主要公开了一种包含盐酸西那卡塞和微晶纤维素的口服制剂。然而,静脉注射对透析患者的用药依从性好,能够有效减小口服给药引起的胃肠道副反应。难溶性药物制成注射液存在析出风险,注射给药后可能会造成药物浓度降低,药效减弱或延迟的现象,因此,急需提高伊万卡塞的水溶性和稳定性,制成一种可供注射用的制剂用于缓解继发性甲状旁腺功能亢进症。
发明内容
本发明的目的是提供一种可注射的伊万卡塞药用组合物及其制备方法,通过添加适宜的药物辅料来提高伊万卡塞的溶解度和稳定性,。
一种注射用伊万卡塞药物组合物,包含伊万卡塞或其可药用盐,载体和注射用水,所述载体选自乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、十二烷基硫酸钠、聚山梨酯、泊洛沙姆、聚维酮中的一种或多种。
作为本发明所述的药物组合物的优选,所述的载体选自乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇、聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12、聚氧乙烯蓖麻油、聚氧乙烯40氢化蓖麻油,更优选聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12、聚氧乙烯40氢化蓖麻油中的一种或多种。
作为本发明所述的药物组合物的优选,所述的伊万卡塞药物组合物或其可药用盐浓度为0.05-80mg/ml,优选0.1-8mg/ml。
作为本发明所述的药物组合物的优选,所述的乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇所占比例为1%-40%(v/v),优选2%-20%(v/v)。
作为本发明所述的药物组合物的优选,所述的聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12、聚氧乙烯40氢化蓖麻油所占比例为0.05%-20%(w/v),优选0.05%-10%(w/v),最优选0.05%-8%(w/v)。
作为本发明所述的药物组合物的优选,含有其他辅料,所述辅料包含抗氧剂、抑菌剂、渗透压调节剂、pH调节剂中的一种或几种。
作为本发明所述的药物组合物的进一步优选,抗氧剂选自但不限于维生素C、亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠及半胱氨酸中的一种或几种,所占比例为0.1%-0.2%。
作为本发明所述的药物组合物的进一步优选,抑菌剂选自但不限于苯扎溴铵、苯甲醇、尼泊金甲酯、尼泊金丁酯及苯酚中的一种或几种,所占比例为0.02%-0.06%。
作为本发明所述的药物组合物的进一步优选,渗透压调节剂选自但不限于葡萄糖和氯化钠中的一种或几种。
作为本发明所述的药物组合物的进一步优选,pH调节剂选自但不限于盐酸、枸橼酸、枸橼酸钠、磷酸、醋酸、甘氨酸、酒石酸、酒石酸钠、磷酸氢二钾、磷酸氢二钠、氢氧化钠中的一种或几种。
作为本发明所述的药物组合物的优选,其所述组合物的pH值为2.0~10.0,优选3.0~9.0。
作为本发明所述的药物组合物的优选,所述的药物组合物还包含维生素D类似物,维生素D类似物与伊万卡塞有药理相互作用,可促进药物吸收,有效作用于甲状旁腺细胞表面的Ca受体,增强伊万卡塞的药理活性,所述维生素D类似物选自骨化三醇、胆骨化醇、阿法骨化醇、帕立骨化醇,优选帕立骨化醇。
作为本发明所述的药物组合物的优选,伊万卡塞或其可药用盐与维生素D类似物的质量比例为5000:1-30000:1,优选10000:1-20000:1。
本发明所述的注射用伊万卡塞药物组合物的制备方法,其特征在于包括:取载体分散于注射用水中,制得空白溶剂,然后取空白溶剂,加入所述的其他辅料,混合均匀,再加入伊万卡塞,搅拌过夜,搅拌过程进行充氮气保护,即可制得组合物溶液。
作为本发明制备方法的一种优选,加入所述的其他辅料的同时加入所述的维生素D类似物。
本发明任一所述药物组合物可制成注射用无菌粉末。
本发明所述的无菌粉末,含有赋形剂,所述赋形剂选自蔗糖、乳糖、麦芽糊精、甘露醇、山梨醇、聚乙烯吡咯烷酮K30、聚乙烯吡咯烷酮K12、聚乙二醇、右旋糖酐中的一种或多种,优选蔗糖、乳糖、麦芽糊精、甘露醇、山梨醇、聚乙烯吡咯烷酮K12中的一种或多种。
本发明所述的无菌粉末的制备方法,包括以下步骤:
a)将伊万卡塞或其可药用盐溶解在载体溶液中得含有伊万卡塞或其可药用盐的载体溶液;
b)将其他辅料和赋形剂加入所述的含有伊万卡塞或其可药用盐的载体溶液中;
c)将上一步得到的溶液冷冻干燥,制得无菌粉末。
所述的制备方法还优选在载体溶液中加入维生素D类似物。
有益效果:
一种可供注射用的伊万卡塞药物组合物及其制备方法,本发明提供的伊万卡塞组合物,利用载体材料与伊万卡塞药物分子间形成的相互作用,极大地提高药物在水中的分散性,可有效改善伊万卡塞的溶解性,并通过干燥工艺将注射用伊万卡塞固态化,能够有效提高伊万卡塞药物组合物的长期稳定性,制备方法简单可行,工艺可控,工业化可操作性强,这为开发伊万卡塞注射液奠定了良好的基础。
具体实施方式
以下为本发明的具体实施方式,所述具体实施例是为了对本发明作进一步说明,但不作为对发明的限制。
对比例1
取1000ml注射用水,加入7g氯化钠、1g亚硫酸氢钠、0.5g尼泊金甲酯、1μg帕立骨化醇以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。
对比例2
取1000ml注射用水,加入7g氯化钠、1g焦亚硫酸钠、0.5g尼泊金丁酯、5μg帕立骨化醇以及适量磷酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。
对比例3
取1000ml注射用水,加入7g氯化钠、1.5g维生素C、0.5g苯甲醇、5μg帕立骨化醇、40g甘露醇以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例1
取泊洛沙姆188分散于注射用水中,制得浓度为2%的空白溶液,然后取1000ml空白溶液,加入1g伊万卡塞,搅拌过夜,搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。
实施例2
取聚山梨酯20分散于注射用水中,制得浓度为0.1%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.5g焦亚硫酸钠、0.5g尼泊金甲酯、100μg胆骨化醇、适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜,搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。
实施例3
取聚山梨酯80分散于注射用水中,制得浓度为8%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1g焦亚硫酸钠、0.5g尼泊金丁酯、100μg胆骨化醇、适量磷酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜,搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。
实施例4
取聚维酮K12分散于注射用水中,制得浓度为0.05%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.2g亚硫酸氢钠、0.3g尼泊金甲酯、80μg阿法骨化醇、30g山梨醇以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例5
取聚山梨酯20分散于注射用水中,制得浓度为4%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.2g维生素C、0.5g苯甲醇、50μg帕立骨化醇、60g乳糖以及适量酒石酸和酒石酸钠,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例6
取聚氧乙烯40氢化蓖麻油分散于注射用水中,制得浓度为2%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.2g维生素C、0.5g尼泊金甲酯、50μg阿法骨化醇、50g甘露醇以及适量枸橼酸和枸橼酸钠,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例7
取丙三醇分散于注射用水中,制得浓度为20%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.2g亚硫酸氢钠、0.6g尼泊金丁酯、50μg帕立骨化醇、45g麦芽糊精以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例8
取丙二醇分散于注射用水中,制得浓度为2%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、1.2g维生素C、0.4g尼泊金甲酯、75μg帕立骨化醇、40g甘露醇以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例9
取乙醇分散于注射用水中,制得浓度为10%的空白溶液,然后取1000ml空白溶液,加入7g氯化钠、2g焦亚硫酸钠、0.4g苯甲醇、90μg帕立骨化醇、40g甘露醇以及适量盐酸,搅拌10min混合均匀,再加入1g伊万卡塞,搅拌过夜搅拌过程进行充氮气保护,经0.22μm微孔滤膜过滤后即可制得组合物溶液。将组合物溶液分装于西林瓶中,经冷冻干燥后充氮、加塞、轧盖、密闭即可制得伊万卡塞注射用无菌粉末。
实施例10
采用无菌注射用水分散对比例3和实施例4-9中制备的无菌粉末,即可重新制得药物组合物溶液,将溶液置于室温下放置1h,考察其稳定性。
表1实施例研究
有关物质检测方法参考专利CN 108135883 A:
检测器:紫外分光光度计(测定波长:220nm);
色谱柱:L-column2(CERI)4.6mm I.D.×150mm;
柱温:40℃;
流动相A:水/乙腈/三氟乙酸(1900/100/1);
流动相B:乙腈/水/三氟乙酸(1800/200/1);
流动相A:流动相B=79:21;
流速:1.0mL/min。
分别考察样品的性状、pH值和有关物质等,其中对比例1-3的样品放置后有少量白色沉淀物析出,而实施例1-9的样品为澄清透明,表明本发明的药物组合物能够有效提高伊万卡塞的溶解性,此外样品的有关物质含量均低于0.5%,表明本发明的药物组合物稳定性良好,可为伊万卡塞注射制剂提供较好的方案。
实施例10稳定性研究
将对比例1-3和实施例1-9的样品分别置于25℃±2℃/60%RH±5%RH条件下24个月(长期试验)、40℃±2℃/75%RH±5%RH放置3个月(加速试验)后的稳定性,其中无菌粉末用无菌注射用水复溶,研究结果如表2和表3所示。
表2长期试验稳定性
样品 | 性状 | pH值 | 有关物质 |
对比例1 | 白色沉淀析出 | 6.35 | 1.50% |
对比例2 | 白色沉淀析出 | 6.50 | 1.80% |
对比例3 | 白色沉淀析出 | 6.46 | 1.74% |
实施例1 | 澄清透明 | 5.90 | 1.06% |
实施例2 | 澄清透明 | 6.10 | 0.95% |
实施例3 | 澄清透明 | 5.80 | 0.33% |
实施例4 | 澄清透明 | 6.05 | 0.43% |
实施例5 | 澄清透明 | 6.20 | 0.68% |
实施例6 | 澄清透明 | 5.93 | 0.41% |
实施例6 | 澄清透明 | 6.04 | 0.47% |
实施例7 | 澄清透明 | 5.96 | 0.50% |
实施例8 | 澄清透明 | 6.22 | 0.42% |
实施例9 | 澄清透明 | 6.02 | 0.55% |
表3加速试验稳定性
样品 | 性状 | pH值 | 有关物质 |
对比例1 | 白色沉淀析出 | 5.95 | 2.50% |
对比例2 | 白色沉淀析出 | 6.65 | 3.80% |
对比例3 | 白色沉淀析出 | 6.58 | 2.96% |
实施例1 | 澄清透明 | 6.10 | 1.15% |
实施例2 | 澄清透明 | 5.85 | 1.04% |
实施例3 | 澄清透明 | 6.25 | 0.73% |
实施例4 | 澄清透明 | 6.40 | 0.63% |
实施例5 | 澄清透明 | 6.05 | 0.62% |
实施例6 | 澄清透明 | 6.12 | 0.76% |
实施例6 | 澄清透明 | 6.06 | 0.69% |
实施例7 | 澄清透明 | 6.14 | 0.54% |
实施例8 | 澄清透明 | 6.18 | 0.62% |
实施例9 | 澄清透明 | 6.24 | 0.48% |
本发明的创造性在于将特定载体与伊万卡塞间形成分子间相互作用,紧密结合,使药物均匀分散在载体溶液中,有效地改善了伊万卡塞水溶性小的缺点,此外,将伊万卡塞组合物制备成注射用无菌粉末,可有效提高制剂的长期稳定性,为实现伊万卡塞注射给药提供可能。
Claims (15)
1.一种注射用伊万卡塞药物组合物,其特征在于包含伊万卡塞或其可药用盐,载体和注射用水,所述载体选自乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、十二烷基硫酸钠、聚山梨酯、泊洛沙姆、聚维酮中的一种或多种。
2.根据权利要求1所述的注射用伊万卡塞药物组合物,其特征在于所述的载体选自乙醇、丙二醇、丙三醇、二甲基亚砜、聚乙二醇、聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12、聚氧乙烯蓖麻油、聚氧乙烯40氢化蓖麻油中的一种或多种,优选聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12、聚氧乙烯40氢化蓖麻油中的一种或多种。
3.根据权利要求1所述的注射用伊万卡塞药物组合物,其特征在于所述的注射用伊万卡塞药物组合物中伊万卡塞或其可药用盐浓度为0.05-80mg/ml,优选0.1-8mg/ml。
4.根据权利要求1所述的注射用伊万卡塞药物组合物,其特征在于所述的乙醇、丙二醇、丙三醇、二甲基亚砜或聚乙二醇占所述注射用伊万卡塞药物组合物的体积百分比为1%-40%,优选2%-20%。
5.根据权利要求1所述的注射用伊万卡塞药物组合物,其特征在于所述的聚山梨酯20、聚山梨酯80、泊洛沙姆188、聚维酮K12或聚氧乙烯40氢化蓖麻油占所述注射用伊万卡塞药物组合物的质量体积百分比为0.05%-20%,优选0.05%-10%,最优选0.05%-8%。
6.根据权利要求1所述的注射用伊万卡塞药物组合物,其特征在于所述的所述注射用伊万卡塞药物组合物含有其他辅料,所述其他辅料包含抗氧剂、抑菌剂、渗透压调节剂、pH调节剂中的一种或几种。
7.根据权利要求6所述的注射用伊万卡塞药物组合物,其特征在于所述所述注射用伊万卡塞药物组合物的pH值为2.0~10.0,优选3.0~9.0。
8.根据权利要求1-7中任一项所述的注射用伊万卡塞药物组合物,其特征还在于所述的药物组合物还包含维生素D类似物,所述维生素D类似物选自骨化三醇、胆骨化醇、阿法骨化醇、帕立骨化醇,优选帕立骨化醇。
9.根据权利要求8所述的药物组合物,其特征在于:伊万卡塞与维生素D类似物的质量比例为5000:1-30000:1,优选10000:1-20000:1。
10.权利要求6所述的注射用伊万卡塞药物组合物的制备方法,其特征在于包括:取载体分散于注射用水中,制得空白溶剂,然后取空白溶剂,加入所述的其他辅料,混合均匀,再加入伊万卡塞,搅拌过夜,搅拌过程进行充氮气保护,即可制得组合物溶液。
11.根据权利要求10所述的制备方法,其特征在于加入所述的其他辅料的同时加入所述的维生素D类似物。
12.权利要求1-9任一所述药物组合物可制成注射用无菌粉末。
13.权利要求10所述的注射用无菌粉末,其特征在于还含有赋形剂,所述赋形剂选自蔗糖、乳糖、麦芽糊精、甘露醇、山梨醇、聚乙烯吡咯烷酮K30、聚乙烯吡咯烷酮K12、聚乙二醇、右旋糖酐中的一种或多种,优选蔗糖、乳糖、麦芽糊精、甘露醇、山梨醇、聚乙烯吡咯烷酮K12中的一种或多种。
14.权利要求12所述的注射用无菌粉末的制备方法,其特征在于包括以下步骤:
a)将伊万卡塞或其可药用盐溶解在载体中;
b)将其他辅料和赋形剂加入含有伊万卡塞或其可药用盐的溶液中;
c)将溶液冷冻干燥,制得注射用无菌粉末。
15.根据权利要求13所述的制备方法,其特征在于所述的制备方法还包括在载体溶液中加入所述的维生素D类似物。
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