CN102579466A - Composition of fosfomycin or fosfomycin arginine salt and arginine - Google Patents
Composition of fosfomycin or fosfomycin arginine salt and arginine Download PDFInfo
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- CN102579466A CN102579466A CN2011100036442A CN201110003644A CN102579466A CN 102579466 A CN102579466 A CN 102579466A CN 2011100036442 A CN2011100036442 A CN 2011100036442A CN 201110003644 A CN201110003644 A CN 201110003644A CN 102579466 A CN102579466 A CN 102579466A
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Abstract
The invention relates to a composition of two antibiotics, in particular to a composition of fosfomycin and arginine and another composition of fosfomycin arginine salt and arginine. The composition of fosfomycin and arginine consists of the fosfomycin and the arginine, wherein the optimal weight ratio of the fosfomycin to the arginine is 1:2.5. The composition of fosfomycin arginine salt and arginine consists of the fosfomycin arginine salt and the arginine, wherein the optimal weight ratio of the fosfomycin arginine salt to the arginine is 1.6:1. Both compositions can be prepared into powder injection for injection; neither compositions contains sodium ions, so that hypernatremia is not caused; and after being dissolved in 5 percent glucose or 0.9 percent sodium chloride solution, the composition can be compatible with a quinolone antibiotic for use. Thus, the composition has a wider and safer application range and is more stable and convenient to use.
Description
Technical field
The present invention relates to fosfomycin or fosfomycin arginine salt and arginine the combination and two kinds of compositionss, belong to field of medicine preparing technology.
Background technology
Fosfomycin, the product another name: 1,2-glycidyl phosphonic acids; English name: Fosfomycin, English another name: Phosphonomycin, (3-Methyloxiran-2-yl) phosphonic acid.
Molecular formula: C3H7O4P, molecular weight: 138.06, CAS accession number: 23155-02-4.
Fosfomycin separates from Streptomyces fradicle at first, is produced by synthetic method at present, and its antibacterial action mechanism is unique, through suppressing the activity of enol pyruvic acid transferring enzyme, can suppress the early stage synthetic of bacteria cell wall, thus the performance antibacterial action.Fosfomycin has three big characteristics: one, has a broad antifungal spectrum, and do not have cross resistance between other antibiotic, majority presents synergism.Two, safe in utilization, tissue distribution is good, does not combine with serum albumin, and no antigen need not to try quick, and toxicity is low.Three, molecular weight is very little, can be penetrated into the various tissues of health, drains through glomerular filtration with original shape behind the entering human body, does not almost have tubular excretion and heavily absorption.
Fosfomycin is originally as acidity, and preparations for oral administration is used its calcium salt or amino butanetriol salt always, and injection preparation its disodium salt commonly used is a fosfomycin sodium.Fosfomycin sodium is soluble in water, shows alkalescence, before being distributed into powder ampoule agent for injection, need an amount of citric acid of interpolation to regulate pH value to neutral, but the amount of adding is little, and mix homogeneously also keeps evenly and is not easy.
Simultaneously fosfomycin sodium for injection to contain the sodium amount very high; Be about 25%; Be prone to cause hypernatremia, so its product description clearly indicates: the careful usefulness of patient such as the heart, renal insufficiency, hypertension, limited the scope of application of fosfomycin sodium for injection to a certain extent.
Because of unique antibacterial action mechanism and other antibiosis of fosfomycin have synergetic antibacterial effect, especially have collaborative, complementary antibacterial action with quinolione class antibiosis, often need in the actual medical and quinolione class antibiotic is united use.But according to bibliographical information; There are incompatibility in fosfomycin sodium for injection and multiple quinolione class antibiotic; Like " Chinese Hospitals pharmaceutical journal " the 2004-24-7 phase; " stability behind fosfomycin sodium for injection and the clinical commonly used drug compatibility " waits many documents that the fosfomycin sodium for injection incompatibility is had report or research.
So fosfomycin sodium for injection exists certain inconvenience and risk in the use of reality, operation, in addition with some kind before and after continuously use all need exactissima diligentia with careful.
The fosfomycin arginine salt, the fosfomycin L-arginine salt that forms for a part fosfomycin and a part L-arginine chemical combination.Molecular formula: C9H19N4O5P, molecular weight: 284.26.Document is arranged: " The 2nd Army Medical College journal ", 1991-4, " antibacterial activity and the structure activity relationship thereof of broad ectrum antibiotic fosfomycin derivant " report is learned experiment through microbial medicine, and the fosfomycin arginine salt increases than the fosfomycin antibacterial activity.But there is not fosfomycin arginine salt launch to sell as yet.
Arginine, i.e. L-arginine, chemical name: L-2-amino-5-guanidine radicals valeric acid, English common name: L-ARGININE, molecular formula: C6H14N4O2, molecular weight: 174.20 is a basic amino acid, and pH value is between 10.5-12.0.It is a kind of pharmaceutic adjuvant commonly used, and the pH value that is mainly used in the adjustment of acidity medicine like the hydrochloride for injection cefepime, is cefepime hydrochloride and arginic compositions to neutral, adds arginine and regulates the injection pH value to neutral, makes it to be suitable for injection.
Summary of the invention
The present invention relates to two kinds of antibiotic compositionss, wherein a kind of compositions that combines by fosfomycin and arginine that is particularly related to, another kind is particularly related to the compositions that is combined by fosfomycin arginine salt and arginine.The fosfomycin arginine composition is combined by fosfomycin and arginine, and fosfomycin and arginic optimum weight ratio are 1: 2.5 (with the pure calculating of giving money as a gift of method under the Chinese Pharmacopoeia item); Fosfomycin arginine salt arginine composition is combined by fosfomycin arginine salt and arginine, and fosfomycin arginine salt and arginic optimum weight ratio are 1.6: 1 (with the pure calculating of giving money as a gift of method under the Chinese Pharmacopoeia item).
Two kinds of compositionss of the present invention all can be adjusted to the neutrality that is fit to injection with tart fosfomycin or fosfomycin arginine salt; Has good mobility and stability; Add the water capacity and be prone to be dissolved to clarification, thereby substitute present employed fosfomycin sodium powder ampoule agent for injection.
More crucial is that the fosfomycin sodium powder ampoule agent for injection contains the sodium amount and reaches 25%, be easy to cause hypernatremia, and two kinds of compositionss of the present invention does not all contain sodium ion; And the fosfomycin sodium powder ampoule agent for injection cannot merge use with quinolione class antibiotic; Mixing back solution becomes muddy easily or produces deposition, crystallization; And two kinds of compositionss of the present invention after the dissolving, can merge with quinolione class antibiotic and use in the sodium chloride that joins 5% glucose or 0.9%.More stable when therefore using, convenient, the scope of application is also more extensive, safety.
The characteristic of two kinds of compositionss of the present invention is:
1, wherein a kind of compositions is characterised in that: said composition is made up of fosfomycin and arginine, and fosfomycin and arginic optimum weight ratio are 1: 2.5 (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) in the said composition.
2, another kind of compositions is characterised in that: said composition is made up of fosfomycin arginine salt and arginine, and fosfomycin and arginic optimum weight ratio are 1.6: 1 (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) in the said composition.
3, the fosfomycin of fosfomycin arginine composition and arginic weight proper ratio scope (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) are 1: 1 to 1: 3.
4, fosfomycin arginine and arginic weight proper ratio scope in the fosfomycin arginine salt arginine composition (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) are 5: 1 to 1: 1.
The fosfomycin sodium for injection that uses on the existing market has added a spot of citric acid and has regulated pH value for neutral, use to be suitable for injection, but mix homogeneously and keep evenly and be not easy has many pieces of patent applications that this is improved.
The present invention adopts aseptic fosfomycin or aseptic fosfomycin arginine salt and arginine to form compositions, and the pH value of regulating mixture easily is to neutral, and mix homogeneously also keeps evenly easily.Find also that simultaneously the present composition has following two unexpected effects:
1. two kinds of compositionss of the present invention all do not contain sodium ion, and the scope of application is more extensive.Reach 25% and the fosfomycin sodium powder ampoule agent for injection contains the sodium amount, be easy to cause hypernatremia, patients such as the heart, renal insufficiency, hypertension should not use.
2. the fosfomycin sodium powder ampoule agent for injection cannot merge use with quinolione class antibiotic; Mixing back solution becomes muddy easily or produces deposition, crystallization; And two kinds of compositionss of the present invention after the dissolving, can merge with quinolione class antibiotic and use in the sodium chloride that joins 5% glucose or 0.9%.More stable when therefore using, convenient.
Concrete result of the test is following:
Following test specimen: fosfomycin sodium for injection, commercially available article are breathed out the production of medicine head factory; The fosfomycin arginine composition is pressed embodiment 1 preparation; The fosfomycin arginine salt composite is pressed embodiment 4 preparations.
1. sodium content
Pressing Chinese Pharmacopoeia general rule method measures.
2. solution compatibility test
Test is mixed with 100mL solution with QNS ciprofloxacin, pefloxacin, norfloxacin and fleroxacin with 5% glucose or 0.9% sodium chloride injection; Add fosfomycin sodium for injection, fosfomycin arginine composition, fosfomycin arginine salt arginine composition (all being equivalent to fosfomycin 0.8g) then; After medicinal liquid behind the compatibility at room temperature placed 1 hour, observe the clarity and the change color of solution.
A.5% glucose injection
B.0.9% sodium chloride injection
Above result of the test confirms that compositions of the present invention does not contain sodium ion, can merge with quinolione class medicine to use, and has enlarged the scope of application, and is more convenient during use, has realistic meanings.
The specific embodiment
Further set forth the present invention through embodiment below, but do not limit the present invention.
The preparation of the fosfomycin arginine composition of embodiment 1 ratio 1:
In gnotobasis, aseptic fosfomycin 1kg and aseptic arginine 2.5kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
The preparation of the fosfomycin arginine composition of embodiment 2 ratios 2:
In gnotobasis, aseptic fosfomycin 2.0kg and aseptic arginine 3.0kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
The preparation of the fosfomycin arginine composition of embodiment 3 ratios 3:
In gnotobasis, aseptic fosfomycin 2.0kg and aseptic arginine 4.0kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
The preparation of the fosfomycin arginine salt arginine composition of embodiment 4 ratios 1:
In gnotobasis, aseptic fosfomycin arginine salt 3.2kg and aseptic arginine 2.0kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
The preparation of the fosfomycin arginine composition of embodiment 5 ratios 2:
In gnotobasis, aseptic fosfomycin arginine salt 2.0kg and aseptic arginine 1.0kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
The preparation of the fosfomycin arginine composition of embodiment 6 ratios 3:
In gnotobasis, aseptic fosfomycin 3.0kg and aseptic arginine 1.0kg (all by the pure calculating of giving money as a gift), cross 60 mesh sieves respectively after, put in the three-dimensional mixer and mix, Revolution Per Minute 100 changes, mixed 1.5 hours.Discharging behind the mix homogeneously, in the antibiotic packaging Aluminum Drum of packing into, aluminium lid sealing, overcoat polyethylene plastic bag, sealing, vanning.
Be transported to sterile preparation packing workshop after the vanning, the removal outer package, Aluminum Drum ultraviolet sterilization back gets into aseptic powder to be divided on the wiring, aseptic subpackaged to antibiotic glass bottle by specification, gets the preparation finished product of the present composition.
Claims (8)
1. two kinds of antibiotic compositions, wherein a kind of compositions is characterised in that: said composition is made up of fosfomycin and arginine, and fosfomycin and arginic optimum weight ratio are 1: 2.5 (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) in the said composition.
2. two kinds of antibiotic compositions; Another kind of compositions is characterised in that: said composition is made up of fosfomycin arginine salt and arginine, and fosfomycin arginine salt and arginic optimum weight ratio are 1.6: 1 (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) in the said composition.
3. according to claim 1. the weight proper ratio scope of said composition (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) is that fosfomycin and arginine ratio are 1: 1 to 1: 3.
4. of claim 2. the weight proper ratio scope of said composition (with the pure calculating of giving money as a gift of Chinese Pharmacopoeia method) is that fosfomycin arginine and arginine ratio are 5: 1 to 1: 1.
5. like the described antibiotic composition of claim 1-4, it is characterized in that: can comprise one or more acceptable accessories in addition in the said compositions.
6. like each described antibiotic composition of claim 1-4, it is characterized in that: this antibiotic composition is clinical acceptable drug preparation.
7. like the described antibiotic composition of claim 1-4, it is characterized in that: the preferred injectable sterile powder preparation of said pharmaceutical preparation.
8. like the method for preparing of the described antibiotic composition of claim 1-4, it is characterized in that: comprise aseptic fosfomycin or aseptic fosfomycin arginine salt and arginine powder mixes, obtain containing the step of the two mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100036442A CN102579466A (en) | 2011-01-10 | 2011-01-10 | Composition of fosfomycin or fosfomycin arginine salt and arginine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011100036442A CN102579466A (en) | 2011-01-10 | 2011-01-10 | Composition of fosfomycin or fosfomycin arginine salt and arginine |
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| CN102579466A true CN102579466A (en) | 2012-07-18 |
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| CN2011100036442A Pending CN102579466A (en) | 2011-01-10 | 2011-01-10 | Composition of fosfomycin or fosfomycin arginine salt and arginine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3812007A1 (en) | 2019-10-24 | 2021-04-28 | Sandoz Ag | New formulations of fosfomycin with reduced sodium content for parenteral use and methods of producing the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2013682A (en) * | 1978-02-02 | 1979-08-15 | Italchemi Spa | Derivatives of (-)-cis-1,2- Epoxypropylphosphonic Acid, Their Preparation, and Pharmaceutical Compositions Containing Them |
| US20040022866A1 (en) * | 2002-08-01 | 2004-02-05 | Zambon Group S.P.A. | Pharmaceutical compositions with antibiotic activity |
-
2011
- 2011-01-10 CN CN2011100036442A patent/CN102579466A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2013682A (en) * | 1978-02-02 | 1979-08-15 | Italchemi Spa | Derivatives of (-)-cis-1,2- Epoxypropylphosphonic Acid, Their Preparation, and Pharmaceutical Compositions Containing Them |
| US20040022866A1 (en) * | 2002-08-01 | 2004-02-05 | Zambon Group S.P.A. | Pharmaceutical compositions with antibiotic activity |
Non-Patent Citations (1)
| Title |
|---|
| 李全，等: "广谱抗生素磷霉素衍生物的抗菌活性及其构效关系", 《第二军医大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3812007A1 (en) | 2019-10-24 | 2021-04-28 | Sandoz Ag | New formulations of fosfomycin with reduced sodium content for parenteral use and methods of producing the same |
| WO2021078695A1 (en) | 2019-10-24 | 2021-04-29 | Sandoz Ag | New formulations of fosfomycin with reduced sodium content for parenteral use and methods of producing the same |
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Application publication date: 20120718 |