CN101056623A - 稳定的头孢菌素衍生物冻干制剂 - Google Patents
稳定的头孢菌素衍生物冻干制剂 Download PDFInfo
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- CN101056623A CN101056623A CNA2005800384621A CN200580038462A CN101056623A CN 101056623 A CN101056623 A CN 101056623A CN A2005800384621 A CNA2005800384621 A CN A2005800384621A CN 200580038462 A CN200580038462 A CN 200580038462A CN 101056623 A CN101056623 A CN 101056623A
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- pvp
- hydrogen
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Links
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- 239000007864 aqueous solution Substances 0.000 claims description 10
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 4
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- 102000003390 tumor necrosis factor Human genes 0.000 description 2
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
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- 235000014755 Eruca sativa Nutrition 0.000 description 1
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- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
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- 239000004310 lactic acid Substances 0.000 description 1
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- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
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- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- ZNOZEKFDBJRBMI-UHFFFAOYSA-M sodium;4-(2-ethylhexoxy)-4-oxo-3-sulfobutanoate Chemical compound [Na+].CCCCC(CC)COC(=O)C(S(O)(=O)=O)CC([O-])=O ZNOZEKFDBJRBMI-UHFFFAOYSA-M 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000008362 succinate buffer Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- A61K47/26—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
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及稳定性增加了的头孢菌素衍生物冻干制剂、用于获得所述制剂的溶液及制备所述制剂的方法，以及某些化合物用于在冻干制剂中增加头孢菌素衍生物的稳定性的应用。在本发明中优选用作稳定剂的化合物是甘露醇、海藻糖和PVP。
Description
本发明涉及一种稳定性增加了的头孢菌素衍生物冻干制剂、用于获得所述制剂的溶液及制备所述制剂的方法，以及某些化合物用于在冻干制剂中增加头孢菌素衍生物的稳定性的应用。
已知冻干工艺可能对制剂中的药物活性成分的降解有一定的影响，同时对冻干形式的活性成分的稳定性也有很强的影响。影响因素主要包括pH、盐的含量、制剂中赋形剂的种类及含量，以及冷冻过程中的温度、压力和持续时间的选择、升华及干燥的操作。
氨基酸、多羟基化合物经常被用于保持冻干产品的稳定性；但如何获得稳定的冻干药物制剂，现有的大量相关文献并没能给出答案。
更具体地讲，根据文献的教导，在结晶相或非结晶相中存在氨基酸或多羟基化合物如甘露醇虽然有一定的益处，但如果冻干产品包含有比如头孢菌素衍生物之类的特别敏感的活性成分，则有不利之处，会缩短冻干产品的有效期和/或要求低存放温度。
针对人生长激素(hGH)，已经对多羟基化合物和氨基酸的作用分别进行了研究，但对于它们的协同作用并没有给出很好的说明(Pikal M.J.，Dellermann K.M.，Roy M.L.，Riggin M.N.，The effects of formulationvariables on the stability of freeze-dried Human Growth Hormone(制剂成分对冻干人生长激素稳定性的影响)，Pharm.Research.，1991，8，No.4，427-436)。
氨基酸和甘露醇存在的利弊如下：
氨基酸存在的优势：
已被证实，在冻干产品中，甘氨酸的存在在冻干过程的冷冻阶段诱发了溶液中分子的结晶(Korey D.J.，Schwartz J.B.，Effects of excipients onthe crystallization of pharmaceutical compounds during lyophilization(赋形剂在冻干过程中对药物化合物结晶的影响)，J.Parenteral Sci.Tech.，1989，43(2)：80-83)。活性成分的结晶有利于增强其稳定性。
在结晶状态下，丙氨酸有利于阻止冻干产品在升华及干燥过程中的塌陷，或者使冻干产品在生产中具有更大的比表面积，从而使干燥过程更加迅速(Pikal M.J.，Freeze-drying of proteins(蛋白质的冷冻干燥)，Biopharm.，26-30 October 1990)。
氨基酸存在的弊端：
把氨基酸加入要冻干的糖或多羟基化合物的溶液，一般会降低糖的玻璃转化温度(te Booy M.P.W.M.，de Ruiter R.A.，de Meere A.L.J.，Evaluation of the physical stability of freeze-dried sucrose containingformulations by differential scanning calorimetry(通过差式扫描热量法对含有蔗糖的冻干制剂物理稳定性的评估)，Pharm.Research.，1992，9，109-114)。当今普遍认为，玻璃转化温度的降低意味着冻干产品稳定性的下降(Franks F.，Freeze-drying；from empiricism to predictability(冷冻干燥；从经验性的到预测性的)，Cryo-letters，1990，11，93-110)。
甘露醇存在的优势：
在冻干的蛋白产品中存在的甘露醇一般起膨胀剂的作用，即它可以保持冻干产品的固体刚性结构体积与要冻干的溶液的体积相当。但它的存在也可以调节注射前重新配置的溶液的渗透压。当一种冻干蛋白产品以甘露醇作为首要的赋形剂时，它通常以晶体状态存在(Lyophilized formulationsrecombinant tumor necrosis factor(重组肿瘤坏死因子的冻干制剂)，HoraM.S.，Rana R.K.，Smith F.W.，Pharm.Res.，1992，9(1)，33-36)。
甘露醇存在的弊端：
有报道指出，冻干形式的甲泼尼龙琥珀酸钠，当有甘露醇存在时，其水解程度高于乳酸存在的情况，并且当冻干产品中甘露醇的量增加时，水解程度随之增加。这一现象被解释为在冻干过程中，甘露醇结晶的形成改变了冻干产品骨架中水分的分布。由此引起的活性成分微环境中水分的增加加速了活性成分的水解，使其稳定性降低(The effect of bulking agent onthe solid state stability of freeze dried methylprednisolone sodiumsuccinate(膨胀剂对冻干甲泼尼龙琥珀酸钠固态稳定性的影响)，HermanB.D.，Sinclair B.D.，Milton N.，Nail S.L.，Pharma.Res.，1994，11(10)，1467-1473)。
在各种不同的碳水化合物、多羟基醇的水溶液中，头孢菌素衍生物的降解动力学显示，随着羟基化合物浓度的增加，降解也会加速(Theinfluence of carbohydrates and polyhydric alcohols on the stability ofcephalosporins in aqueous solutions(碳水化合物和多羟基醇对头孢菌素水溶液稳定性的影响)，Hans Bundgaard，Claus Larsen，Intl.Journal ofPharmaceutics，October 1983，16，3，319-325)。
另外，在冷冻干燥中，甘露醇通常被用作载体或构成介质，以使冻干产品均匀，稳定并有好的外观。对于非蛋白化合物，特别是头孢菌素衍生物，甘露醇作为稳定剂的作用是未知的(参见，例如Handbook ofpharmaceutical Excipients，Rowe，R.C.，Sheskey，P.J.，Weller，P.J，第4版，Php，Londong，373-377)。
总之，关于不同特性的赋形剂对药物活性成分稳定性的影响，有关科技文献给出的是相互矛盾的信息，也就不能由此获得冻干产品的结构与其稳定性之间的因果关系。同样地，多羟基化合物和氨基酸的作用，无论单独或共同使用，都不能总结出系列规律，但根据所研究的有效成分和赋形剂的用量，观察到了相互矛盾的结果。
基于上述现有技术，本发明的目的是提供一种头孢菌素衍生物的冻干制剂，该制剂在生产和/或后期存放的过程中显示出增加的稳定性。
通过权利要求1的冻干制剂、权利要求14的用于制备冻干制剂的溶液、权利要求15的制备所述制剂的方法、权利要求17的某些稳定剂的应用解决了该问题。
本发明出人意料地发现了某些物质对头孢菌素衍生物冻干制剂具有意想不到的增强稳定性的作用。
因此，本发明涉及冻干产品形式的药物制剂，该制剂至少含有一种头孢菌素衍生物作为活性成分，并且至少含有一种选自碳水化合物、多羟基醇及聚乙烯吡咯烷酮(PVP)的稳定剂。
在本发明的制剂中，头孢菌素衍生物可在25℃或甚至更高的温度下保持稳定，从而增加其有效期。
本发明的制剂对所述头孢菌素衍生物的稳定作用包括在生产过程中所起到的稳定作用。
在特别优选的实施方案中，稳定剂选自甘露醇、海藻糖以及PVP。
本发明中，制剂所含的活性成分可以是单一活性成分，也可以同其他蛋白类或非蛋白类的抗生素活性成分共存。
除了碳水化合物、多羟基醇和/或PVP，制剂还可包含一种或多种选自缓冲剂、氨基酸、调节pH值的酸或碱、表面活性剂、盐、防腐剂、抗氧化剂、螯合剂的化合物。
尽管缓冲剂和氨基酸可能会有附加的稳定作用，但前面提到的其它成分均是常用于冻干制剂的公知的可药用赋形剂。也可加入药物制剂领域的技术人员已知的其它常规添加剂，如矫味剂、染料等。
关于可以加入到本发明制剂中的缓冲剂，可具体提及的是柠檬酸盐、三(羟甲基)氨基甲烷、马来酸盐、琥珀酸盐、酒石酸盐、碳酸盐、碳酸氢盐缓冲剂，以及一元酸缓冲剂，如乳酸盐、氨基乙酸或醋酸盐缓冲系统。可以理解，组成所述缓冲剂的酸和碱还可以单独加入，包括水合物，也可以以其任意组合的形式加入。
关于可以加入到本发明制剂中的表面活性剂，可提及的是聚山梨醇酯、泊洛沙姆、四丁酚醛、卵磷脂。
关于可以加入到本发明制剂中的盐，可以具体提及的是钠盐，例如依地酸钠(EDTA四钠盐)、氯化钠、辛丁酯磺酸钠(1，4-二(2-乙基己基)磺基琥珀酸酯钠)、碳酸氢钠、谷氨酸钠、醋酸钾、碳酸钾和硬脂酸镁。
关于可以加入到本发明制剂中的防腐剂，可以具体提及的是对羟基苯甲酸甲酯和丙酯、氯化苄乙氧铵、硫柳汞、硝酸苯汞、苯甲醇、苯酚和间甲酚。
本发明的制剂可以通过加入适当的溶剂或重构溶液重新配制成液体形式而用于通过胃肠外、肌肉内或口服途径给药，也可以通过口服途径直接给药于人或动物。另外，液体或干燥制剂也可通过吸入给药。
本发明的头孢菌素衍生物包括所有的可药用盐和多晶型以及水合物。此外，术语头孢菌素衍生物也包括药物及前药。
在一个优选的实施方案中，本发明的制剂包含如下通式I的头孢菌素衍生物：
其中：
R1是氢、任选地被氟取代的C1-6-烷基，或者C3-6-环烷基；
R2是氢或选自下列的基团：-CH2(＝CHR)-COOR、-CH2OCOR、-CH(R)OCOR、-CH(R)OCOOR、-CH(OCOR)OCOR、-CH2COCH2OCOR和
R3是氢或选自下列的基团：-CH2C(＝CH2)-COOR、-COOCH2C(＝CHR)-COOR、-COOCH2OCOR、-COOCH(R)OCOR、-COOCH(R)OCOOR、-COOCH(OCOR)OCOR、-COOCH2COCH2OCOR和
条件是R2和R3之一是氢且R2和R3中的另一个不是氢；
R是氢或C1-6-烷基；
R4是氢或羟基；
R5是氢或ω-羟基烷基；且
X是CH或N，
以及所述化合物的可药用盐和多晶型和式I化合物及其盐的水合物。
已知上述结构式I的化合物在制成冻干制剂时存在稳定性的问题，参见欧洲专利EP 1 087 980 B1的描述。
结构式I的化合物中的一个特别优选的例子是(6R，7R)-7-[(Z)-2-(氨基-[1，2，4]噻二唑-3-基)-2-羟基亚氨基-乙酰氨基]-3-[(E)-(3’R，5’R)-5’-羟甲基-1’-(5-甲基-2-氧代-[1，3]二氧杂环戊烯-4-基甲氧基羰基-2-氧代-[1，3’]联吡啶-3-亚基甲基-8-氧代-5-硫杂-1-氮杂-二环[4.2.0]辛-2-烯-2-甲酸，其中R1、R2、R4和R5均为氢，R3为：
且R为甲基。在下文中，该化合物被称为BAL 5788。
本发明的制剂可以通过冻干一种水溶液获得，所述溶液至少含有一种头孢菌素衍生物作为活性成分，并且至少含有一种选自碳水化合物、多羟基醇和PVP的稳定剂。具体地讲，稳定剂选自甘露醇、海藻糖和PVP。
稳定剂在溶液中的浓度范围优选为5-80重量％。具体地讲，甘露醇、海藻糖和PVP的浓度范围为2-40重量％。特别优选的浓度范围是10-25重量％。在本申请中，重量百分比总是指干重。
溶液还可含有可药用的缓冲剂用于进一步稳定和/或用于调节pH值，例如柠檬酸盐、酒石酸盐、碳酸盐、碳酸氢盐、乳酸盐、氨基乙酸、醋酸盐或琥珀酸盐缓冲剂。
优选的pH值范围为2.0至6.5，其中pH值4.0至5.0最佳。
活性成分的量是由其在水溶液中的溶解度决定的。本发明的制剂是通过冷冻干燥水溶液获得的，在该溶液中，活性成分优选是溶解了的。
用于形成本发明制剂的特别优选的溶液含有结构式I的头孢菌素衍生物、稳定剂甘露醇和柠檬酸缓冲水溶液。
用于冷冻干燥的溶液是按照例如如下方法制备的：
将需要量的活性成分、稳定剂、缓冲剂和其它任选的添加剂例如防腐剂在合适的溶解温度下加入到注射用量的水中或增溶所需量的增溶剂中，直到全溶。所得溶液经无菌过滤，灌装到容器中，优选小瓶或胶囊中。
溶液的冷冻干燥可按如下进行：
将溶液进行包含如下过程的循环：冷冻，然后根据冻干的体积和盛放溶液的容器进行升华和干燥。
升华和干燥的时间、温度及压力，需要根据被冻干溶液的体积以及冻干产品中所需的水的残余量进行调整。
本发明将以具体实施例的方式来说明，但这些实施例并不限制本发明的范围。
制备以下的溶液，冻干，所得的制剂对其稳定性进行检测。
溶液A的制备(含有甘露醇)：
溶液A通过将192.0克BAL 5788(合成参照EP-A-1 087 980)和34.38克甘露醇(得自Roquette America，Inc.)溶解于pH为4.2-4.8的氢氧化钠/柠檬酸缓冲液系统(通过将2.18克一水柠檬酸溶于WFI(注射用水)然后用氢氧化钠调节pH值制得)至总重为1389.5克制得。溶液过滤后灌入小瓶。
溶液A的冷冻干燥：
溶液A按下表中所总结的条件冷冻干燥，以获得制剂A：
| 冻干阶段 | 搁板温度℃ | 压力[μbar] |
| 冷冻 | 大约-48 | 常压 |
| 1次干燥 | -40至-30之间 | 大约≤70 |
| 2次干燥 | -30至30之间 | 大约≤70 |
参照溶液B(不含甘露醇)的制备：
按制与溶液A相同的方法制备参照溶液B：将同样量的BAL 5788溶解于同样的氢氧化钠/柠檬酸注射用水缓冲液中，只是不加甘露醇。溶液过滤后灌入小瓶。
参照溶液按上列的条件冻干，获得制剂B。
对由溶液A和溶液B制成的冻干产品进行分析定性，并在不同的温度开始稳定性检测程序。
制剂A和制剂B的成分(标称值)
制剂A的组成(每瓶)：
| 化合物 | 重量[毫克] |
| Bal 5788 | 999.8 |
| 一水柠檬酸 | 15.9 |
| 甘露醇 | 179.1 |
| 氢氧化钠加至 | pH 4.2-4.8 |
| 注射用水 | ≤3％ |
制剂B的组成(每瓶)：
| 化合物 | 重量[毫克] |
| Bal 5788 | 999.8 |
| 一水柠檬酸 | 15.9 |
| 氢氧化钠加至 | pH 4.2-4.8 |
| 注射用水 | ≤3％ |
结果：
与制剂B(不含甘露醇)相比，制剂A(含甘露醇)在生产过程中形成的降解产物的量低约9％。
在储存过程中(5℃，12个月)，由溶液A(含甘露醇)制备的冻干产品中形成的降解产物的量比由溶液B(不含甘露醇)制备的冻干产品在储存过程中形成的量低约10％。
以相同的方式用海藻糖或PVP以及用其他缓冲系统制备了其它制剂。
Claims (18)
1.可药用的头孢菌素衍生物冻干制剂，其至少含有一种头孢菌素衍生物作为活性成分，并且至少含有一种选自碳水化合物、多羟基醇和聚乙烯吡咯烷酮(PVP)的稳定剂。
2.权利要求1所述的冻干制剂，其中的碳水化合物是海藻糖。
3.权利要求1所述的冻干制剂，其中的多羟基醇是甘露醇。
4.权利要求1至3中任意一项所述的冻干制剂，还含有另外一种抗菌活性成分。
5.权利要求1至4中任意一项所述的冻干制剂，还含有一种或多种选自下列的化合物：缓冲剂、氨基酸、调节pH值的酸或碱、表面活性剂、盐、防腐剂、抗氧化剂、螯合剂。
6.权利要求1至5中任意一项所述的冻干制剂，用于重新配制成溶液以通过胃肠外途径、肌肉内途径、口服途径或通过吸入给药；或者用于通过口服途径或通过吸入途径直接给药。
7.权利要求1至6中任意一项所述的冻干制剂，其中的头孢菌素是如下通式I的化合物：
其中：
R1是氢、任选地被氟取代的C1-6-烷基，或者C3-6-环烷基；
R2是氢或选自下列的基团：-CH2(＝CHR)-COOR、-CH2OCOR、-CH(R)OCOR、-CH(R)OCOOR、-CH(OCOR)OCOR、-CH2COCH2OCOR和
R3是氢或选自下列的基团：-CH2C(＝CH2)-COOR、-COOCH2C(＝CHR)-COOR、-COOCH2OCOR、-COOCH(R)OCOR、-COOCH(R)OCOOR、-COOCH(OCOR)OCOR、-COOCH2COCH2OCOR和
条件是R2和R3之一是氢且R2和R3中的另一个不是氢；
R是氢或C1-6-烷基；
R4是氢或羟基；
R5是氢或ω-羟基烷基；且
X是CH或N，
以及所述化合物的可药用盐和多晶型和式I化合物及其盐的水合物。
8.权利要求1至7中任意一项所述的制剂，经过冻干溶液获得，所述溶液含有至少一种头孢菌素作为活性成分，至少一种选自碳水化合物、多元醇和PVP的稳定剂，以及水溶液。
9.权利要求8所述的制剂，其中的稳定剂是甘露醇、海藻糖或PVP。
10.权利要求8或9所述的制剂，其中的水溶液是一种缓冲溶液，优选柠檬酸盐、酒石酸盐、碳酸盐、碳酸氢盐、琥珀酸盐、氨基乙酸、乳酸盐或醋酸盐缓冲液。
11.权利要求8至10中任意一项所述的制剂，其中的水溶液是一元酸缓冲液，例如醋酸盐、氨基乙酸或乳酸盐缓冲液。
12.权利要求8至11中任意一项所述的制剂，其中稳定剂在溶液中的浓度为5-80重量％。
13.权利要求8至12中任意一项所述的制剂，其中溶液的pH值是2.0-6.5，特别是4.0-5.0。
14.用于制备冻干制剂的溶液，其在水溶液中含有至少一种头孢菌素衍生物作为活性成分，至少一种选自甘露醇、海藻糖和PVP的稳定剂。
15.制备头孢菌素衍生物的稳定的可药用冻干制剂的方法，包括两步：
(a)将至少一种选自碳水化合物、多羟基醇和PVP的稳定剂加入头孢菌素衍生物的水溶液中；并且
(b)冻干上述溶液。
16.权利要求15所述的方法，其特征在于加入甘露醇、海藻糖或PVP作为稳定剂。
17.选自碳水化合物、多羟基醇和PVP的化合物用于稳定冻干制剂中的头孢菌素衍生物的用途。
18.根据权利要求17的用途，其特征在于所述化合物是甘露醇、海藻糖和PVP。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04405690A EP1656930A1 (en) | 2004-11-10 | 2004-11-10 | Stabilized freeze-dried formulation for cephalosporin derivatives |
| EP04405690.1 | 2004-11-10 | ||
| PCT/CH2005/000665 WO2006050631A1 (en) | 2004-11-10 | 2005-11-10 | Stabilized freeze-dried formulation for cephalosporin derivatives |
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| Publication Number | Publication Date |
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| CN101056623A true CN101056623A (zh) | 2007-10-17 |
| CN101056623B CN101056623B (zh) | 2011-04-06 |
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| CN2005800384621A Expired - Fee Related CN101056623B (zh) | 2004-11-10 | 2005-11-10 | 稳定的头孢菌素衍生物冻干制剂 |
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| Country | Link |
|---|---|
| US (2) | US20080032962A1 (zh) |
| EP (3) | EP1656930A1 (zh) |
| JP (1) | JP2008519775A (zh) |
| KR (1) | KR20070084150A (zh) |
| CN (1) | CN101056623B (zh) |
| AR (1) | AR052233A1 (zh) |
| AT (1) | ATE468844T1 (zh) |
| AU (1) | AU2005304252B2 (zh) |
| BR (1) | BRPI0517305A (zh) |
| CA (1) | CA2585296A1 (zh) |
| CY (1) | CY1110731T1 (zh) |
| DE (1) | DE602005021530D1 (zh) |
| DK (1) | DK1809253T3 (zh) |
| ES (1) | ES2342833T3 (zh) |
| HR (1) | HRP20100364T1 (zh) |
| MX (1) | MX2007005677A (zh) |
| MY (1) | MY142648A (zh) |
| PL (1) | PL1809253T3 (zh) |
| PT (1) | PT1809253E (zh) |
| RS (1) | RS51380B (zh) |
| SI (1) | SI1809253T1 (zh) |
| TW (1) | TW200630118A (zh) |
| WO (1) | WO2006050631A1 (zh) |
| ZA (1) | ZA200703760B (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716075A (zh) * | 2012-07-03 | 2012-10-10 | 哈药集团制药总厂 | 一种含有头孢唑肟钠的药物组合物 |
| CN102727451A (zh) * | 2012-07-03 | 2012-10-17 | 哈药集团制药总厂 | 一种含有头孢美唑钠的药物组合物 |
| CN103271877A (zh) * | 2012-12-18 | 2013-09-04 | 张宏民 | 一种头孢西丁钠注射剂及其制备方法 |
| CN110507619A (zh) * | 2019-08-19 | 2019-11-29 | 湖北美林药业有限公司 | 注射用头孢哌酮钠及其制备方法 |
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| US20080103121A1 (en) * | 2006-10-30 | 2008-05-01 | Gole Dilip J | Cephalosporin derivative formulation |
| US20100280064A1 (en) * | 2006-12-07 | 2010-11-04 | Tomoyuki Watanabe | Pharmaceutical composition having improved storage stability |
| TWI482641B (zh) | 2006-12-07 | 2015-05-01 | Daiichi Sankyo Co Ltd | 含有低取代度羥丙基纖維素之醫藥組成物 |
| KR20100137439A (ko) * | 2008-03-04 | 2010-12-30 | 엘란 파마 인터내셔널 리미티드 | 항감염제의 안정성 액체 포뮬레이션 및 항감염제의 조정된 용량투여 요법 |
| EP2106788A1 (en) * | 2008-04-04 | 2009-10-07 | Ipsen Pharma | Liquid and freeze dried formulations |
| EP2236520A1 (en) * | 2009-03-31 | 2010-10-06 | Leukocare Ag | Stabilizing composition for immobilized biomolecules |
| US20130089638A1 (en) | 2011-10-11 | 2013-04-11 | Mead Johnson Nutrition Company | Compositions Comprising Maltotriose And Methods Of Using Same To Inhibit Damage Caused By Dehydration Processes |
| BR112015022716A2 (pt) | 2013-03-13 | 2017-07-18 | Theravance Biopharma Antibiotics Ip Llc | sais de cloridrato de um composto antibiótico |
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| JP2690009B2 (ja) * | 1986-07-10 | 1997-12-10 | エーザイ 株式会社 | セフアロスポリン注射剤 |
| DE3801179A1 (de) * | 1988-01-18 | 1989-07-27 | Hoechst Ag | Stabilisierung von cephalosporinderivaten durch trocknung mit einem stabilisator sowie stabile zubereitungsformen mit cephalosporinderivaten |
| ES2059947T3 (es) * | 1989-09-30 | 1994-11-16 | Eisai Co Ltd | Preparados inyectables que contienen cefalosporina y utilizacion de los mismos. |
| JPH0459730A (ja) * | 1990-06-26 | 1992-02-26 | Dai Ichi Seiyaku Co Ltd | セフェム系抗生物質含有凍結乾燥製剤 |
| DK1087980T3 (da) * | 1998-06-15 | 2003-05-26 | Basilea Pharmaceutica Ag | 3-[2-oxo-(1,3')bipyrrolidinyl-3-yliden-methyl]-cephemderivater |
| US7378408B2 (en) * | 2001-11-30 | 2008-05-27 | Pfizer Inc. | Methods of treatment and formulations of cephalosporin |
| AU2003241675A1 (en) * | 2002-06-21 | 2004-01-06 | Shionogi And Co., Ltd. | Medicinal cephem compound composition for injection |
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- 2005-11-09 TW TW094139525A patent/TW200630118A/zh unknown
- 2005-11-10 PL PL05798682T patent/PL1809253T3/pl unknown
- 2005-11-10 JP JP2007540473A patent/JP2008519775A/ja active Pending
- 2005-11-10 WO PCT/CH2005/000665 patent/WO2006050631A1/en active Application Filing
- 2005-11-10 BR BRPI0517305-1A patent/BRPI0517305A/pt not_active IP Right Cessation
- 2005-11-10 RS RSP-2010/0324A patent/RS51380B/en unknown
- 2005-11-10 CN CN2005800384621A patent/CN101056623B/zh not_active Expired - Fee Related
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- 2005-11-10 EP EP05798682A patent/EP1809253B1/en active Active
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- 2005-11-10 AT AT05798682T patent/ATE468844T1/de active
- 2005-11-10 SI SI200531069T patent/SI1809253T1/sl unknown
- 2005-11-10 DK DK05798682.0T patent/DK1809253T3/da active
- 2005-11-10 PT PT05798682T patent/PT1809253E/pt unknown
- 2005-11-10 MX MX2007005677A patent/MX2007005677A/es active IP Right Grant
- 2005-11-10 US US11/667,535 patent/US20080032962A1/en not_active Abandoned
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716075A (zh) * | 2012-07-03 | 2012-10-10 | 哈药集团制药总厂 | 一种含有头孢唑肟钠的药物组合物 |
| CN102727451A (zh) * | 2012-07-03 | 2012-10-17 | 哈药集团制药总厂 | 一种含有头孢美唑钠的药物组合物 |
| CN102727451B (zh) * | 2012-07-03 | 2013-07-03 | 哈药集团制药总厂 | 一种含有头孢美唑钠的药物组合物 |
| CN102716075B (zh) * | 2012-07-03 | 2013-08-21 | 哈药集团制药总厂 | 一种含有头孢唑肟钠的药物组合物 |
| CN103271877A (zh) * | 2012-12-18 | 2013-09-04 | 张宏民 | 一种头孢西丁钠注射剂及其制备方法 |
| CN110507619A (zh) * | 2019-08-19 | 2019-11-29 | 湖北美林药业有限公司 | 注射用头孢哌酮钠及其制备方法 |
| CN110507619B (zh) * | 2019-08-19 | 2021-12-03 | 湖北美林药业有限公司 | 注射用头孢哌酮钠及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2008519775A (ja) | 2008-06-12 |
| PL1809253T3 (pl) | 2010-10-29 |
| KR20070084150A (ko) | 2007-08-24 |
| CY1110731T1 (el) | 2015-06-10 |
| AU2005304252A1 (en) | 2006-05-18 |
| AR052233A1 (es) | 2007-03-07 |
| WO2006050631A1 (en) | 2006-05-18 |
| MY142648A (en) | 2010-12-15 |
| RS51380B (en) | 2011-02-28 |
| TW200630118A (en) | 2006-09-01 |
| CN101056623B (zh) | 2011-04-06 |
| EP1809253B1 (en) | 2010-05-26 |
| US20100160278A1 (en) | 2010-06-24 |
| DK1809253T3 (da) | 2010-07-12 |
| DE602005021530D1 (de) | 2010-07-08 |
| AU2005304252B2 (en) | 2009-07-16 |
| MX2007005677A (es) | 2007-07-20 |
| ATE468844T1 (de) | 2010-06-15 |
| HRP20100364T1 (hr) | 2010-07-31 |
| CA2585296A1 (en) | 2006-05-18 |
| EP2210592A3 (en) | 2011-12-14 |
| PT1809253E (pt) | 2010-09-03 |
| SI1809253T1 (sl) | 2010-09-30 |
| EP2210592A2 (en) | 2010-07-28 |
| ES2342833T3 (es) | 2010-07-15 |
| EP1809253A1 (en) | 2007-07-25 |
| ZA200703760B (en) | 2008-06-25 |
| EP1656930A1 (en) | 2006-05-17 |
| US20080032962A1 (en) | 2008-02-07 |
| BRPI0517305A (pt) | 2008-10-07 |
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