CN1249309A - Gentianate of macrolides antibiotics - Google Patents
Gentianate of macrolides antibiotics Download PDFInfo
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- CN1249309A CN1249309A CN 98120782 CN98120782A CN1249309A CN 1249309 A CN1249309 A CN 1249309A CN 98120782 CN98120782 CN 98120782 CN 98120782 A CN98120782 A CN 98120782A CN 1249309 A CN1249309 A CN 1249309A
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- macrolide antibiotics
- clarithromycin
- gentisate
- macrolide
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Abstract
The present invention relates to the gentianate of macrolides antibiotics (erythromycin, chrestomycin, roxithromycin and azithromycin), the medicinal composition containing it, and the solution-type injection of the lactobionate of macrolides antibiotics.
Description
The present invention relates to the macrolide antibiotics gentisate, contain its pharmaceutical composition and the solution type injection agent of Macrolide Lactobionate.
Macrolide antibiotics all has stronger anti-microbial activity to gram-positive microorganism, hemophilus influenza, Bradley Chinese bacterium, chlamydozoan, mycoplasma and legionella, particularly medicines such as the clarithromycin of developing in recent years, Roxithromycin, azithromycin have overcome the weakness of erythromycin, more acidproof, gastrointestinal side effect is littler, so range of application is wider.Because they are still effective to the bacterial strain of anti-beta-lactam, thereby are widely used in the treatment that sensitive organism infects, the formulation of this class medicine mainly is an oral preparations at present.The injection of macrolide antibiotics is being used for sensitive organism severe infections or can not be oral or should not oral patient have crucial meaning, but because macrolide antibiotics poorly water-soluble, reach the required enough water-soluble salifies that often needs of injection, the salt of macrolide antibiotics is its Lactobionate preferably at present.Though the Lactobionate of macrolide antibiotics can improve the water-soluble of medicine, yet the less stable of macrolide antibiotics Lactobionate, being easy to hydrolysis lost efficacy, to such an extent as to be difficult to tolerate sterilization process as clarithromycin Lactobionate aqueous stability is very poor, so the solution type injection agent of the macrolide antibiotics of solution-type still belongs to blank.Mainly be to make powder pin (as the erythromycin lactobionate lyophilized powder) or emulsion-type injection at present, the working condition of this class preparation requires high, and production cost is big, and use still has many inconveniences.Reported in the European patent EP 0 426 029 that the method for using cholate Micellar Solubilization clarithromycin Lactobionate and erythromycin lactobionate invented the micro-emulsion type injection of erythromycin, clarithromycin.But the prescription of this invention, method for making are complicated, and therefore, exploitation has the macrolide antibiotics of better stability and their solution type injection agent and remains and very need.
The objective of the invention is to develop macrolide antibiotics with better stability and their solution type injection agent.Through research extensively and profoundly, find that the salt that macrolide antibiotics and gentisinic acid obtain has better water solubility and stability, and have antibiotic synergy to a certain degree; Meanwhile, the contriver finds that also the Lactobionate of macrolide antibiotics (for example erythromycin, clarithromycin, Roxithromycin, azithromycin etc.) has preferably stability in ethanol-water solution, thereby is applicable to and makes solution type injection agent.
The term that uses among the present invention " macrolide antibiotics " has clarithromycin, erythromycin, Roxithromycin and azithromycin for example.
What first aspect present invention related to is the gentisinic acid (chemical name: 2 of macrolide antibiotics, the 5-resorcylic acid) salt, this salt demonstrates collaborative anti-microbial activity, have good solubleness and stability simultaneously, (alcohol concn is can stablize at least 2 years 10 ℃ of following lucifuges placements in 30～100v/v%) at the ethanol-water solution of pH5.0-8.0 for it.Say for example,, therefore, be better than clarithromycin as the anti-microbial activity of the clarithromycin gentisate of macrolide antibiotic gentisate because gentisinic acid itself has certain bacteriostatic activity.In addition, the water-soluble clarithromycin that is better than greatly of clarithromycin gentisate, so its stripping is better, bioavailability is higher.
What second aspect present invention related to is pharmaceutical composition, and it comprises as the macrolide antibiotics gentisate of activeconstituents and/or the microbiotic and the pharmaceutical excipient of other non-macrolide antibiotics.
That further aspect of the present invention relates to is the preparation method of macrolide antibiotics gentisate, and it is included under the pH5.0-8.0, in 30-100wt% (w/v) aqueous ethanolic solution, macrolide antibiotics and gentisinic acid is pressed 1-3: 1 mixed in molar ratio.
What further aspect of the present invention related to is the solution type injection agent of macrolide antibiotics Lactobionate, and wherein used solvent is that (alcohol concn is 30～100v/v%) for the ethanol-water solution of pH5.0-8.0 in this solution type injection agent.The route of administration of this solution type injection agent comprises subcutaneous injection, intramuscular injection, peritoneal injection, intravenous drip etc.According to the present invention, (alcohol concn is 30～100v/v%) to be that injection that solvent makes is placed 10 ℃ of following lucifuges and can be stablized at least 2 years to the Lactobionate of macrolide antibiotics with the ethanol-water solution of pH5.0-8.0.
According to the present invention, macrolide antibiotics gentisate of the present invention is preferably the clarithromycin gentisate.
According to the present invention, pharmaceutical composition of the present invention preferably contains clarithromycin gentisate and the pharmaceutical excipient as active ingredient.
According to the present invention, pharmaceutical composition of the present invention is by enteron aisle or parenteral route administration, as with tablet, and capsule, solution, suspension, creme, suppository, injection or instillation form administration.
According to the present invention, the fluid injection type injection of macrolide antibiotics Lactobionate of the present invention is preferably: clarithromycin Lactobionate solution type injection agent.
The following examples are used to further specify the present invention, but here and do not mean that any restriction to the present invention.
Embodiment 1: the preparation of clarithromycin gentisate
Gentisinic acid and the clarithromycin getting mol ratio and be 1: 1 add in the dehydrated alcohol, and reflux 5 minutes is put coldly, promptly has the crystallization of clarithromycin gentisate to separate out, and yield is 95%.Gained clarithromycin gentisate crystalline fusing point is: 196-198 ℃.Ultimate analysis: reason human relations value: C59.92%, H8.38%, O30.15%, N1.55%; Measured value: C59.77%, H8.41%, O30.21%, N1.61%.
Embodiment 2: the preparation of clarithromycin gentisate injection liquid
Be 500mg clarithromycin and gentisinic acid to be dissolved in 3: 1 the ethanol of 20mlpH7.0 in molar ratio: water (50: 50v/v) in the mixed solvent.This solution gets final product through 115 ℃ of pressure sterilizings 30 minutes.
Embodiment 3: the preparation of clarithromycin gentisate injection liquid
Be 500mg clarithromycin and gentisinic acid to be dissolved in 2: 1 the ethanol of 20mlpH7.0 in molar ratio: water (50: 50v/v) in the mixed solvent.This solution gets final product through 115 ℃ of pressure sterilizings 30 minutes.
Embodiment 4: the preparation of clarithromycin gentisate injection liquid
500mg clarithromycin and gentisinic acid were dissolved in 1: 1 in molar ratio the ethanol of 20ml pH7.0: water (50: 50v/v) in the mixed solvent.This solution gets final product through 115 ℃ of pressure sterilizings 30 minutes.
Embodiment 5: the preparation of clarithromycin Lactobionate injection liquid
Be 500mg clarithromycin and gentisinic acid to be dissolved in 1: 1 the ethanol of 20mlpH7.0 in molar ratio: water (50: 50v/v) in the mixed solvent.This solution gets final product through 115 ℃ of pressure sterilizings 30 minutes.
Stability test: sample thief places 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ following lucifuges to place respectively, take a sample in different time points, the content of liquid chromatography for measuring clarithromycin, and the observation degraded product, the validity period (clarithromycin was degraded for 10% required time) under calculating 10 ℃ by the chemical kinetics method.
The liquid phase chromatography condition is as follows:
The system suitability test: with octadecylsilane chemically bonded silica is weighting agent, and (55: 45v/v) be moving phase, the detection wavelength is 210nm with 0.067mol/L potassium primary phosphate/acetonitrile.Theoretical plate number is pressed clarithromycin calculating should be greater than 1500.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the clarithromycin reference substance, is mixed with the solution of 0.5mg/ml with moving phase, and this solution is as standardized solution.
Accurate respectively 20 μ l need testing solutions and the standardized solution injection liquid chromatograph drawn, the record color atlas, the record peak area calculates content by external standard method and calculates in accordance with the law, promptly.
The result shows (table 1): embodiment 1,2 all places 10 ℃ of following lucifuges and can stablize more than 2 years.
The validity period measurement result of each embodiment of table 1
| Embodiment | 2??????3??????4??????5 |
| Validity period (year) | 3.4????3.2????2.8????3.1 |
Claims (13)
1. the gentisate of macrolide antibiotics.
2. the gentisate of the macrolide antibiotics of claim 1, wherein said gentisate is following obtaining: under pH5.8-8.0, in 30-100% (v/v) aqueous ethanolic solution, with macrolide antibiotics and gentisinic acid by 1-3: 1 mixed in molar ratio obtains.
3. the gentisate of claim 1 or 2 macrolide antibiotics, wherein said macrolide antibiotics is selected from clarithromycin, erythromycin, Roxithromycin and azithromycin.
4. the gentisate of the macrolide antibiotic of aforementioned arbitrary claim, wherein said macrolide antibiotic is a clarithromycin.
5. prepare the method for the gentisate of macrolide antibiotics, it is included under the pH5.8-8.0, in 30-100% (v/v) aqueous ethanolic solution, macrolide antibiotics and gentisinic acid is pressed 1-3: 1 mixed in molar ratio.
6. pharmaceutical composition, it comprises as the gentisate of the macrolide antibiotics of active ingredient and pharmaceutical excipient.
7. the pharmaceutical composition of claim 6, it also can comprise at least a biorefractive microbiotic of non-Macrolide that is selected from.
8. the pharmaceutical composition of claim 6, wherein said macrolide antibiotics is selected from clarithromycin, erythromycin, Roxithromycin and azithromycin.
9. claim 6,7 and the pharmaceutical composition of arbitrary requirement, wherein said macrolide antibiotics is a clarithromycin.
10. the pharmaceutical composition of the arbitrary requirement of claim 6-9, wherein this pharmaceutical composition can tablet, capsule, solution, suspension, creme, suppository, injection or instillation form are used.
11. the solution type injection agent of macrolide antibiotics Lactobionate, it is characterized in that this injection is following obtaining: in pH5.0-8.0, in 30-100% (v/v) aqueous ethanolic solution, with macrolide antibiotics and lactobionic acid by 1: 1 rub the heart than mixing.
12. the solution type injection agent of claim 11, wherein said macrolide antibiotics is selected from clarithromycin, erythromycin, Roxithromycin and azithromycin.
13. the solution type injection agent of claim 11 or 12, wherein said macrolide antibiotic are clarithromycin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98120782 CN1249309A (en) | 1998-09-29 | 1998-09-29 | Gentianate of macrolides antibiotics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 98120782 CN1249309A (en) | 1998-09-29 | 1998-09-29 | Gentianate of macrolides antibiotics |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1249309A true CN1249309A (en) | 2000-04-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 98120782 Pending CN1249309A (en) | 1998-09-29 | 1998-09-29 | Gentianate of macrolides antibiotics |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102532223A (en) * | 2010-10-08 | 2012-07-04 | 塔科敏斯基制药厂波尔法合资公司 | Process for the preparation of 11,12-cyclic erythromycin a carbonate lactobionate and the use thereof |
| CN101624412B (en) * | 2008-07-10 | 2012-07-04 | 刘力 | Derivative of macrolides, method for preparing same and application 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 |
| CN115010768A (en) * | 2022-07-11 | 2022-09-06 | 山东科源制药股份有限公司 | Preparation method of clarithromycin lactobionate |
-
1998
- 1998-09-29 CN CN 98120782 patent/CN1249309A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101624412B (en) * | 2008-07-10 | 2012-07-04 | 刘力 | Derivative of macrolides, method for preparing same and application thereof |
| CN102532223A (en) * | 2010-10-08 | 2012-07-04 | 塔科敏斯基制药厂波尔法合资公司 | Process for the preparation of 11,12-cyclic erythromycin a carbonate lactobionate and the use 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 |
| CN113173956B (en) * | 2021-04-26 | 2021-12-24 | 广东金城金素制药有限公司 | Preparation method of clarithromycin lactobionate |
| CN115010768A (en) * | 2022-07-11 | 2022-09-06 | 山东科源制药股份有限公司 | Preparation method of clarithromycin lactobionate |
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