CN116712394B - Injection-use clarithromycin lactobionate preparation, and its preparing process and use - Google Patents
Injection-use clarithromycin lactobionate preparation, and its preparing process and use Download PDFInfo
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- CN116712394B CN116712394B CN202310755605.0A CN202310755605A CN116712394B CN 116712394 B CN116712394 B CN 116712394B CN 202310755605 A CN202310755605 A CN 202310755605A CN 116712394 B CN116712394 B CN 116712394B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 48
- ZEZXVIRBOFKOMW-UHFFFAOYSA-N 3,5-dibromo-2-methylbenzoic acid Chemical compound CC1=C(Br)C=C(Br)C=C1C(O)=O ZEZXVIRBOFKOMW-UHFFFAOYSA-N 0.000 title claims abstract description 16
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims abstract description 56
- 229960002626 clarithromycin Drugs 0.000 claims abstract description 56
- 238000001816 cooling Methods 0.000 claims abstract description 47
- 238000010438 heat treatment Methods 0.000 claims abstract description 45
- 238000001035 drying Methods 0.000 claims abstract description 43
- 238000004108 freeze drying Methods 0.000 claims abstract description 39
- 238000002347 injection Methods 0.000 claims abstract description 34
- 239000007924 injection Substances 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 24
- 238000007710 freezing Methods 0.000 claims abstract description 22
- 230000008014 freezing Effects 0.000 claims abstract description 20
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 6
- 239000008101 lactose Substances 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 claims description 7
- 229940099563 lactobionic acid Drugs 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
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- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000011068 loading method Methods 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 description 30
- 239000000523 sample Substances 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 20
- 238000000137 annealing Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000000859 sublimation Methods 0.000 description 5
- 230000008022 sublimation Effects 0.000 description 5
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000012792 lyophilization process Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010062255 Soft tissue infection Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
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- 238000000227 grinding Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 2
- 206010040872 skin infection Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 206010024971 Lower respiratory tract infections 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
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000004708 ribosome subunit Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 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
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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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- 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a lactose acid clarithromycin preparation for injection and a process and application thereof, wherein the lactose acid clarithromycin preparation for injection is prepared by a freeze-drying process; the freeze-drying process comprises a pre-freezing process and a primary drying process, and specifically comprises the following steps of (1) pre-freezing: 1a) Cooling the clarithromycin solution to-35 to-45 ℃ from normal temperature and keeping for 1-2h; 1b) Heating the sample obtained in the step 1 a) to 2-8 ℃ and keeping the temperature for 6-8h; 1c) Cooling the sample obtained in the step 1 b) to-35 to-45 ℃ and keeping the temperature for 2-4 hours; (2) primary drying. Compared with the prior art, the method has the advantages of short freeze-drying time and low cost, avoids the bottle breaking problem in the freeze-drying process, ensures that the obtained clarithromycin lactobionate is quickly redissolved, has Guan Zazhi less, and provides technical support for improving the quality of the clarithromycin injection.
Description
Technical Field
The invention belongs to the technical field of preparation production, and particularly relates to a lactose acid clarithromycin preparation for injection, a process and application thereof.
Background
Clarithromycin is a macrolide antibiotic that inhibits intracellular protein synthesis by sensitive bacteria by selectively binding to the 50s ribosomal subunit of the sensitive bacteria to prevent the transport of active amino acids. The 14-hydroxy metabolite of clarithromycin is a metabolite of the parent drug and also has antibacterial activity.
The injectable use of clarithromycin lactobionate was originally developed by the yaban company and was marketed in the uk in 1993 for the treatment of respiratory tract infections, skin and soft tissue infections caused by bacteria.
The existing commercial injection clarithromycin product has the defects of long freeze-drying period, easy bottle breakage in the freeze-drying process and poor re-solubility of the freeze-dried clarithromycin due to low solubility of the raw material medicine and large freeze-dried raw liquid. In addition, the impurities of the clarithromycin preparation are mainly introduced by raw materials, the impurity level of the raw materials basically determines the impurity level of the preparation, and the technical problem of how to further reduce the impurity content of the preparation and improve the product quality of the preparation is also faced by enterprises.
According to the search, few reports are about optimizing a sterile freeze-drying process to improve the quality of a lacosaccharide preparation for injection, CN109453125A discloses a freeze-drying process of a bortezomib freeze-dried powder injection, a solvent system of the bortezomib freeze-dried powder injection is acetonitrile-water solution, an annealing step is added in the process, and the specific freeze-drying process comprises the following steps: A. and (3) feeding: feeding to a freeze dryer with the temperature of the plate layer of 4-6 ℃; B. freezing: the temperature of the freeze drying chamber is 4-6 ℃, and the product is pre-frozen for 10-15min; cooling to-55 to-50 ℃, and pre-freezing the product for 3-4 hours; heating to-12 to-8 ℃, and pre-freezing the product for 5-6 hours; cooling to-55 to-50 ℃, and pre-freezing the product for 3-4 hours; C. sublimation drying: regulating the temperature to-45 to-40 ℃ and keeping the temperature for 10-12 hours under vacuum conditions; heating to-2-2deg.C, and maintaining under vacuum for 10-12 hr; D. and (5) desorption and drying: regulating the temperature to 35-45 ℃ and keeping the temperature for 5-6h under vacuum condition; the invention solves the problems of organic solvent residue and bottle spraying in the freeze-drying process through the annealing process and the stepwise control of the temperature and the vacuum degree in the freeze-drying period, and the finished product is better in molding and higher in qualification rate.
The existing freeze-drying process is applied to the production of the injection-use clarithromycin, so that the bottle breaking problem can be reduced to a certain extent, the re-solubility of the preparation is improved, but the drying time is long, the cost is higher, the influence on impurities in the preparation is smaller, and the requirement of improving the product quality cannot be met. Therefore, on the basis of the existing freeze-drying process, a process of the injection clarithromycin preparation, which can improve the quality of the product, is developed more economically and efficiently, and has important significance for the production of the injection clarithromycin preparation.
Disclosure of Invention
In order to solve the technical problems, the invention provides a lactose acid clarithromycin preparation for injection, a process and application thereof. The injection clarithromycin preparation is prepared by prefreezing and primary drying, has short freeze-drying time and low cost, avoids the problem of bottle breaking in the freeze-drying process, has quick re-dissolution of the obtained clarithromycin, has Guan Zazhi less, and provides technical support for improving the quality of the clarithromycin preparation.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation of the lacosaccharide for injection is prepared by a freeze-drying process; the freeze-drying process comprises a pre-freezing process and a primary drying process, and specifically comprises the following steps:
(1) Pre-freezing:
1a) Cooling the clarithromycin solution to-35 to-45 ℃ from normal temperature and keeping for 1-2h;
1b) Heating the sample obtained in the step 1 a) to 2-8 ℃ and keeping the temperature for 6-8h;
1c) Cooling the sample obtained in the step 1 b) to-35 to-45 ℃ and keeping the temperature for 2-4 hours;
(2) And (5) primary drying.
According to the invention, the pre-freezing is added with an annealing step, and during annealing, the ice layer changes in morphology to be in a semitransparent state, so that the structure is more uniform, larger crystals are formed after partial melting and recrystallization are carried out in the ice layer, the sublimation channel is also enlarged, the bottle breaking phenomenon is effectively improved, and the drying efficiency, the re-dissolution speed and the stability of a finished product are improved.
Preferably, the cooling rate in step 1 a) is 1.0-5.0 ℃/min; further preferably 2.0-3.0deg.C/min.
Preferably, in the step 1 a), the temperature is reduced to-37 to-40 ℃.
Preferably, the rate of temperature increase in step 1 b) is 1.0-2.0 ℃/min; further preferably 1.2-1.5 deg.C/min.
The temperature rise in step 1 b) is to 5-6 ℃.
Preferably, the cooling rate in step 1 c) is 0.5-1.5 ℃/min; further preferably 1.0-1.2 ℃/min.
Preferably, in the step 1 c), the temperature is reduced to-37 to-40 ℃.
The freeze-drying process only comprises one stage, and the sublimation efficiency is improved, the drying process time is shortened, and the secondary drying step is omitted by accurately controlling the relation among the drying temperature, the heating rate and the vacuum degree in the drying process.
Preferably, the primary drying in step (2) includes: heating the sample obtained in the step 1 c) to 10-20 ℃ at a heating rate of 0.5-1.5 ℃/min under the condition of vacuum degree of 0.10-0.50mbar, and keeping for 26-28h.
Further preferably, the step of primary drying is: and (3) heating the sample obtained in the step (1 c) to 15 ℃ at a heating rate of 1.0-1.2 ℃/min under the condition of vacuum degree of 0.30-0.40mbar, and keeping for 26.5-27h.
The invention also provides a preparation process of the injection-use clarithromycin preparation, which comprises the following steps:
s1, sterilizing and filtering a clarithromycin lactobionate liquid medicine, and filling the liquid medicine into a container;
s2, pre-freezing and drying the container for loading the clarithromycin flux by adopting the freeze-drying process to obtain clarithromycin freeze-dried powder;
and S3, sealing a container loaded with the clarithromycin freeze-dried powder to obtain the clarithromycin injection.
Preferably, the clarithromycin flux of lactobionic acid in step S1 is 45-55% of the volume of the container.
The invention also provides the application of the injection-use clarithromycin preparation or the injection-use clarithromycin preparation prepared by the preparation process in preparing medicaments for treating infections caused by clarithromycin-sensitive pathogenic bacteria, and the medicaments are particularly suitable for severe patients.
In particular, the infections include, but are not limited to, lower respiratory tract infections, upper respiratory tract infections, skin and soft tissue infections.
Unless otherwise specified, the "clarithromycin solution of lactobionic acid" described in the present invention is an aqueous solution of clarithromycin of lactobionic acid and is adjusted to pH 4.5 to 5.5 by means of the lactobionic acid solution.
Compared with the prior art, the invention has the beneficial effects that:
(1) The injection-use clarithromycin preparation is prepared by a freeze-drying process, and the annealing process in the pre-freezing stage can obtain larger crystals, so that larger pore channels are formed after drying, the bottle breaking phenomenon is effectively improved, and the drying efficiency, the re-dissolution speed and the stability of a finished product are improved; in the primary drying stage, the relation among the drying temperature, the heating rate and the vacuum degree in the drying process is accurately controlled, so that the sublimation efficiency is improved, the drying process time is shortened, the secondary drying step is omitted, and the cost is saved.
(2) Experiments show that the total impurity content of related substances in the clarithromycin can be controlled below 0.54% by controlling the pre-freezing temperature, the annealing temperature, the heating and cooling rate and other technological parameters.
(3) The injection prepared by the invention has shorter redissolution time, fewer related impurities and better product quality compared with the original ground product.
Drawings
FIG. 1 is a diagram of the relevant materials of the product of example 1; wherein: 1 is impurity L,2 is impurity D,3 is clarithromycin and 4 is impurity E.
FIG. 2 is a diagram of the related substances of the original ground product; wherein, 1 is impurity A,2 is impurity C,3 is impurity D,4 is clarithromycin, 5 is impurity E,6 is impurity F,7 is impurity G,8 is impurity H.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes embodiments of the present invention in conjunction with specific embodiments. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
The invention does not limit the sources of the adopted raw materials, and if no special description exists, the adopted raw materials are all common commercial products in the technical field.
Method for detecting substance
Liquid chromatography conditions: octadecylsilane chemically bonded silica is used as filler (Kromasil 100-3.5-C18 column, 4.6 mm. Times.100 mm,3.5 μm or equivalent efficacy column); 4.76g/L potassium dihydrogen phosphate solution (pH adjusted to 4.4 with 10% phosphoric acid solution or 4.5% potassium hydroxide solution) and acetonitrile (75:25) were used as mobile phase A, and 4.76g/L potassium dihydrogen phosphate solution (pH adjusted to 4.4 with 10% phosphoric acid solution or 4.5% potassium hydroxide solution) and acetonitrile (40:60) were used as mobile phase B; gradient elution was performed as in table 1; column temperature 40 ℃; a detection wavelength of 205nm; the flow rate is 1.1ml per minute; and the sample injection volume is 10 mu l.
TABLE 1 elution gradient
Taking a proper amount of the product, adding a diluting agent (50% acetonitrile water solution) for dissolving and quantitatively diluting to prepare a solution containing about 1.5mg of the product in each 1ml of the product, and taking the solution as a test sample solution; taking a proper amount of the product, adding a diluting agent (50% acetonitrile water solution) for dissolving and quantitatively diluting to prepare a solution containing about 1.5mg of the product in each 1ml of the product, and taking the solution as a reference substance solution; the product was taken in an appropriate amount, dissolved in a diluent (50% acetonitrile aqueous solution) and quantitatively diluted to prepare a solution containing about 1.5mg per 1ml as a system applicability solution. In the system applicability solution, the peak-to-valley ratio of the impurity D to the clarithromycin peak should be not less than 3.0.
Precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. The sample solution chromatograms have impurity peaks (blank solvent peak and chromatographic peaks before impurity I and after impurity H are not counted), the content of each impurity is calculated according to an external standard method of adding correction factors, the limit requirement of table 2 is met by each impurity, less than 4 impurities exceeding 0.4%, the total impurities are less than 3.5%, and the report limit is 0.1%.
TABLE 2 relative retention time, correction factor and limit for each impurity
The preparation method of the injection-use clarithromycin preparation adopted in the embodiment of the invention comprises the following steps: slowly adding 250kg of water for injection into a liquid preparation tank, slowly stirring at 25-30 ℃ under the condition that the water temperature is controlled, slowly adding 29.58kg of clarithromycin lactobionate (equivalent to 20kg of clarithromycin) into the liquid preparation tank in 4 batches, and then adding 30kg of water for injection to wash the wall of the liquid preparation tank; after the raw materials are completely dispersed, slowly dripping 15% lactobionic acid solution, adjusting the pH to 5.0, fixing the volume to 400kg, sterilizing, filtering, filling into a 20ml penicillin bottle, filling the liquid medicine with the volume of 10g, freeze-drying, taking out from a box, and capping to obtain the injection lactobionic acid clarithromycin preparation with the specification of 500 mg.
The effect of the freeze-drying process on the quality of the injectable clarithromycin lactose preparation is examined by combining different freeze-drying processes.
Example 1 preparation of Clarithromycin lactobionate for injection and preparation process thereof
The freeze-drying of the injectable clarithromycin formulation in this example was accomplished by a two-step process of prefreezing and primary drying, specifically,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-35deg.C at cooling rate of 5.0deg.C/min and maintaining for 1 hr;
1b) Heating the sample obtained in the step 1 a) to 2 ℃ at a heating rate of 1.0 ℃/min and keeping for 6 hours;
1c) Cooling the sample obtained in the step 1 b) to-35 ℃ at a cooling speed of 0.5 ℃/min and keeping for 2 hours.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 20℃for 26h at a heating rate of 0.5℃per minute under a vacuum of 0.50 mbar.
Example 2 preparation of Clarithromycin lactobionate for injection and preparation process thereof
The freeze-drying of the injectable clarithromycin formulation in this example was accomplished by a two-step process of prefreezing and primary drying, specifically,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-40deg.C at cooling rate of 2.0deg.C/min and maintaining for 1.5 hr;
1b) Heating the sample obtained in the step 1 a) to 5 ℃ at a heating rate of 1.5 ℃/min and keeping for 7 hours;
1c) Cooling the sample obtained in the step 1 b) to-40 ℃ at a cooling speed of 1.0 ℃/min and keeping for 3 hours.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 15℃for 27h at a heating rate of 1.0℃per minute under a vacuum of 0.30 mbar.
Example 3 preparation of Clarithromycin lactobionate for injection and preparation process thereof
The freeze-drying of the injectable clarithromycin formulation in this example was accomplished by a two-step process of prefreezing and primary drying, specifically,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-45deg.C at cooling rate of 1.0deg.C/min and maintaining for 2 hr;
1b) Heating the sample obtained in the step 1 a) to 8 ℃ at a heating rate of 2.0 ℃/min and keeping for 8 hours;
1c) Cooling the sample obtained in the step 1 b) to-45 ℃ at a cooling speed of 1.5 ℃/min and keeping for 4 hours.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 10℃for 28h at a heating rate of 1.5℃per minute under a vacuum of 0.10 mbar.
Example 4 preparation of Clarithromycin lactobionate for injection and preparation process thereof
The freeze-drying of the injectable clarithromycin formulation in this example was accomplished by a two-step process of prefreezing and primary drying, specifically,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-37deg.C at cooling rate of 3.0deg.C/min and maintaining for 1.5 hr;
1b) Heating the sample obtained in the step 1 a) to 6 ℃ at a heating rate of 1.2 ℃/min and keeping for 7.5h;
1c) Cooling the sample obtained in the step 1 b) to-37 ℃ at a cooling speed of 1.2 ℃/min and keeping for 2.5h.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 15℃for 26.5h at a heating rate of 1.2℃per minute under a vacuum of 0.40 mbar.
Product performance evaluation
The products prepared in examples 1-4 were compared with the as-ground product KLARICID in quality, as shown in Table 3.
Table 3 comparison of examples with quality of raw ground product
Remarks: ND indicates undetected.
The clarithromycin for injection (hereinafter referred to as "product") obtained in examples 1 to 4 of the present invention has a shorter reconstitution time than the original ground product, and the impurity A, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H and total impurities are lower than the original ground product, as shown in Table 3, FIG. 1 and FIG. 2. From the aspect of impurity control, the impurity level of the product obtained by the invention is better than that of the original grinding, the quality controllability is higher, and from the aspect of clinical compliance, the product obtained by the invention has a reconstitution speed faster than that of the original grinding product, and the clinical use is more convenient.
To further verify the technical contribution of the lyophilization process of the present invention to the prior art, the inventors performed performance evaluations for comparative examples 1-4 and example 1, with the results shown in tables 4 and 5.
Comparative example 1 preparation of clarithromycin lactobionate for injection and preparation process thereof
The difference between this comparative example and example 1 is that the lyophilization process of the present invention is replaced by the lyophilization process with reference to CN109453125a, and the specific steps are:
A. and (3) feeding: feeding to a freeze dryer with the plate layer temperature of 5 ℃;
B. freezing: the temperature of the freeze drying chamber is 5 ℃, and the product is pre-frozen for 12min; cooling to-52 ℃, and pre-freezing the product for 3.5 hours; heating to-10deg.C, and pre-freezing for 5.5 hr; cooling to-52 ℃, and pre-freezing the product for 3.5 hours;
C. sublimation drying: regulating the temperature to-42 ℃ and keeping the temperature for 11h under vacuum condition; heating to 0deg.C, and maintaining under vacuum condition for 11 hr;
D. and (5) desorption and drying: the temperature was adjusted to 40℃and kept under vacuum for 5.5h.
Comparative example 2 preparation of clarithromycin lactobionate for injection and preparation process thereof
The difference between this comparative example and example 1 is the annealing temperature and time in the pre-freezing in the freeze-drying process, specifically:
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-35deg.C at cooling rate of 5.0deg.C/min and maintaining for 1 hr;
1b) Heating the sample obtained in the step 1 a) to-4 ℃ at a heating rate of 1.0 ℃/min and keeping for 10 hours;
1c) Cooling the sample obtained in the step 1 b) to-35 ℃ at a cooling speed of 0.5 ℃/min and keeping for 2 hours.
Comparative example 3 preparation of clarithromycin lactobionate for injection and preparation process thereof
The present comparative example is different from example 1 in that the cooling rate and the heating rate of the pre-freeze in the freeze-drying process are different, and the degree of vacuum and the heating rate of the primary drying, in particular,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-35deg.C at cooling rate of 0.5 deg.C/min and maintaining for 1 hr;
1b) Heating the sample obtained in the step 1 a) to 2 ℃ at a heating rate of 3 ℃/min and keeping for 6 hours;
1c) Cooling the sample obtained in the step 1 b) to-35 ℃ at a cooling speed of 2 ℃/min and keeping for 2 hours.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 20℃for 26h at a heating rate of 0.2℃per minute under a vacuum of 0.60 mbar.
Comparative example 4 preparation of clarithromycin lactobionate for injection and preparation process thereof
The present comparative example is different from example 1 in that the cooling rate and the heating rate of the pre-freeze in the freeze-drying process are different, and the degree of vacuum and the heating rate of the primary drying, in particular,
(1) Prefreezing, comprising the following steps:
1a) Cooling the liquid medicine from normal temperature (20deg.C) to-35deg.C at cooling rate of 6deg.C/min and maintaining for 1 hr;
1b) Heating the sample obtained in the step 1 a) to 2 ℃ at a heating rate of 0.5 ℃/min and keeping for 6 hours;
1c) Cooling the sample obtained in the step 1 b) to-35 ℃ at a cooling speed of 0.3 ℃/min and keeping for 2 hours.
(2) The primary drying comprises the following specific steps: the sample obtained in step 1 c) was heated to 20℃for 26h at a heating rate of 2℃per minute under a vacuum of 0.080 mbar.
Table 4 comparison of the physicochemical results of the examples and examples
| Product information | Freeze-drying phenomenon | Moisture content | Time of reconstitution |
| Example 1 | Bottle without breaking | 0.5% | 1 min 12 s |
| Comparative example 1 | Bottle without breaking | 0.7% | 5 minutes 05 seconds |
| Comparative example 2 | Bottle without breaking | 0.8% | 4 minutes 54 seconds |
| Comparative example 3 | Broken bottle | 3.4% | 2 minutes 32 seconds |
| Comparative example 4 | Broken bottle | 2.8% | 3 minutes 07 seconds |
As can be seen from comparative example 1, the conventional freeze-drying process can solve the problem of bottle breakage, but the reconstitution time of the prepared product is long, and the original ground product level cannot be achieved. In the technical scheme of the invention, the conventional annealing process (the annealing temperature is-4 ℃ C. And the time is 10 hours) is adopted in the pre-freezing process, so that the bottle breaking problem can be solved, but the re-dissolution time is longer, as shown in comparative example 2; when the pre-freezing cooling rate, the heating rate and the primary drying vacuum degree and the heating rate are adjusted to be different, the re-dissolution time of the product can be shortened, but the water content is higher, and the bottle breaking problem cannot be solved, as shown in comparative examples 3 and 4.
Table 5 comparison of results of substances related to examples and comparative examples
By examining the matters related to comparative examples 1 to 4, it was found that: the conventional freeze-drying process has great influence on related substances of the product, and cannot reach the level of the original ground product, as shown in comparative example 1. When the factors such as the annealing temperature, the heating and cooling rate and the like are changed, the content of related substances in the product can be controlled to be about 2, and the content of the related substances is not greatly different from that of the original ground product, as shown in comparative examples 2-4.
According to the invention, through the improvement of the freeze-drying process, the bottle breaking phenomenon is improved, the re-dissolution speed of the product is improved, the production cost is reduced, the impurity level of the product can be effectively controlled, and the technical support is provided for improving the quality of the injection-use clarithromycin lactobionate preparation.
Claims (6)
1. The preparation of the lacosaccharide for injection is prepared by a freeze-drying process; the method is characterized in that the freeze-drying process comprises a pre-freezing process and a primary drying process, and specifically comprises the following steps:
(1) Pre-freezing:
1a) Cooling the clarithromycin solution to-35 to-45 ℃ from normal temperature and keeping for 1-2h;
1b) Heating the sample obtained in the step 1 a) to 2-8 ℃ and keeping the temperature for 6-8h;
1c) Cooling the sample obtained in the step 1 b) to-35 to-45 ℃ and keeping the temperature for 2-4 hours;
(2) Primary drying;
the cooling speed in the step 1 a) is 1.0-5.0 ℃/min; the temperature rising speed in the step 1 b) is 1.0-2.0 ℃/min; the cooling speed in the step 1 c) is 0.5-1.5 ℃/min;
the primary drying step comprises the following steps: heating the sample obtained in the step 1 c) to 10-20 ℃ at a heating rate of 0.5-1.5 ℃/min under the condition of vacuum degree of 0.10-0.50mbar, and keeping for 26-28h;
the clarithromycin solution in step 1 a) is an aqueous solution of clarithromycin and is adjusted to a pH of 4.5-5.5 with a lactobionic acid solution.
2. The formulation of clarithromycin for injection according to claim 1, wherein said rate of decrease in temperature in step 1 a) is from 2.0 to 3.0 ℃/min; and the temperature is reduced to-37 to-40 ℃.
3. The formulation of clarithromycin for injection according to claim 1, wherein said rate of temperature rise in step 1 b) is from 1.2 to 1.5 ℃/min; the temperature is raised to 5-6 ℃.
4. The formulation of clarithromycin for injection according to claim 1, wherein said rate of decrease in temperature in step 1 c) is from 1.0 to 1.2 ℃/min.
5. The formulation of clarithromycin for injection according to claim 1, wherein said primary drying step is: heating the sample obtained in the step 1 c) to 15 ℃ at a heating rate of 1.0-1.2 ℃/min under the condition of vacuum degree of 0.30-0.40mbar, and keeping for 26.5-27h.
6. The preparation process of the lactose acid clarithromycin preparation for injection is characterized by comprising the following steps:
s1, sterilizing and filtering a clarithromycin lactobionate liquid medicine, and filling the liquid medicine into a container;
s2, pre-freezing and primary drying a container for loading the clarithromycin flux, by adopting the freeze-drying process in the clarithromycin preparation for high-quality injection according to any one of claims 1-5, to obtain clarithromycin freeze-dried powder;
and S3, sealing a container loaded with the clarithromycin freeze-dried powder to obtain the clarithromycin injection.
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| CN104586791A (en) * | 2014-12-25 | 2015-05-06 | 海南卫康制药(潜山)有限公司 | Clarithromycin composition freeze-dried tablet and preparation method thereof |
| CN108078930A (en) * | 2017-11-24 | 2018-05-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of injection nicorandil freeze-dried injection and preparation method thereof |
| CN113173956A (en) * | 2021-04-26 | 2021-07-27 | 广东金城金素制药有限公司 | Preparation method of clarithromycin lactobionate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104586791A (en) * | 2014-12-25 | 2015-05-06 | 海南卫康制药(潜山)有限公司 | Clarithromycin composition freeze-dried tablet and preparation method thereof |
| CN108078930A (en) * | 2017-11-24 | 2018-05-29 | 扬子江药业集团北京海燕药业有限公司 | A kind of injection nicorandil freeze-dried injection and preparation method thereof |
| CN113173956A (en) * | 2021-04-26 | 2021-07-27 | 广东金城金素制药有限公司 | Preparation method of clarithromycin lactobionate |
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