CN107789324B - Delaxacin meglumine for injection and preparation method thereof - Google Patents

Delaxacin meglumine for injection and preparation method thereof Download PDF

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CN107789324B
CN107789324B CN201610780347.1A CN201610780347A CN107789324B CN 107789324 B CN107789324 B CN 107789324B CN 201610780347 A CN201610780347 A CN 201610780347A CN 107789324 B CN107789324 B CN 107789324B
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meglumine
injection
delafloxacin
delafloxacin meglumine
cyclodextrin
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CN107789324A (en
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张贵民
董其松
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Lunan Pharmaceutical Group Corp
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4709Non-condensed quinolines and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40Cyclodextrins; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate 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

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to delafloxacin meglumine for injection and a preparation method thereof. The delafloxacin meglumine for injection provided by the invention comprises the following components: mainly comprises delafloxacin meglumine, sulfobutyl ether-beta-cyclodextrin, benzyl benzoate, pH regulator and water for injection. The technical scheme of the invention has small filling amount, is convenient for production and transportation, and simultaneously reduces the medical cost of patients in clinical use; the invention reduces the usage amount of sulfobutyl ether-beta-cyclodextrin, thereby further improving the safety of the product in clinical use.

Description

Delaxacin meglumine for injection and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to delafloxacin meglumine for injection and a preparation method thereof.
Background
Delafloxacin (english name: delafloxacin) is a new generation of broad-spectrum fluoroquinolone antibacterial drugs developed by Rib-X pharmaceutical company, and the results of double-blind phase II clinical studies on 150 patients hospitalized with cSSSIs show that: 300mg and 450mg of the product are injected into the vein every 12 hours for 5 to 14 days, the cure rate of patients with cSSSIS respectively reaches 97.2 percent and 92.5 percent, and the cure rate of tigecycline (tigecycline) group is 91.2 percent. The antibacterial activity of the product to quinolone drug resistant MRSA bacteria is at least 32 times of that of levofloxacin, ciprofloxacin, gatifloxacin and moxifloxacin (the MIC90 of the product is less than or equal to 0.5ug/mL, and the MIC90 of other drugs is more than 16 ug/mL); whereas the antibacterial activity against MRSA is 2 times that of daptomycin.
Chinese patent publication No. CN 103705942A and publication No. CN 104958296A disclose antimicrobial compositions of delafloxacin meglumine for injection, which both utilize the inclusion technology of sulfobutyl ether-beta-cyclodextrin to improve the solubility of delafloxacin in an aqueous solution, so that the solubility of delafloxacin in water reaches 25mg/ml, and because 300mg and 450mg of the delafloxacin meglumine preparation are intravenously injected every 12 hours in clinic, 500mg of the delafloxacin meglumine preparation for injection is preferred to be filled in 20ml, so that containers with more than 60ml are needed for filling, thus not only increasing the treatment cost of patients in clinic use, but also bringing great inconvenience to production and transportation.
Therefore, if the solubility of the delafloxacin meglumine in the aqueous solution can be improved, the loading amount is reduced, and a small-specification container is used for filling, the unit production quantity of the delafloxacin meglumine for injection can be effectively improved, the production speed is accelerated, and the inconvenience in production, transportation and use caused by the overlarge packaging container is solved.
Disclosure of Invention
In view of the above problems, the present invention provides delafloxacin meglumine for injection: mainly comprises active ingredients of delafloxacin meglumine, sulfobutyl ether-beta-cyclodextrin, benzyl benzoate, a pH regulator and water for injection.
The concentration range of the delafloxacin meglumine is 50 mg/ml-100 mg/ml, preferably 75 mg/ml;
the mass ratio of the delafloxacin meglumine to the sulfobutyl ether-beta-cyclodextrin ranges from 1:1.2 to 1:1.6, and is preferably 1: 1.4;
the mass ratio of the benzyl benzoate to the sulfobutyl ether-beta-cyclodextrin is 1: 3-1: 2, preferably 1: 2.5;
the mass ratio of delafloxacin meglumine (calculated by delafloxacin) to meglumine is 1: 0.1-1: 0.5, preferably 1: 0.15;
the pH regulator is one or a mixed solution of more of hydrochloric acid, phosphoric acid, acetic acid or citric acid, and preferably hydrochloric acid;
the pH range is 7.0-8.0, and preferably 7.5.
The invention further provides a preparation method of the delafloxacin meglumine for injection, which mainly comprises the following steps: weighing benzyl benzoate according to the prescription amount, adding the benzyl benzoate into proper amount of water for injection precooled to room temperature, uniformly stirring, adding sulfobutyl ether-beta-cyclodextrin according to the prescription amount, heating and uniformly stirring, adding delafloxacin meglumine and meglumine according to the prescription amount, keeping the temperature and stirring until the materials are completely dissolved, adjusting the pH value, fixing the volume to the total amount, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The above object of the present invention has the following advantages:
1. the invention has small filling amount, uses small-specification penicillin bottles for filling, is convenient for production and transportation, and simultaneously reduces the medical cost of patients in clinical use;
2. because sulfobutyl ether-beta-cyclodextrin has certain hemolytic property and carcinogenicity and may have unknown more serious toxic and side effects, the invention reduces the using amount of sulfobutyl ether-beta-cyclodextrin, thereby further improving the safety of products in clinical use.
Detailed Description
Example 1:
prescription
Figure BDA0001104483040000021
Preparation process
Weighing benzyl benzoate according to the prescription amount, adding a proper amount of water for injection, stirring uniformly, adding sulfobutyl ether-beta-cyclodextrin according to the prescription amount, heating and stirring uniformly, adding delafloxacin meglumine and meglumine according to the prescription amount, keeping the temperature and stirring for 15min until the materials are completely dissolved, adjusting the pH value to 7.0 by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total amount, and stirring uniformly; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
Example 2:
prescription
Figure BDA0001104483040000031
Preparation method (same as example 1)
Example 3:
prescription
Figure BDA0001104483040000032
Preparation method (same as example 1)
Example 4:
prescription
Figure BDA0001104483040000033
Preparation process (same as example 1)
Example 5:
prescription
Figure BDA0001104483040000034
Figure BDA0001104483040000041
Preparation method (same as example 1)
Example 6:
prescription
Figure BDA0001104483040000042
Preparation method (same as example 1)
Example 7:
prescription
Figure BDA0001104483040000043
Preparation method (same as example 1)
Comparative example 1:
prescription
Figure BDA0001104483040000044
Preparation method
Weighing sulfobutyl ether-beta-cyclodextrin with a prescription amount, adding a proper amount of water for injection, stirring for dissolving, adding delafloxacin meglumine and meglumine with the prescription amount, stirring until the desarafloxacin meglumine and the meglumine are completely dissolved, adjusting the pH value to 9.0 by using dilute hydrochloric acid or dilute meglumine solution, fixing the volume to the total amount, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
Comparative example 2:
prescription
Figure BDA0001104483040000051
Weighing benzyl benzoate according to the prescription amount, adding the benzyl benzoate into water for injection, stirring until the benzyl benzoate is dissolved, heating and stirring uniformly, adding delafloxacin meglumine and meglumine according to the prescription amount, keeping the temperature and stirring for 60min, wherein the delafloxacin meglumine is not completely dissolved, adjusting the pH value to 7.5 by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total amount, keeping the temperature and stirring for 60min, and the delafloxacin meglumine is not completely dissolved.
Comparative example 3:
prescription
Figure BDA0001104483040000052
Weighing 45.00g of benzyl benzoate according to the prescription amount, adding the benzyl benzoate into 600ml of injection water precooled to room temperature, stirring until the benzyl benzoate is dissolved, heating and stirring for 15min, adding 75.00g of delafloxacin meglumine and 11.25g of meglumine according to the prescription amount, keeping the temperature and stirring for 60min, wherein the delafloxacin meglumine is not completely dissolved, adjusting the pH value to 9.0 by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total volume, keeping the temperature and stirring for 60min, and the delafloxacin meglumine is not completely dissolved.
Comparative example 4:
prescription
Figure BDA0001104483040000053
Figure BDA0001104483040000061
The preparation method comprises the steps of weighing 105.00g of the formula amount of sulfobutyl ether-beta-cyclodextrin, adding the sulfobutyl ether-beta-cyclodextrin into 600ml of water for injection precooled to room temperature, stirring until the sulfobutyl ether-beta-cyclodextrin is dissolved, heating and stirring for 15min, adding 75.00g of delafloxacin meglumine and 11.25g of meglumine, keeping the temperature and stirring for 60min, wherein the delafloxacin meglumine is not completely dissolved, adjusting the pH value to 7.5 by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total volume, keeping the temperature and stirring for 60min, and the delafloxacin meglumine is not completely dissolved.
Comparative example 5:
prescription
Figure BDA0001104483040000062
The preparation method comprises the steps of weighing 105.00g of the formula amount of sulfobutyl ether-beta-cyclodextrin, adding the sulfobutyl ether-beta-cyclodextrin into 600ml of water for injection precooled to room temperature, stirring until the sulfobutyl ether-beta-cyclodextrin is dissolved, heating and stirring for 15min, adding 75.00g of delafloxacin meglumine and 11.25g of meglumine, keeping the temperature and stirring for 60min, wherein the delafloxacin meglumine is not completely dissolved, adjusting the pH value to 9.0 by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total volume, keeping the temperature and stirring for 60min, and the delafloxacin meglumine is not completely dissolved.
Comparative example 6:
prescription
Figure BDA0001104483040000063
Weighing benzyl benzoate according to the prescription amount, adding a proper amount of water for injection, stirring until the benzyl benzoate is dissolved, heating and stirring for 15min, adding delafloxacin meglumine according to the prescription amount, keeping the temperature and stirring for 60min, adjusting the pH value by using dilute hydrochloric acid or dilute sodium hydroxide solution, fixing the volume to the total amount, keeping the temperature and stirring for 60min, wherein the delafloxacin meglumine is still not completely dissolved.
Verification examples
Test for influencing factor
The finished preparations obtained in the examples 1-7 and the comparative examples 1-6 are placed in a constant temperature and humidity box with the temperature of 25 ℃ and RH 60%, and the change of appearance, pH, moisture, related substances and content before and after re-dissolution is inspected by sampling respectively at 0, 12 and 24 months, and the test results are shown in Table 1
TABLE 1 test results of influence factors (60 ℃ C. at high temperature)
Figure BDA0001104483040000071
Figure BDA0001104483040000081
Remarking: ■ white to off-white lyophilized cake; ● A colorless clear liquid.
Filling in container (penicillin bottle) in one third of the total volume
The mass of delafloxacin-containing meglumine (calculated as delafloxacin) in each bottle was the same (500 mg in each bottle).
According to long-term examination experiments, the following results are obtained: the appearance, pH, moisture, related substances and contents of the samples of examples 1 to 7 and comparative example 1 were consistent and did not change significantly within 24 months. Under the condition that the contents of main drugs are equal, the filling amount is large in comparative example 1, and the used container penicillin bottle is large, so that the production and transportation are not facilitated, and meanwhile, the cost is increased. In contrast, in the comparative examples 2 to 5, the main drug was not completely dissolved during the solution preparation process. The related substances of comparative example 6 were significantly enlarged.

Claims (8)

1. The delafloxacin meglumine for injection is characterized by comprising active ingredients of delafloxacin meglumine, sulfobutyl ether-beta-cyclodextrin, benzyl benzoate, a pH regulator and water for injection; the concentration range of the delafloxacin meglumine is 50 mg/ml-100 mg/ml; the mass ratio of the benzyl benzoate to the sulfobutyl ether-beta-cyclodextrin ranges from 1:3 to 1: 2; the mass ratio of the delafloxacin meglumine to the meglumine is 1: 0.1-1: 0.5; wherein the mass of the delafloxacin meglumine is calculated by delafloxacin.
2. The delafloxacin meglumine for injection as claimed in claim 1, wherein the mass ratio of the delafloxacin meglumine to the sulfobutyl ether-beta-cyclodextrin is 1: 1.2-1: 1.6.
3. The delafloxacin meglumine for injection as claimed in claim 2, wherein the mass ratio of the delafloxacin meglumine to the sulfobutyl ether-beta-cyclodextrin is in the range of 1: 1.4.
4. The delafloxacin meglumine for injection as claimed in claim 1, wherein the mass ratio of the benzyl benzoate to the sulfobutyl ether- β -cyclodextrin is in the range of 1: 2.5.
5. The delafloxacin meglumine for injection as claimed in claim 1, wherein the pH regulator is one or more of hydrochloric acid, phosphoric acid, acetic acid and citric acid.
6. The process for preparing delafloxacin meglumine for injection according to any one of claims 1 to 5, comprising the steps of: weighing benzyl benzoate according to the prescription amount, adding the benzyl benzoate into proper amount of water for injection precooled to room temperature, uniformly stirring, adding sulfobutyl ether-beta-cyclodextrin according to the prescription amount, heating and uniformly stirring, adding delafloxacin meglumine and meglumine according to the prescription amount, keeping the temperature and stirring until the materials are completely dissolved, adjusting the pH value, fixing the volume to the total amount, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
7. The method for preparing delafloxacin meglumine for injection according to claim 6, wherein the pH is 7.0-8.0.
8. The process for the preparation of delafloxacin meglumine for injection according to claim 6, wherein the pH is 7.5.
CN201610780347.1A 2016-08-31 2016-08-31 Delaxacin meglumine for injection and preparation method thereof Active CN107789324B (en)

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CN113413389B (en) * 2021-07-19 2024-03-15 成都赜灵生物医药科技有限公司 Preparation of histone deacetylase inhibitor, preparation method and application thereof
CN113509476B (en) * 2021-07-23 2023-01-13 杭州剂泰医药科技有限责任公司 Ruideciclovir composition and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010096551A2 (en) * 2009-02-18 2010-08-26 Rib-X Pharmaceuticals, Inc. Antimicrobial compositions
CN104958296A (en) * 2008-11-15 2015-10-07 麦林塔医疗有限公司 Antimicrobial compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104958296A (en) * 2008-11-15 2015-10-07 麦林塔医疗有限公司 Antimicrobial compositions
WO2010096551A2 (en) * 2009-02-18 2010-08-26 Rib-X Pharmaceuticals, Inc. Antimicrobial compositions

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