JP5004964B2 - 再溶解後の改善された安定性を有する凍結乾燥ピペラシリンナトリウムの調製方法 - Google Patents
再溶解後の改善された安定性を有する凍結乾燥ピペラシリンナトリウムの調製方法 Download PDFInfo
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- JP5004964B2 JP5004964B2 JP2008543801A JP2008543801A JP5004964B2 JP 5004964 B2 JP5004964 B2 JP 5004964B2 JP 2008543801 A JP2008543801 A JP 2008543801A JP 2008543801 A JP2008543801 A JP 2008543801A JP 5004964 B2 JP5004964 B2 JP 5004964B2
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- piperacillin
- tazobactam
- acid
- sodium
- sodium bicarbonate
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- 238000000034 method Methods 0.000 title claims abstract description 35
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 title claims description 70
- 229960005264 piperacillin sodium Drugs 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000004090 dissolution Methods 0.000 title description 22
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 60
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims abstract description 51
- 229960003865 tazobactam Drugs 0.000 claims abstract description 50
- 229960002292 piperacillin Drugs 0.000 claims abstract description 49
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 30
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 30
- 238000007872 degassing Methods 0.000 claims abstract description 15
- 238000004108 freeze drying Methods 0.000 claims abstract description 14
- 238000010979 pH adjustment Methods 0.000 claims abstract description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 86
- 239000002253 acid Substances 0.000 claims description 53
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 43
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 43
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000011859 microparticle Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 claims description 5
- 238000011146 sterile filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- 230000015572 biosynthetic process Effects 0.000 description 25
- NBXPLBPWMYNZTC-IDYPWDAWSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 NBXPLBPWMYNZTC-IDYPWDAWSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 22
- 239000006260 foam Substances 0.000 description 17
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 15
- 239000002245 particle Substances 0.000 description 14
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 10
- 238000006731 degradation reaction Methods 0.000 description 10
- 229960000373 tazobactam sodium Drugs 0.000 description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- LITBAYYWXZOHAW-XDZRHBBOSA-N (2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]hept Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 LITBAYYWXZOHAW-XDZRHBBOSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 239000002738 chelating agent Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 229940104641 piperacillin / tazobactam Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000007664 blowing Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000013618 particulate matter Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012931 lyophilized formulation Substances 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000376 reactant Substances 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
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 206010003011 Appendicitis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010060803 Diabetic foot infection Diseases 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- 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 1
- 208000036209 Intraabdominal Infections Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034576 Peripheral ischaemia Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010040867 Skin hypertrophy Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229940126574 aminoglycoside antibiotic Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003952 β-lactams Chemical class 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(発明の概要)
驚くべきことに、凍結乾燥に先立って、ピペラシリンナトリウム(単独でまたはタゾバクタムナトリウムと混合して)の溶液から二酸化炭素を低濃度まで十分に除去することにより、所望のpH値にpHを調整する整合性のある方法が得られ、従って、再溶解溶液の放置後の粒子形成の問題が克服されることが見出された。
凍結乾燥に先立つピペラシリンおよびタゾバクタム溶液のpH値の調整は、凍結乾燥された製品の再溶解後の沈澱 および粒子形成を避けるために最も重要である。
a)反応が異なった程度で停止される。
A)重炭酸ナトリウムおよび/または炭酸塩を水に懸濁した酸ピペラシリン、場合により、酸タゾバクタム上に添加する、
B)酸ピペラシリンを水に溶解した重炭酸ナトリウムおよび/または炭酸塩上に、ついで場合によりタゾバクタムを全体の上に添加する、
C)重炭酸ナトリウムおよび/または炭酸塩、酸ピペラシリンおよび酸タゾバクタムを水の上に添加する、のいずれかを選択する。
それぞれの選択肢に対して、複数の温度、攪拌速度および時間条件が調査されてきた。
・溶解が完全でない
・低温で行えない
・強い泡の形成が避けられない
第一の問題点は、それが、pH調整における慣性の潜在的な問題の根源であるので重要である。酸ピペラシリンが、重炭酸ナトリウムおよび/または炭酸塩の限られた量と反応する時、当該反応の最後の部分におけると同様、反応は非常に遅い。
・低温を含め、種々の温度で行い得る。
・溶解が完全である。
・泡の形成が円滑である。
i.酸ピペラシリン(単独でまたはタゾバクタムと混合して)を重炭酸ナトリウムおよび/または炭酸ナトリウムとの反応により、水に溶解する段階、
ii.200mg/L未満の二酸化炭素含量まで脱ガスする段階、
iii.5.6と7.9の間の値にpHを調整する段階、
iv.凍結乾燥の段階、
を含む、再溶解溶液の改善された安定性を有する凍結乾燥ピペラシリンナトリウム(単独でまたはタゾバクタムと混合して)の製造方法が提供される。
肉眼では見えない粒子含量
実験方法
溶液の安定性試験(SST)
ピペラシリンナトリウム2.35gまたはピペラシリンナトリウム/タゾバクタムナトリウム(8:1)の混合物2.35gを30mLのバイアルに入れる。水10.0mLを加え、バイアルに栓をし、全体が溶液になるまで振とうする。
T:透明
O:乳白色
P:沈澱
異なる含量(2.25g、3.375g、4.5g)のピペラシリンナトリウム/タゾバクタムナトリウム(8:1)の凍結乾燥粉末をバイアルに入れる。その粉末を振とうし、水の等量(10,15,20mL)を注射器でバイアルに加える。透明な溶液が観察されるまでの時間を測定する。
pH測定器/イオン測定器の組み合わせを用いる。
イオン測定器は1−1000mgCO2/Lの範囲で目盛がつけられている。
(参考例)
脱ガスなし
1Lの攪拌された反応器中に、水109mL、ピペラシリン(11.2cMol)1水和物60.00gおよびタゾバクタム7.24g(2.4cMol)を装填する。よく攪拌して、重炭酸ナトリウム11.43(13.6cMol)を1時間かけて一部ずつ装填する。攪拌を30分続け、必要に応じて、ピペラシリン1水和物(PIP)または重炭酸ナトリウム(BIC)の添加により、pHを5.5と7.0の間の値に調整する。ついで、その溶液を凍結乾燥する。
Claims (14)
- i.酸ピペラシリン(単独でまたはタゾバクタムと混合して)を、重炭酸ナトリウムおよび/または炭酸ナトリウムとの反応により、水に溶解する段階、
ii.200mg/L未満の二酸化炭素含量まで脱ガスする段階、
iii.5.6および7.9の間の値へのpH調整段階、
iv.凍結乾燥の段階、
を含む、再溶解溶液の向上した安定性を有する凍結乾燥されたピペラシリンナトリウム(単独でまたはタゾバクタムと混合して)の製造方法。 - 凍結乾燥に先立って、滅菌ろ過を更に含む、請求項1に記載の方法。
- 酸、即ち、酸ピペラシリン(単独でまたはタゾバクタムと混合して)に関して、塩基(即ち、重炭酸ナトリウムおよび/または炭酸ナトリウム)のほぼ同等のモル量が用いられる、請求項1または2のいずれかに記載の方法。
- 酸ピペラシリンおよび酸タゾバクタムに関して、重炭酸ナトリウムのほぼ同等のモル量が用いられる、請求項1または2のいずれかに記載の方法。
- 酸、即ち、酸ピペラシリン(単独でまたはタゾバクタムと混合して)が、15℃を超えない温度で水に溶解した塩基(即ち、重炭酸ナトリウムおよび/または炭酸ナトリウム)上に加えられる、請求項1から4のいずれかに記載の方法。
- 酸ピペラシリンおよび酸タゾバクタムが、5および9℃の間の温度で、水に溶解した重炭酸ナトリウム上に加えられる、請求項1から4のいずれかに記載の方法。
- 脱ガスが、75mg/L未満の二酸化炭素含量まで適用される、請求項1から6のいずれかに記載の方法。
- 脱ガスが、100mBarより低い絶対圧における真空により達成される、請求項1から6のいずれかに記載の方法。
- 脱ガスが、30mBarより低い絶対圧における真空により達成される、請求項1から6のいずれかに記載の方法。
- pHが、6.3および7.1の間の値に調整される、請求項1から6のいずれかに記載の方法。
- ピペラシリンのタゾバクタムに対する割合が、20:1から1:1の範囲内である、請求項1から10のいずれかに記載の方法。
- ピペラシリンのタゾバクタムに対する割合が、8:1である、請求項1から11のいずれかに記載の方法。
- ピペラシリンのタゾバクタムに対する割合が、4:1である、請求項1から11のいずれかに記載の方法。
- 1.0%(重量/重量)より低い水分含量および多くとも50%の微粒子(50μm未満)の量を有する、請求項1に記載の方法により得られるピペラシリンナトリウムおよびタゾバクタムナトリウムの凍結乾燥混合物を含む医薬組成物。
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US74240805P | 2005-12-05 | 2005-12-05 | |
US60/742,408 | 2005-12-05 | ||
PCT/EP2006/069232 WO2007065862A1 (en) | 2005-12-05 | 2006-12-01 | Process for the perparation of lyophilized piperacilline sodium with improved stability after reconstitution |
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CN101269072B (zh) * | 2008-05-09 | 2010-06-02 | 郑飞雄 | 含量稳定的含β-内酰胺酶抑制剂和哌拉西林钠的药物组合物及其制备方法 |
CN101632677B (zh) * | 2009-08-26 | 2013-11-20 | 海南永田药物研究院有限公司 | 一种头孢哌酮钠他唑巴坦钠药物组合物混悬粉针剂及其新应用 |
JP5852316B2 (ja) * | 2010-03-30 | 2016-02-03 | 富山化学工業株式会社 | ピペラシリン含有懸濁液の製造法 |
CN102382123A (zh) * | 2011-03-10 | 2012-03-21 | 海南美好西林生物制药有限公司 | 一种他唑巴坦钠的制备方法 |
CN102228460A (zh) * | 2011-04-12 | 2011-11-02 | 宁辉 | 一种抗菌药物组合物及其制备方法 |
WO2013014544A1 (en) * | 2011-07-25 | 2013-01-31 | Vardhman Chemtech Limited | Method for preparation of composition of piperacillin sodium and tazobactam sodium |
EA028342B1 (ru) | 2011-09-09 | 2017-11-30 | Мерк Шарп И Доум Корп. | Способы лечения пневмонии |
US8476425B1 (en) | 2012-09-27 | 2013-07-02 | Cubist Pharmaceuticals, Inc. | Tazobactam arginine compositions |
DE102012021655B4 (de) | 2012-11-03 | 2023-03-30 | Hof Sonderanlagenbau Gmbh | Verfahren zur Gefriertrocknung eines mit einem Lösungsmittel versehenen, feuchten Produktes |
CN103054818B (zh) * | 2013-01-28 | 2014-03-05 | 苏州二叶制药有限公司 | 一种优质高效的冷冻干燥技术 |
US9872906B2 (en) | 2013-03-15 | 2018-01-23 | Merck Sharp & Dohme Corp. | Ceftolozane antibiotic compositions |
US20140274997A1 (en) | 2013-03-15 | 2014-09-18 | Cubist Pharmaceuticals, Inc. | Cephalosporin pharmaceutical compositions |
NZ700372A (en) * | 2013-03-15 | 2016-01-29 | Merck Sharp & Dohme | Ceftolozane antibiotic compositions |
CN103239454B (zh) * | 2013-05-06 | 2014-11-05 | 齐鲁天和惠世制药有限公司 | 一种注射用哌拉西林钠他唑巴坦钠冻干制剂的生产方法 |
EP3043797B1 (en) | 2013-09-09 | 2020-04-08 | Merck Sharp & Dohme Corp. | Treating infections with ceftolozane/tazobactam in subjects having impaired renal function |
US8906898B1 (en) | 2013-09-27 | 2014-12-09 | Calixa Therapeutics, Inc. | Solid forms of ceftolozane |
CN103550216B (zh) * | 2013-10-30 | 2015-03-11 | 济南康和医药科技有限公司 | 一种哌拉西林钠他唑巴坦钠药物组合物及其制备方法 |
CN104083372A (zh) * | 2014-07-13 | 2014-10-08 | 江苏海宏制药有限公司 | 降低注射用哌拉西林钠他唑巴坦钠有关物质的方法 |
CN106714799A (zh) * | 2014-10-08 | 2017-05-24 | 泽井制药株式会社 | 冷冻干燥制剂的制造方法 |
CN105640959B (zh) * | 2016-01-23 | 2017-03-15 | 阎虎林 | 哌拉西林钠和他唑巴坦钠药物组合物 |
DE102017217415B4 (de) * | 2017-09-29 | 2022-11-10 | OPTIMA pharma GmbH | Verfahren und Vorrichtung zur Gefriertrocknung |
CN112076162A (zh) * | 2020-08-07 | 2020-12-15 | 安徽康正康仁药业有限公司 | 一种注射用哌拉西林钠他唑巴坦钠丙磺舒钠三方冻干制剂 |
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US6900184B2 (en) * | 2003-04-14 | 2005-05-31 | Wyeth Holdings Corporation | Compositions containing pipercillin and tazobactam useful for injection |
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