CN1531931A - Method for improving solubility of clarithromycin - Google Patents
Method for improving solubility of clarithromycin Download PDFInfo
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- CN1531931A CN1531931A CNA031210740A CN03121074A CN1531931A CN 1531931 A CN1531931 A CN 1531931A CN A031210740 A CNA031210740 A CN A031210740A CN 03121074 A CN03121074 A CN 03121074A CN 1531931 A CN1531931 A CN 1531931A
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- clarithromycin
- pharmaceutical excipient
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Abstract
The present invention provides the method of improving solubility and stability of clarithromycin, the medicine composition containing clarithromycin and its preparation process.
Description
Technical field
The present invention relates to improve the method for antibiotic medicine dissolubility, what contain this medicine is suitable for pharmaceutical composition that specific crowd uses and preparation method thereof.
Background technology
Clarithromycin (clarithromycin, chemistry 6-0-erythromycin by name) is 14 yuan of semi-synthetic erythromycin derivatives of ring.Be used for respiratory tract due to the sensitive organism, urinary tract, skin and soft tissue infection etc.
Because the effect of clarithromycin is remarkable, develops its preparation that is suitable for specific crowd (for example patient of old man, child and dysphagia) and has great importance.At present, clarithromycin has dosage forms such as injection, tablet, capsule, granule, dry suspension and suppository.Safety evaluatio to the clarithromycin injection shows that its adverse reaction rate is 86.36%, sees at most with transfusion part pain, mostly be can tolerate mild to moderate.But phlebitis appears in minority weight person, and individual patient can't be finished the course of treatment (Miao Jia etc., West China medical science, 2002,17 (1): 48-49).As for peroral dosage forms such as the tablet (comprising dispersible tablet) of clarithromycin, capsule, dry suspension, prior art is studied the bioavailability and the antibacterial activity of above-mentioned multiple dosage form, but relate to more between it and erythromycin effectiveness relatively, or the research that lays particular emphasis on the bioequivalence aspect between different dosage form (for example: Song Hongjie etc., the The 2nd Army Medical College journal, 1998,19 (1): 92-94; Chu Xiaoman etc., The Chinese Journal of Clinical Pharmacology 1998,14 (2): 94-98; Zhu Lianna etc., Guangxi Medical University's journal, 1999,16 (1): 29-32 etc.).And, clearly do not instruct corresponding solution in the prior art at the major obstacle in its preparation (especially oral formulations) exploitation (for example, dissolubility is low and bioavailability is relatively poor).
Clarithromycin insoluble in water (dissolubility only is 1: 1000), so stripping is the speed limit process of its oral administration post-absorption, this also is the relatively poor main causes of existing most oral formulations bioavailability.It is prepared into preparation efficient, quick-acting and that patient's compliance is good is a difficult problem on the preparation always.Therefore, the method for improving the clarithromycin dissolubility need be developed in this area, has the settled solution type pharmaceutical composition of the bioavailability and the stability of raising with preparation.
Summary of the invention
We have carried out deep research to pharmaceutical technology, particularly by screening, prescription to specific pharmaceutical excipient, address the above problem effectively, and the present invention has promptly been finished in further research on this basis.
Purpose of the present invention provides the method for improving clarithromycin dissolubility and stability.In galenic pharmacy, adopt organic solvent, cosolvent or surfactant to promote the dissolving of insoluble drug usually.Yet clarithromycin not only is insoluble in water, and very unstable in water, does not instruct the pharmaceutical excipient that is suitable for this class medicine in the prior art.The inventor is surprised to find, in clarithromycin, add specific surfactant or medicinal macromolecule or their combination, (its dissolubility was brought up to about 100: 1000 by about 1: 1000 not only can to improve the dissolubility of clarithromycin preferably, preferably bring up to about 5: 1000 to 50: 1000), also can improve its stability in solution, and obtain clarifying clarithromycin solution.
Be suitable for surfactant of the present invention or medicinal macromolecule includes but not limited to: Macrogol 200, Liquid Macrogol, PEG400, tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone, carbomer or their mixture, be preferably 1,2-propylene glycol, polyvinylpyrrolidone, carbomer or their mixture.It should be noted that; above-mentioned pharmaceutical excipient is used for the solubilising insoluble drug more in galenic pharmacy; usually can form homogeneous phase or heterogeneous system (for example micelle, liposome, complex or dispersion etc.), it is beat all therefore obtaining the stable settled solution of the present invention.Simultaneously, can be contemplated that and adopt the conventional formulation method, can further the present invention have been improved the clarithromycin of dissolubility and stability and make, be preferably peroral dosage form for injection or dosage form for oral use.
Advantageously, also can add medicinal stabilizing agent and/or pH regulator agent, with further clarithromycin dissolubility and the stability improved.Therefore, the stabilizing agent of described adding comprises but is not limited to: L-cysteine hydrochloride, nicotiamide, poloxamer or their mixture.The pH regulator agent of described adding includes but not limited to: various phosphate buffers, hydrochloric acid, sodium hydroxide and their mixture.
Another object of the present invention provides and comprises the above-mentioned pharmaceutical composition that has improved the clarithromycin of dissolubility and stability.Preferably, described compositions is the clear solutions state, and oral administration is with producing general action, and the patient who is particularly suited for old man, child and dysphagia takes.
In a preferred embodiment of the invention, its pH value scope of described pharmaceutical composition is preferably 5.5-7.0 between 3.5-7.5.
In order to overcome the unusual bitterness of medicine, also can add the correctives and/or the sweeting agent that are selected from sucrose, disodium glycyrrhizinate, stevia glucoside, sweetener, saccharin sodium, sodium glutamate, chocolate essence, aspartame, the match of peace honey and their mixture, be preferably stevia glucoside, saccharin sodium, sodium glutamate.Wherein the part by weight of clarithromycin and sweeting agent and correctives about 1: 1-1: 100.
In a preferred embodiment of the invention, the parts by weight of described various compositions, optimum ratio is as follows:
Clarithromycin 10-500mg
Surfactant or medicinal macromolecule 0.01-30g
Stabilizing agent 0.01-10g
PH regulator 0.001-5g
Preferably, in another preferred embodiment of the present invention, the parts by weight proportioning of described various compositions is:
Clarithromycin 50-250mg
Surfactant or medicinal macromolecule 0.1-10g
Stabilizing agent 0.05-5g
The present invention provides the method for preparing the clarithromycin composition of liquid medicine on the other hand, this method is simple, be suitable for industrialized great production, described method comprises: active component, pharmaceutical excipient, PH regulator are mixed, add the suitable quantity of water stirring and dissolving then, the optional stabilizing agent that adds, after waiting to dissolve, regulate pH value, optional sweeting agent and the correctives of adding, add water to certain volume, promptly.Products obtained therefrom is colourless to yellowish clear liquid.
The preparation of embodiment 1 clarithromycin oral liquid
1, prescription 1
Clarithromycin 125mg
Polyvinylpyrrolidone 300mg
Poloxamer 500mg
Nicotiamide 300mg
1,2-propylene glycol 1ml
Aspartame 100mg
Hydrochloric acid is an amount of
2, prescription 2
Clarithromycin 125mg
Polyvinylpyrrolidone 500mg
Carbomer 500mg
1,2-propylene glycol 1ml
Sodium glutamate 100mg
Phosphate buffer is an amount of
3, preparation method
Active component, pharmaceutical excipient, PH regulator are mixed, add suitable quantity of water, after the stirring and dissolving, add stabilizing agent, after waiting to dissolve, regulating pH value with the PH regulator is 5.5-7.0, adds sweeting agent and correctives, adds water to 10ml, promptly.The clarithromycin oral liquid of gained is clear and bright liquid.
Influence factor's stability of test example 1 clarithromycin oral liquid
Determination on content: adopt the content assaying method (be microorganism tire method) of two middle clarithromycins of Chinese Pharmacopoeia version in 2000, the oral liquid (prescription 1) that makes by embodiment 1 is tested.
For with a collection of test specimen, the influence factor adopts under the illumination of 4500LX illumination, 60 ℃ of high temperature and low temperature were placed 10 days for 4 ℃, and respectively the 5th day and the tenth day sampling and measuring, pH, content all do not have obvious change (be no more than ± 5%), and clarity keeps well.
Three batches of test specimens are through quickening test in 6 months, and above-mentioned test parameters does not also have obvious change.
Compare with dry suspension, relative bioavailability is 114.7 ± 17.9%.
Above result shows: the clarithromycin oral liquid is in respect to more exacting terms test down of room temperature condition, still can be settled solution, and its stability is in the scope of quality controllable system.This fine solubility and stability characteristic have not only guaranteed clinical application safety, have also correspondingly prolonged the effect duration of drawing the mycin oral liquid formulations.
Claims (11)
1. improve the method for clarithromycin dissolubility, comprise clarithromycin is mixed with pharmaceutical excipient and/or pH regulator agent, described pharmaceutical excipient is selected from: Macrogol 200, Liquid Macrogol, PEG400, tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone, carbomer or their mixture.
2. method as claimed in claim 1, wherein pharmaceutical excipient is 1,2-propylene glycol, polyvinylpyrrolidone, carbomer or their mixture.
3. as the method for claim 1 or 2, also comprise medicinal stabilizing agent and/or pH regulator agent.
4. method as claimed in claim 3, wherein medicinal stabilizing agent are L-cysteine hydrochloride, nicotiamide, poloxamer or their mixture.
5. liquid oral compositions, comprising clarithromycin, pharmaceutical excipient and/or pH regulator agent, described pharmaceutical excipient is selected from: Macrogol 200, Liquid Macrogol, PEG400, tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone, carbomer or their mixture.
6. compositions as claimed in claim 5, wherein pharmaceutical excipient is 1,2-propylene glycol, polyvinylpyrrolidone, carbomer or their mixture.
7. compositions as claimed in claim 5, the wherein part by weight 1 of clarithromycin and pharmaceutical excipient: 1-1: 10.
8. as the compositions of one of claim 5-7, also comprise medicinal stabilizing agent, correctives, sweeting agent.
9. compositions as claimed in claim 8, wherein medicinal stabilizing agent are L-cysteine hydrochloride, nicotiamide, poloxamer or their mixture.
10. compositions as claimed in claim 5 is colourless extremely yellowish clear liquid.
11. prepare the method for fluid composition as claimed in claim 5, comprising: active component, pharmaceutical excipient, PH regulator are mixed, add the suitable quantity of water stirring and dissolving after, add stabilizing agent, after waiting to dissolve, regulate pH value with the PH regulator, add sweeting agent and correctives, add water to certain volume then.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031210740A CN1531931A (en) | 2003-03-24 | 2003-03-24 | Method for improving solubility of clarithromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031210740A CN1531931A (en) | 2003-03-24 | 2003-03-24 | Method for improving solubility of clarithromycin |
Publications (1)
| Publication Number | Publication Date |
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| CN1531931A true CN1531931A (en) | 2004-09-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031210740A Pending CN1531931A (en) | 2003-03-24 | 2003-03-24 | Method for improving solubility of clarithromycin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505733A (en) * | 2013-09-12 | 2014-01-15 | 合肥今越制药有限公司 | Oral liquid preparation with macrolides medicine as active component |
| CN103505404A (en) * | 2013-09-12 | 2014-01-15 | 合肥今越制药有限公司 | Oral liquid preparation with roxithromycin as active component |
-
2003
- 2003-03-24 CN CNA031210740A patent/CN1531931A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505733A (en) * | 2013-09-12 | 2014-01-15 | 合肥今越制药有限公司 | Oral liquid preparation with macrolides medicine as active component |
| CN103505404A (en) * | 2013-09-12 | 2014-01-15 | 合肥今越制药有限公司 | Oral liquid preparation with roxithromycin as active component |
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| DD01 | Delivery of document by public notice |
Addressee: Xu Xinsheng Document name: Correction notice |
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| WD01 | Invention patent application deemed withdrawn after publication |