CN107951846A - 一种注射用赖氨匹林冻干粉及其制备方法 - Google Patents
一种注射用赖氨匹林冻干粉及其制备方法 Download PDFInfo
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- lysine
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- 239000007924 injection Substances 0.000 title claims abstract description 43
- 238000002347 injection Methods 0.000 title claims abstract description 43
- 239000000843 powder Substances 0.000 title claims abstract description 40
- 239000004472 Lysine Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 15
- 239000003381 stabilizer Substances 0.000 claims abstract description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 16
- 239000000872 buffer Substances 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group 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
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- -1 sorbierite Chemical compound 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 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 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 238000005261 decarburization Methods 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 239000008215 water for injection Substances 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000012982 microporous membrane Substances 0.000 claims description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 2
- HXMWJLVXIHYART-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide;hydrochloride Chemical group [OH-].[Na+].Cl.OC(=O)CC(O)(C(O)=O)CC(O)=O HXMWJLVXIHYART-UHFFFAOYSA-M 0.000 claims description 2
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 240000004307 Citrus medica Species 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 235000009508 confectionery Nutrition 0.000 claims 1
- BYTCDABWEGFPLT-UHFFFAOYSA-L potassium;sodium;dihydroxide Chemical compound [OH-].[OH-].[Na+].[K+] BYTCDABWEGFPLT-UHFFFAOYSA-L 0.000 claims 1
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims 1
- 206010067484 Adverse reaction Diseases 0.000 abstract description 3
- 230000006838 adverse reaction Effects 0.000 abstract description 3
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 6
- 229960004889 salicylic acid Drugs 0.000 description 6
- 239000008354 sodium chloride injection Substances 0.000 description 6
- 239000001509 sodium citrate Substances 0.000 description 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003182 parenteral nutrition solution Substances 0.000 description 3
- 208000001297 phlebitis Diseases 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical class CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 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
- VCMFGDACKBCWDX-UHFFFAOYSA-K dipotassium sodium hydrogen phosphate hydroxide Chemical compound [OH-].[Na+].P(=O)(O)([O-])[O-].[K+].[K+] VCMFGDACKBCWDX-UHFFFAOYSA-K 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
本发明公开了一种注射用赖氨匹林冻干粉，其包括如下按照质量百分比计的组分：赖氨匹林65～74％、pH调节剂4～7％和稳定剂14～30％。本发明注射用赖氨匹林冻干粉可有效避免赖氨匹林发生分解，具备较好的稳定性，减少不良反应的发生率，提高临床应用的安全性，具有良好的应用前景和市场价值。本发明还公开了一种注射用赖氨匹林冻干粉的制备方法。
Description
技术领域
本发明属于制药领域，更具体地说，本发明涉及一种具有良好稳定性的注射用赖氨匹林冻干粉及其制备方法。
背景技术
赖氨匹林，化学名DL-赖氨酸单[2-(乙酰氧基)苯酸钾]盐，是乙酰水杨酸的DL-赖氨酸盐，临床主要用于发热及轻、中度的疼痛。
赖氮匹林在水中具有很好的溶解度，可供注射给药，从而避免口服引起的胃肠道副作用，并提高疗效，但赖氨匹林在贮存过程中较不稳定，易发生分解，导致水解生成的游离水杨酸含量超过质量标准的限度要求。由于游离水杨酸对人体有刺激性和致命性，导致出现用药后刺激性和致命性的不良反应增加，严重时出现肌肉坏死或严重的过敏反应，甚至危及生命，直接影响其生产与临床应用。
另外，赖氨匹林吸湿性较强，置于空气中易吸附水蒸气使含水量增加，其分解受湿度的影响较大，降解速率加快、含量变低。国内目前尚无有关克服注射用赖氨匹林应用时分解不稳定的文献或专利报道。
发明内容
本发明的目的在于：克服现有赖氨匹林存在的容易分解、稳定性较差等问题，提供一种注射用赖氨匹林冻干粉及其制备方法。
为了实现上述发明目的，本发明提供了一种注射用赖氨匹林冻干粉，其包括如下按照质量百分比计的组分：赖氨匹林65～74％、pH调节剂4～7％和稳定剂14～30％。
优选地，上述注射用赖氨匹林冻干粉包括如下按照质量百分比计的组分：赖氨匹林68～73％、pH调节剂5～7％和稳定剂20～27％。
优选地，所述pH调节剂选自枸橼酸-磷酸氢二钠组成的缓冲剂、枸橼酸-柠檬酸钠组成的缓冲剂、枸橼酸-氢氧化钠-盐酸组成的缓冲剂、醋酸-醋酸钠组成的缓冲剂、磷酸二氢钠-磷酸氢二钠组成的缓冲剂、磷酸氢二钾-氢氧化钠组成的缓冲剂中的任意一组；所述稳定剂选自甘露醇、甘氨酸、山梨醇、甘油、葡萄糖、海藻糖、蔗糖中的一种或几种。
更优选地，选择枸橼酸-磷酸氢二钠组成的缓冲液作为pH调节剂，选择甘露醇作为稳定剂。
作为本发明注射用赖氨匹林冻干粉的最优选择：其包括如下按照质量百分比计的组分：赖氨匹林70％、枸橼酸3％-磷酸氢二钠3％组成的缓冲剂和甘露醇24％。
为了实现上述发明目的，本发明还提供了上述注射用赖氨匹林冻干粉的制备方法，其包括如下步骤：
S1、在注射用水中加入赖氨匹林和稳定剂，无菌条件下搅拌使其溶解；
S2、加入活性炭吸附脱色，然后过滤脱碳；
S3、加入pH调节剂，将pH调节至4.0～7.0，用0.228～0.45μm的无菌微孔滤膜过滤2～3次；
S4、将过滤后的药液进行冷冻干燥，得到注射用赖氨匹林冻干粉；
其中，所述冷冻干燥的方法如下：
将所述过滤后的药液装入载药瓶中，置于冻干箱-40±5℃预冻2～4h，药液冻结后，开启冷凝器，当冷凝器温度达到-50℃时，调节真空度达到10Pa，保持1h，然后加热，使药品温度为10～20℃，保持6～10h；最后将药品升温至35～40℃，真空保温干燥6～8h。
相对于现有技术，本发明具有如下有益效果：
本发明提供的注射用赖氨匹林冻干粉通过添加了pH调节剂和稳定剂，并制备成冻干粉制剂，具有较好的稳定性，可避免高温和水分对赖氨匹林的影响，减少不良反应的发生率，提高临床应用的安全性，具有良好的应用前景和市场价值。
具体实施方式
为了使本发明的目的、技术方案和有益技术效果更加清晰，以下结合实施例，对本发明进行进一步详细说明。应当理解的是，本说明书中描述的实施例仅仅是为了解释本发明，并非为了限定本发明，实施例的参数、比例等可因地制宜做出选择而对结果并无实质性影响。
实施例1
制备15组(A组～O组)注射用赖氨匹林冻干粉，各组分及用量如下所示。根据下方A组～O组的组分和用量，将赖氨匹林和稳定剂溶解于1000ml注射用水中，加入活性炭吸附脱色，然后过滤脱碳。用pH调节剂调节pH值至4.0～7.0，用0.228μm-0.45μm的无菌微孔滤膜过滤2-3次。每组液体分装于1000支玻璃瓶中，放入冻干箱中预冻，温度为-40±5℃，时间为3小时；药品冻结后，开启冷凝器，冷凝器温度达到-50℃时，开启真空系统，使系统真空度达10Pa，维持1小时；启动加热装置，使药品温度保持在10-20℃，时间为8小时；再将药品升温至35-40℃，真空保温干燥8小时，得到注射用赖氨匹林冻干粉。
A组：赖氨匹林900g，枸橼酸37g，磷酸氢二钠39g，甘露醇308g。
B组：赖氨匹林250g，枸橼酸10g，枸橼酸钠11g，甘氨酸87g。
C组：赖氨匹林900g，枸橼酸34g，磷酸氢二钠35g，甘露醇276g。
D组：赖氨匹林250g，枸橼酸11g，枸橼酸钠12g，甘露醇67g。
E组：赖氨匹林900g，枸橼酸45g，磷酸氢二钠43g，甘氨酸350g。
F组：赖氨匹林258g，磷酸二氢钠14g，磷酸氢二钠13g，甘氨酸111g。
G组：赖氨匹林900g，磷酸二氢钠36g，磷酸氢二钠40g，甘露醇373g。
H组：赖氨匹林250g，枸橼酸7g，磷酸氢二钠8g，甘露醇105g。
I组：赖氨匹林900g，醋酸38g，醋酸钠40g，山梨醇365g。
J组：赖氨匹林300g，磷酸氢二钾10g，氢氧化钠13g，甘油85g。
K组：赖氨匹林900g，枸橼酸25g，氢氧化钠26g，盐酸25g，海藻糖358g。
L组：赖氨匹林250g，枸橼酸11g，磷酸氢二钠14g，葡萄糖91g。
M组：赖氨匹林900g，枸橼酸43g，枸橼酸钠46g，蔗糖360g。
N组：赖氨匹林250g，枸橼酸10g，磷酸氢二钠14g，甘露醇61g，葡萄糖26g。
O组：赖氨匹林900g，枸橼酸38g，枸橼酸钠41g，甘氨酸251g，葡萄糖107g。
实施例2
对实施例1中15组注射用赖氨匹林冻干粉进行不同条件下的稳定性考察。取15组注射用赖氨匹林冻干粉，在高温60℃或光照4500lx条件下放置10天，测定第0天、5天、10天注射用赖氨匹林冻干粉的外观、溶液颜色、pH值、有关物质(水杨酸)、含量指标。检测溶液颜色、pH值、有关物质(水杨酸)、含量指标时，用注射用水5或18ml溶解实施例1中的一瓶(赖氨匹林含量0.25、0.9g)，配制成为赖氨匹林注射液50mg/ml。实施例1中15组注射用赖氨匹林冻干粉的检测结果详见表2、表3、表4。在15组注射用赖氨匹林冻干粉中，A-G、L、N-O组注射用赖氨匹林冻干粉更稳定，在不同条件下放置10天，其溶液颜色、pH值、含量变化较小，A、C、N组的外观状态最好，放置10天后仍保持白色疏松状；H-K、M组注射用赖氨匹林冻干粉不稳定，K组在不同条件下放置10天，其有关物质(水杨酸)不合格，其含量变化较大。
表2 15组注射用赖氨匹林冻干粉在0天条件下的稳定性
表3 15组注射用赖氨匹林冻干粉在高温60℃条件下5天和10天的稳定性
表4 15组注射用赖氨匹林冻干粉在光照4500Lx条件下5天和10天的稳定性
实施例3
将实施例1A-O组溶于0.9％氯化钠注射液中，配制成的赖氨匹林注射液可直接临床给药。如表5所示，通过测本发明注射用赖氨匹林冻干粉A-O组与市售的赖氨匹林(无任何辅料添加)，在0.9％氯化钠注射液中不同时间的pH变化、有关物质(水杨酸)、含量变化，以判断赖氨匹林组合物因水解不稳定带来的安全性问题。如表5所示，注射用赖氨匹林冻干粉A-O组与0.9％氯化钠注射液配伍后，溶液pH降低速度减缓，配伍15分钟后，溶液pH均在4.0左右，且含量变化小，A-O组有关物质均符合要求；而市售的赖氨匹林配伍15分钟后，溶液pH＜4.3，含量变化较大，其中A、C、N组pH变化和含量变化均较小；市售的赖氨匹林在配伍1小时后出现有关物质变化较大，而A-I、L-O组有关物质均低于市售组。A、C、H、L、N组溶液在1小时后，溶液pH仍大于5，减少了静脉炎风险；A组溶液含量变化更小，与0.9％氯化钠注射液配伍更稳定。因此本发明的注射用赖氨匹林冻干粉能有效减少赖氨匹林水解造成溶液pH较大的变化，进而降低了注射液pH＜4带来的静脉炎风险；同时减小赖氨匹林的含量变化，使赖氨匹林与0.9％氯化钠注射液配伍更稳定。
表5注射用赖氨匹林冻干粉A-O组与市售药物在0.9％氯化钠注射液中的稳定性比较
综上所述，本发明所制备的注射用赖氨匹林组合物稳定性好、安全性高，能防止赖氨匹林水解造成pH、含量的变化，有关物质得到有效控制，能降低临床应用时发生的静脉炎风险，能增强临床配伍时的稳定性。
根据上述说明书的揭示和教导，本发明所属领域的技术人员还可以对上述实施方式进行适当的变更和修改。因此，本发明并不局限于上面揭示和描述的具体实施方式，对本发明的一些修改和变更也应当落入本发明的权利要求的保护范围内。此外，尽管本说明书中使用了一些特定的术语，但这些术语只是为了方便说明，并不对本发明构成任何限制。
Claims (9)
1.一种注射用赖氨匹林冻干粉，其特征在于，包括如下按照质量百分比计的组分：赖氨匹林65～74％、pH调节剂4～7％和稳定剂14～30％。
2.根据权利要求1所述的注射用赖氨匹林冻干粉，其特征在于，包括如下按照质量百分比计的组分：赖氨匹林68～73％、pH调节剂5～7％和稳定剂20～27％。
3.根据权利要求1所述的注射用赖氨匹林冻干粉，其特征在于，所述pH调节剂选自枸橼酸-磷酸氢二钠组成的缓冲剂、枸橼酸-柠檬酸钠组成的缓冲剂、枸橼酸-氢氧化钠-盐酸组成的缓冲剂、醋酸-醋酸钠组成的缓冲剂、磷酸二氢钠-磷酸氢二钠组成的缓冲剂、磷酸氢二钾-氢氧化钠组成的缓冲剂中的任意一组。
4.根据权利要求3所述的注射用赖氨匹林冻干粉，其特征在于，所述pH调节剂为枸橼酸-磷酸氢二钠组成的缓冲剂。
5.根据权利要求4所述的注射用赖氨匹林冻干粉，其特征在于，包括如下按照质量百分比计的组分：赖氨匹林70％、pH调节剂6％和稳定剂24％；其中，所述pH调节剂为枸橼酸3％-磷酸氢二钠3％组成的缓冲剂。
6.根据权利要求1所述的注射用赖氨匹林冻干粉，其特征在于，所述稳定剂选自甘露醇、甘氨酸、山梨醇、甘油、葡萄糖、海藻糖、蔗糖中的一种或几种。
7.根据权利要求6所述的注射用赖氨匹林冻干粉，其特征在于，所述稳定剂为甘露醇。
8.权利要求1～7中任意一条权利要求所述注射用赖氨匹林冻干粉的制备方法，其特征在于，包括如下步骤：
S1、在注射用水中加入赖氨匹林和稳定剂，无菌条件下搅拌使其溶解；
S2、加入活性炭吸附脱色，然后过滤脱碳；
S3、加入pH调节剂，将pH调节至4.0～7.0，用0.228～0.45μm的无菌微孔滤膜过滤2～3次；
S4、将过滤后的药液进行冷冻干燥，得到注射用赖氨匹林冻干粉；
其中，所述冷冻干燥的方法如下：
将所述过滤后的药液装入载药瓶中，置于冻干箱-40±5℃预冻2～4h，药液冻结后，开启冷凝器，当冷凝器温度达到-50℃时，调节真空度达到10Pa，保持1h，然后加热，使药品温度为10～20℃，保持6～10h；最后将药品升温至35～40℃，真空保温干燥6～8h。
9.根据权利要求8所述注射用赖氨匹林冻干粉的制备方法，其特征在于，所述pH调节至4.5～6.5。
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