CN107789323B - Delafloxacin meglumine freeze-dried preparation for injection and preparation method thereof - Google Patents

Delafloxacin meglumine freeze-dried preparation for injection and preparation method thereof Download PDF

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CN107789323B
CN107789323B CN201610777423.3A CN201610777423A CN107789323B CN 107789323 B CN107789323 B CN 107789323B CN 201610777423 A CN201610777423 A CN 201610777423A CN 107789323 B CN107789323 B CN 107789323B
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freeze
injection
meglumine
delafloxacin
preparation
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CN107789323A (en
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李书剑
董其松
臧营
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Lunan Pharmaceutical Group Corp
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a delafloxacin meglumine freeze-dried preparation for injection and a preparation method thereof. The preparation mainly comprises delafloxacin meglumine, absolute ethyl alcohol, 15-hydroxystearic acid polyethylene glycol ester and a pH regulator. The ethanol used in the invention is removed in the freeze-drying process, wherein the usage amount of the 15-hydroxystearic acid polyethylene glycol ester is small, the safety is high, and the clinical application range of the delafloxacin meglumine for injection due to the potential safety problem of the sulfobutyl ether-beta-cyclodextrin is expanded; meanwhile, the product is a loose block, can be quickly dissolved after being added with water, has good re-solubility and stable quality after being stored for a long time.

Description

Delafloxacin meglumine freeze-dried preparation for injection and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a delafloxacin meglumine freeze-dried preparation 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 aqueous solution, and the safety information of cyclodextrin which is an auxiliary material at present is less, and the auxiliary material has certain hemolysis and carcinogenicity and may have unknown more serious toxic and side effects. The national drug evaluation center stipulates that the auxiliary material can be considered to be used when the medicine which is intended to be used for critical diseases and has a short clinical treatment period is not replaced by other means.
Therefore, if the commonly used auxiliary materials in the injection can be adopted, the dosage is as small as possible, and the auxiliary materials with the safety which cannot be ensured such as cyclodextrin and the like are not added, the application range of the delafloxacin meglumine for injection can be enlarged, and meanwhile, the inventor finds that related substances of the delafloxacin meglumine for injection are obviously changed after the delafloxacin meglumine for injection is diluted by 0.9% sodium chloride solution in practical tests, thereby bringing troubles to the clinical preparation of medical personnel and bringing potential safety hazards to the use of patients.
Disclosure of Invention
In order to solve the problems, the invention provides a delafloxacin meglumine freeze-dried preparation for injection, which comprises the following components in percentage by weight: mainly comprises active ingredients of delafloxacin meglumine, absolute ethyl alcohol, 15-hydroxystearic acid polyethylene glycol ester, a pH regulator and water for injection, wherein the absolute ethyl alcohol is removed in the freeze-drying process.
The volume ratio of the 15-hydroxystearic acid polyethylene glycol ester to the ethanol is 1: 3-1: 4, preferably 1: 3.5;
the volume of the mixed solution of the 15-hydroxystearic acid polyethylene glycol ester and the ethanol accounts for 10 to 16 percent of the total volume, and the concentration range is preferably 12 to 14 percent;
the mass ratio of delafloxacin meglumine (calculated by delafloxacin) to meglumine is 1: 0.1-1: 0.5, and preferably 1: 0.25.
The invention further provides a preparation method of the delafloxacin meglumine freeze-dried preparation for injection, which mainly comprises the following steps: weighing absolute ethyl alcohol and 15-hydroxystearic acid polyethylene glycol ester according to the prescription amount, adding a proper amount of water for injection, stirring the solution to be colorless clear liquid, adding delafloxacin meglumine and meglumine according to the prescription amount, stirring until the desfloxacin meglumine and the meglumine are completely dissolved, adjusting the pH value to 6.0-7.0 by using an adjusting agent, fixing the volume, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The concentration of delafloxacin meglumine (calculated by delafloxacin) is 10-40 mg/ml, preferably 25 mg/ml;
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 was 6.5.
The invention also provides a freeze-drying method of the delafloxacin meglumine freeze-dried preparation for injection.
The freeze-drying method is carried out in the following three stages:
1) a pre-freezing stage: placing the filled and half-plugged semi-finished product on a partition board in a freeze-drying machine box for pre-freezing, and enabling the semi-finished product to reach the pre-freezing temperature within the shortest possible time, wherein the pre-freezing temperature range is-35 to-45 ℃ and the time is about 2 to 4 hours; preferably, the prefreezing temperature is-40 ℃, and the prefreezing time is 3 hours;
2) a sublimation drying stage: when the vacuum degree in the drying oven reaches 80 mTorr-120 mTorr, the preferred is 100 mTorr; raising the main drying temperature to-17.5 to-12.5 ℃, preferably to-15 ℃; the time is about 1 to 2 hours, and 1.5 hours is preferred; after the temperature is raised, the heat preservation time is about 8-12 hours, preferably 10 hours;
3) and a re-drying stage: raising the re-drying temperature to 20-30 ℃, preferably 25 ℃; the time is about 2 to 4 hours, preferably 3 hours; and (3) pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for about 5-7 hours, preferably 6 hours to obtain the freeze-dried preparation of the delafloxacin meglumine freeze-dried preparation for injection.
The above object of the present invention has the following advantages:
1. the auxiliary material used in the invention is the conventional auxiliary material in the injection, so that the safety is high, and the clinical application range of the delafloxacin meglumine for injection due to the potential safety problem of sulfobutyl ether-beta-cyclodextrin is expanded;
2. the ethanol in the invention is removed in the freeze-drying process, wherein the use amount of the 15-hydroxystearic acid polyethylene glycol ester is small, the safety of the product is further improved, and meanwhile, the product is in a loose block shape, is rapidly dissolved after being added with water, has good re-solubility and stable quality after long-term storage.
Detailed Description
Example 1:
prescription
Figure BDA0001104482860000021
Figure BDA0001104482860000031
Preparation process
Weighing anhydrous ethanol and 15-hydroxystearic acid polyethylene glycol ester according to the prescription amount, adding into about 700ml of water for injection precooled to room temperature, stirring the solution to be colorless clear liquid, adding delafloxacin meglumine and meglumine according to the prescription amount, stirring until the solution is completely dissolved, adjusting the pH value to 6.0 by using 1M hydrochloric acid solution, fixing the volume to the total amount, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
Freeze-drying curve:
Figure BDA0001104482860000032
example 2:
prescription
Figure BDA0001104482860000033
Preparation method (same as example 1)
Example 3:
prescription
Figure BDA0001104482860000034
Figure BDA0001104482860000041
Preparation method (same as example 1)
Example 4:
prescription
Figure BDA0001104482860000042
Preparation method (same as example 1)
Example 5:
prescription
Figure BDA0001104482860000043
Preparation method (same as example 1)
Example 6:
prescription
Figure BDA0001104482860000044
Figure BDA0001104482860000051
Preparation method (same as example 1)
Example 7:
prescription
Figure BDA0001104482860000052
Preparation method (same as example 1)
Comparative example 1:
prescription
Figure BDA0001104482860000053
Preparation method
Weighing 200.0g of sulfobutyl ether-beta-cyclodextrin according to the prescription amount, adding 700ml of water for injection precooled to room temperature, stirring for dissolving, adding 28.86g of delafloxacin meglumine and 4.88g of meglumine according to the prescription amount, stirring until the components are completely dissolved, adjusting the pH value to 9.0 by using 1M hydrochloric acid solution, fixing the volume to the total amount, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
Freeze-drying curve:
Figure BDA0001104482860000054
Figure BDA0001104482860000061
comparative example 2:
prescription
Figure BDA0001104482860000062
Preparation method (same as example 1)
Comparative example 3:
prescription
Figure BDA0001104482860000063
Preparation method (same as example 1)
Comparative example 4:
prescription
Figure BDA0001104482860000064
Preparation method (same as example 1)
Comparative example 5: meglumine is not added
Prescription
Figure BDA0001104482860000065
Figure BDA0001104482860000071
Preparation method (same as example 1)
Verification examples
1. Test for influencing factor
The finished preparations obtained in the examples 1 to 7 and the comparative examples 1 to 5 of the present invention were placed in a high temperature constant humidity chamber at 60 ℃ and sampled for examining the changes of appearance, pH, moisture, related substances and contents before and after re-dissolution on the 5 th and 10 th days, respectively, and the test results are shown in Table 1
TABLE 1 test results of influence factors (60 ℃ C. at high temperature)
Figure BDA0001104482860000072
Figure BDA0001104482860000081
Remarking: ■ white to off-white lyophilized cake; ● a colorless clear liquid;
according to the influence factor test, the following results are obtained: the samples of examples 1-7 and comparative examples 1-5 were consistent in appearance, pH, moisture, and related substances and contents, all of which did not change significantly in the samples of examples 1-7 and comparative example 1 at a high temperature of 60 ℃ within 10 days.
2. Examples and comparative examples compatibility test with 0.9% sodium chloride solution
The finished preparations obtained in examples 1 to 7 of the present invention and comparative example 1 were dissolved in 250ml of 0.9% sodium chloride solution, and the changes of the relevant substances were examined at 0, 2, 4, 6, and 8 hours, respectively.
Compatibility test investigation results Table 2
Figure BDA0001104482860000082
Figure BDA0001104482860000091
According to the experimental investigation result, the following results are obtained: after the invention is compatible with 0.9% sodium chloride solution, the examples 1-7 of the invention are obviously superior to the finished product preparation obtained in the comparative example 1, and simultaneously, the test with reference to influence factors shows that the advantages of the invention are obviously superior to those of the comparative example, and the advantages of the invention are reflected again.

Claims (10)

1. A delafloxacin meglumine freeze-dried preparation for injection is characterized by mainly comprising active ingredients of delafloxacin meglumine, absolute ethyl alcohol, 15-hydroxystearic acid polyethylene glycol ester and a pH regulator, wherein the absolute ethyl alcohol is removed in the freeze-drying process, and the volume ratio of the 15-hydroxystearic acid polyethylene glycol ester to the ethyl alcohol is 1: 3-1: 4; the preparation process mainly comprises the following steps: weighing absolute ethyl alcohol and 15-hydroxystearic acid polyethylene glycol ester according to the prescription amount, adding a proper amount of water for injection, stirring the solution to be colorless clear liquid, adding delafloxacin meglumine and meglumine according to the prescription amount, stirring until the desfloxacin meglumine and the meglumine are completely dissolved, adjusting the pH value to 6.0-7.0 by using an adjusting agent, fixing the volume, and uniformly stirring; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
2. The freeze-dried preparation of delafloxacin meglumine for injection of claim 1: the method is characterized in that the volume ratio of the 15-hydroxystearic acid polyethylene glycol ester to the ethanol is 1: 3.5.
3. The freeze-dried preparation of delafloxacin meglumine for injection of claim 1: the method is characterized in that the volume of the mixed solution of the 15-hydroxystearic acid polyethylene glycol ester and the ethanol accounts for 10-16% of the total volume.
4. The freeze-dried preparation of delafloxacin meglumine for injection of claim 1: the method is characterized in that the volume of the mixed solution of the 15-hydroxystearic acid polyethylene glycol ester and the ethanol accounts for 12-14% of the total volume.
5. The freeze-dried preparation of delafloxacin meglumine for injection of claim 1: the delafloxacin hydrochloride injection is characterized in that the mass ratio of delafloxacin meglumine to meglumine is 1: 0.1-1: 0.5; wherein the mass of the delafloxacin meglumine is calculated by delafloxacin.
6. The freeze-dried delafloxacin meglumine preparation for injection as claimed in any one of claims 1 to 5, wherein the concentration of delafloxacin meglumine is 10 to 40 mg/ml; wherein the mass of the delafloxacin meglumine is calculated by delafloxacin.
7. The freeze-dried delafloxacin meglumine preparation for injection as claimed in any one of claims 1 to 5, wherein the pH regulator is one or more of hydrochloric acid, phosphoric acid, acetic acid and citric acid.
8. The freeze-dried delafloxacin meglumine preparation for injection as claimed in any one of claims 1 to 5, wherein the pH regulator is hydrochloric acid.
9. The freeze-dried delafloxacin meglumine preparation for injection according to any one of claims 1 to 5, wherein the pH is 6.5.
10. The freeze-dried preparation of delafloxacin meglumine for injection as claimed in any one of claims 1 to 5, wherein the freeze-drying method is carried out in the following three stages:
1) a pre-freezing stage: placing the filled and half-plugged semi-finished product on a partition board in a freeze-drying machine box for pre-freezing, and enabling the semi-finished product to reach the pre-freezing temperature within the shortest possible time, wherein the pre-freezing temperature range is-35 to-45 ℃ and the time is 2 to 4 hours;
2) a sublimation drying stage: the vacuum degree in the drying box reaches 80 mTorr-120 mTorr; raising the temperature of the main drying to-17.5 to-12.5 ℃, wherein the time is about 1 to 2 hours, and the heat preservation time is about 8 to 12 hours after the temperature is raised;
3) and a re-drying stage: raising the re-drying temperature to 20-30 ℃; the time is about 2 to 4 hours; and (3) pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for about 5-7 hours to obtain the freeze-dried preparation of the delafloxacin meglumine for injection.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102215690A (en) * 2008-11-15 2011-10-12 Rib-X制药有限公司 Antimicrobial compositions
WO2014152317A2 (en) * 2013-03-15 2014-09-25 Melinta Therapeutics, Inc. Methods of treating gonorrhea infections using quinolone antibiotics

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102215690A (en) * 2008-11-15 2011-10-12 Rib-X制药有限公司 Antimicrobial compositions
CN104958296A (en) * 2008-11-15 2015-10-07 麦林塔医疗有限公司 Antimicrobial compositions
WO2014152317A2 (en) * 2013-03-15 2014-09-25 Melinta Therapeutics, Inc. Methods of treating gonorrhea infections using quinolone antibiotics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
几种注射用表面活性剂的质量标准及安全性概述;易红等;《中国实验方剂学杂志》;20100131;第16卷(第1期);第115-119页 *

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Inventor after: Li Shujian

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Inventor before: Zhang Guimin

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