CN1785193A - Amino acid (-) ofloxacin water soluble salt - Google Patents
Amino acid (-) ofloxacin water soluble salt Download PDFInfo
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- CN1785193A CN1785193A CNA2005101252462A CN200510125246A CN1785193A CN 1785193 A CN1785193 A CN 1785193A CN A2005101252462 A CNA2005101252462 A CN A2005101252462A CN 200510125246 A CN200510125246 A CN 200510125246A CN 1785193 A CN1785193 A CN 1785193A
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- ofloxacin
- soluble salt
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Abstract
本发明公开了一种氨基酸(－)氧氟沙星水溶性盐及其制备方法。它改善了(－)氧氟沙星水溶性盐的溶出度和生物利用度，增强了(－)氧氟沙星的抗菌效果。本发明通过(－)氧氟沙星半水合物(C18H20FN3O4·1/2H2O)与氨基酸成水溶性盐，其分子式为：C18H20FN3O4·A·nH2O。将左旋氧氟沙星半水合物和门冬氨酸或谷氨酸一起加入水中，得澄明溶液，测得pH5.0－7.0。将该溶液注入装有95％乙醇10升的容器中，析出类白色结晶物质，干燥得淡黄色结晶粉末即为左旋氧氟沙星左旋门冬氨酸盐或左旋氧氟沙星谷氨酸盐，将上述盐类分别与各种药物辅料混合按常规制药方法混合制成各种药物剂型。本发明扩展了(－)氧氟沙星的应用范围。The invention discloses a water-soluble salt of amino acid (-) ofloxacin and a preparation method thereof. It improves the dissolution rate and bioavailability of (-) ofloxacin water-soluble salt, and enhances the antibacterial effect of (-) ofloxacin. In the invention, (-) ofloxacin hemihydrate (C18H20FN3O4·1/2H2O) forms water-soluble salt with amino acid, and its molecular formula is: C18H20FN3O4·A·nH2O. Add levofloxacin hemihydrate and aspartic acid or glutamic acid into water together to obtain a clear solution with a measured pH of 5.0-7.0. This solution is injected in the container that 10 liters of 95% ethanol is housed, and off-white crystalline substance is separated out, and the pale yellow crystalline powder that dries is levofloxacin L-aspartate or levofloxacin glutamate, The above-mentioned salts are mixed with various pharmaceutical excipients according to conventional pharmaceutical methods to prepare various pharmaceutical dosage forms. The invention expands the application range of (-) ofloxacin.
Description
Technical field:
The present invention relates to medical technical field, definite say that it is the amino acid salts of a kind of carbostyril family antibacterial drugs (-) ofloxacin and pharmaceutical preparation-one seed amino acid (-) ofloxacin water soluble salt formed of salt thus.
Background technology:
Levofloxacin (L-ofloxacin) is a third generation carbostyril family antibacterial drugs, external to staphylococcus, streptococcus (comprising enterococcus), streptococcus pneumoniae, gonococcus, escherichia coli, bacillus citrate, bacillus dysenteriae, bacillus canalis capsulatus, Enterobacter, serratia marcecens genus, Bacillus proteus, hemophilus influenza, do not prop up bacillus, pylori etc. antibacterial action preferably all arranged, bacillus pyocyaneus and chlamydia trachomatis are also had certain inhibitory action.The acute and chronic infection at positions such as respiratory tract, throat, tonsil, urinary tract, skin and soft tissue, gallbladder and the bile duct that can be used for causing, middle ear, nasal sinuses, lachrymal sac, intestinal by sensitive bacterial.Levofloxacin dissolubility in water is very little, is difficult to meet clinical needs, and what use at present mainly is its mineral acid as hydrochlorate etc., acylate such as lactate, mesylate etc.
Aminoacid is as (-) Aspartic Acid slightly soluble in water, behind itself and some organic weak base class medicine salifies, can make its dissolubility increase tens of times to thousands of times, make this this weak base class medicine can be easy to make liquid preparation such as injection, oral liquid etc., simultaneously the dissolution and the bioavailability of oral dosage form can be increased, even the antibacterial effect of these antibacterials can be strengthened.At present in the quinolones existing lomefloxacin and fleroxacin made aspartate be used for clinical, and proved its clinical effect with by the effect of the salt of other acids preparation quite or win.Therefore by (-) ofloxacin and the effect of (-) Aspartic Acid are prepared its salt, can effectively expand the range of application of (-) ofloxacin, also can strengthen the fungistatic effect of (-) ofloxacin simultaneously.
Summary of the invention:
The purpose of this invention is to provide seed amino acid (-) ofloxacin water soluble salt.Be characterized in can be used for preparing injection and lyophilized injection, also can be used for preparing other the preparation that is used for oral or topical.Expand the range of application of (-) ofloxacin, also can strengthen the fungistatic effect of (-) ofloxacin simultaneously.
Levofloxacin is an ofloxacin, and three nitrogen-atoms are arranged in its structure, so its apparent more weak alkalescence, and Aspartic Acid is weakly acidic aminoacid, can form the water soluble salt water soluble salt with levofloxacin.With the water soluble salt that (-) ofloxacin and aminoacid are made, its structural formula is C
18H
20FN
3O
4AnH
2O.Described aminoacid (A) can be left-handed Aspartic Acid, glutamic acid, glycine, alanine, serine, cysteine, methionine, valine, leucine, asparagine, glutamine, phenylalanine, Lip river propylhomoserin, acidic amino acids such as tryptophan.Described aminoacid (-) ofloxacin water soluble salt can contain water of crystallization, also can not contain, be the described aminoacid of n=0-3. (-) ofloxacin water soluble salt, add the oral agents that suitable pharmaceutical adjuvant is made, injection as antibacterial, eye drop, unguentum and suppository.Aminoacid adds when also can be the preparation of (-) ofloxacin preparation in the pharmaceutical formulation.The antibacterial that described aminoacid (-) ofloxacin water soluble salt is made is for human and animal applications.
Technical essential of the present invention is: with (-) ofloxacin semihydrate (C
18H
20FN
3 O
41/2H
2O) and acidic amino acid be raw material, adopt chemical method to prepare water soluble salt at ambient temperature, i.e. aminoacid (-) ofloxacin.Its molecular formula general formula is: C
18H
20FN
3O
4AnH
2O.
Preparation technology of the present invention is as follows:
The preparation of levofloxacin aspartate and glutamate, Glu:
Levofloxacin semihydrate and Aspartic Acid or glutamic acid are added in the entry together, clear and bright solution, record pH5.0-7.0.This solution is injected the container that 10 liters of 95% ethanol are housed, separate out the off-white color crystalline material, dry that light yellow crystalline powder is left-handed aspartate of levofloxacin or levofloxacin glutamate, Glu, mixing routinely with various excipient substances above-mentioned salt respectively, pharmaceutical methods is mixed and made into various pharmaceutical dosage forms.
The invention has the advantages that: the present invention has improved the dissolubility of (-) ofloxacin, make it can make liquid preparation, and can increase the dissolution and the bioavailability of oral dosage form, and expanded the range of application of (-) ofloxacin, also strengthened the fungistatic effect of (-) ofloxacin simultaneously.And preparation process is simple and easy to do.
Description of drawings:
Fig. 1 is the collection of illustrative plates of (-) ofloxacin in (-) Aspartic Acid physical mixture
Fig. 2 is the collection of illustrative plates of (-) ofloxacin (-) aspartate
The specific embodiment:
For several embodiment, embodiment only plays a part to explain explanation, is not protect in this patent whole below:
The preparation of levofloxacin aspartate:
Raw material: (-) ofloxacin semihydrate 370g
(-) Aspartic Acid 133g
Pure water 2L
95% ethanol 10L
Preparation method:
(-) ofloxacin semihydrate (370 gram) and (-) Aspartic Acid (133 gram) are added in the entry together, get clear and bright solution, record pH5.0-7.0.This solution is injected the container that 95% ethanol (10 liters) are housed, separate out the off-white color crystalline material, dry that light yellow crystalline powder is (-) ofloxacin (-) aspartate, product yield about 70%.
The affirmation and the analysis of (-) ofloxacin (-) aspartate:
1. dissolubility is relatively:
(-) ofloxacin (-) aspartate very easily dissolving in water (1 gram (-) ofloxacin aspartate may be dissolved in greater than 0.5 milliliter and less than in 1 ml pure water); And its raw material (-) ofloxacin becomes slightly soluble (1 gram (-) ofloxacin semihydrate needs to dissolve) respectively with (-) Aspartic Acid in greater than 250 milliliters pure water in water.
2. infrared spectrum is differentiated:
Can judge that by the situation of change of carboxyl hydrogen on the infrared spectrogram and amino hydrogenation displacement study and oscillation intensity the generation of (-) ofloxacin (-) aspartate (sees Figure of description, Fig. 1 is the collection of illustrative plates of (-) ofloxacin in (-) Aspartic Acid physical mixture, and Fig. 2 is the collection of illustrative plates of (-) ofloxacin (-) aspartate).
Embodiment 2
The preparation of (-) ofloxacin (-) glutamate, Glu:
Raw material: (-) ofloxacin semihydrate 370g
(-) glutamic acid 147g
Pure water 2L
95% ethanol 10L
Preparation method:
(-) ofloxacin semihydrate (370 gram) and (-) glutamic acid (133 gram) are added in the entry together, get clear and bright solution, record pH5.0-7.0.This solution is injected the container that 95% ethanol (10 liters) are housed, separate out the off-white color crystalline material, dry that light yellow crystalline powder is (-) ofloxacin (-) glutamate, Glu, product yield about 70%.
Embodiment 3
The prescription of tablet
(-) ofloxacin (-) aspartate 140g
Microcrystalline Cellulose 30g
Starch 60g
HPMC 10g
Magnesium stearate 5g
Make 1000
Preparation method: get (-) ofloxacin (-) aspartate of recipe quantity and the starch mixing of microcrystalline Cellulose and 1/2 recipe quantity, add 1%HPMC solution system soft material, 16 mesh sieves are granulated, 70 ℃ of dryings 6 hours add remaining starch and magnesium stearate, mixing, tabletting, promptly.
Embodiment 4
Capsular prescription
(-) ofloxacin (-) aspartate 70g
CMC-Na 10g
MCC 10g
Lactose 60g
Make 1000 of capsules
Preparation method: (-) ofloxacin (-) aspartate, CMC-Na, MCC, the lactose of getting recipe quantity are crossed 80 mesh sieve mix homogeneously, and the soft ability of the ethanol system with 50% is granulated through 16 mesh sieves, in 70 ℃ of dryings 4 hours, and through 20 order granulate, the capsule of packing into No. 2, promptly.
Embodiment 5
The prescription of syrup:
(-) ofloxacin (-) aspartate 27g
Sucrose 200g
Aspartame 4g
Essence 1ml
Add water to 1000ml
Preparation method: get recipe quantity sucrose, aspartame is dissolved in water, filtered while hot is cooled to room temperature, and after other got recipe quantity (-) ofloxacin (-) aspartate and is dissolved in water, with aforementioned solution mixing, sterilization added essence, packing, promptly.
Embodiment 6
The prescription of aqueous injection:
(-) Aspartic Acid (-) ofloxacin 68g
Water for injection adds to 1000ml
Preparation method: after getting recipe quantity (-) ofloxacin (-) aspartate and being dissolved in water, add needle-use activated carbon, 50 ℃ are stirred 15～30min, filter carbon removal, cross 0.22 μ m microporous filter membrane, packing, and sterilization, promptly.
Embodiment 7
The prescription of aqueous injection:
(-) ofloxacin semihydrate 50g
(-) Aspartic Acid 18g
Water for injection adds to 1000ml
Preparation method: recipe quantity (-) ofloxacin is become clear solution with (-) Aspartic Acid in water for injection, and add the injection water, add needle-use activated carbon to 1000ml, 50 ℃ are stirred 15～30min, filter carbon removal, cross 0.22 μ m microporous filter membrane, packing, sterilization, promptly.
Embodiment 8
The prescription of lyophilized injection:
(-) ofloxacin semihydrate 50g
(-) Aspartic Acid 18g
Water for injection adds to 1000ml
Preparation method: recipe quantity (-) ofloxacin is become clear solution with (-) Aspartic Acid in water for injection, and add the injection water, add needle-use activated carbon to 1000ml, 50 ℃ are stirred 15～30min, filter carbon removal, cross 0.22 μ m microporous filter membrane, packing, lyophilization, promptly.
Embodiment 9
The prescription of injectable powder:
(-) ofloxacin (-) aspartate 50g
Water for injection adds to 1000ml
Preparation method: after getting (-) ofloxacin (-) aspartate and being dissolved in water, add needle-use activated carbon, 50 ℃ are stirred 15～30min, filter carbon removal, cross 0.22 μ m microporous filter membrane, packing, and spray drying, promptly.
The prescription of eye drop
(-) ofloxacin (-) aspartate 10.0g
Sodium chloride 9.0g
Hyaluronic acid sodium 1.0g
Benzene is pricked bromine ammonia 1.0g
Water for injection adds to 1000ml
Preparation method: get (-) ofloxacin (-) aspartate of recipe quantity, add an amount of water for injection dissolving, the sodium chloride, hyaluronic acid sodium, the benzene that add recipe quantity are again pricked bromine ammonia, transfer about PH6.0, add the injection water to 1000ml, packing, promptly.
Embodiment 11
The prescription of ear drop
(-) ofloxacin (-) aspartate 30g
Glycerol 300ml
Sodium citrate 10g
Water for injection adds to 1000ml
Preparation method: (-) ofloxacin (-) aspartate of getting recipe quantity adds an amount of water for injection dissolving, adds the glycerol of recipe quantity while stirring; The sodium citrate that other gets recipe quantity adds an amount of water for injection dissolving, and this solution is added in the aforementioned solution, transfers PH5.5～6.0, adds the injection water again to 1000ml, packing, promptly.
Embodiment 12
The prescription of ointment
(-) ofloxacin (-) aspartate 270g
Stearic acid 30g
Liquid Paraffin 30g
Vaseline 200g
Tween 80 5g
Sorbitan Oleate 80 5g
Adding distil water is to 1000g
Preparation method: press recipe quantity with oil-phase component (stearic acid, liquid Paraffin, vaseline and Sorbitan Oleate 80,) and water-phase component ((-) ofloxacin (-) aspartate, Tween 80 and distilled water) be heated to 80 ℃ respectively, water is joined in the oil phase, the limit edged is stirred to condensation, packing, promptly.
Embodiment 13
The prescription of suppository
(-) ofloxacin (-) aspartate 400g
Glycerin gelatine 300g
Glycerol 50g
Add water and make 1000g
Preparation method: get glycerin gelatine and melt in water-bath, (-) ofloxacin (-) aspartate is dissolved in the suitable quantity of water, add glycerol in this saline solution, slowly add in the glycerin gelatine liquid while stirring then, stir evenly, insulation is irritated mould, promptly.
Claims (6)
1, seed amino acid (-) ofloxacin water soluble salt is characterized in that: described water soluble salt is the water soluble salt made from (-) ofloxacin and aminoacid, and its structural formula is C
18H
20FN
3O
4AnH
2O.
2, according to the described aminoacid of claim 1 (-) ofloxacin water soluble salt, it is characterized in that: described aminoacid (A) can be left-handed Aspartic Acid, glutamic acid, glycine, alanine, serine, cysteine, methionine, valine, leucine, asparagine, glutamine, phenylalanine, the Lip river propylhomoserin, acidic amino acids such as tryptophan.
3, according to the described aminoacid of claim 2 (-) ofloxacin water soluble salt, it is characterized in that: described aminoacid (-) ofloxacin water soluble salt, can contain water of crystallization, can not contain, i.e. n=0-3 yet.
4, according to the described aminoacid of claim 3 (-) ofloxacin water soluble salt, it is characterized in that: described aminoacid (-) ofloxacin water soluble salt adds oral agents, injection, eye drop, unguentum and the suppository that suitable pharmaceutical adjuvant is made as antibacterial.
5, according to the described aminoacid of claim 4 (-) ofloxacin water soluble salt, it is characterized in that: add when aminoacid also can be the preparation of (-) ofloxacin preparation in the pharmaceutical formulation.
6, the preparation method of a kind of (-) as claimed in claim 4 ofloxacin water soluble salt pharmaceutical dosage form is characterized in that:
Preparation technology of the present invention is as follows:
A. the preparation of levofloxacin aspartate and glutamate, Glu:
Levofloxacin semihydrate and Aspartic Acid or glutamic acid are added in the entry together, clear and bright solution, record pH5.0-7.0.This solution is injected the container that 10 liters of 95% ethanol are housed, separate out the off-white color crystalline material, dry that light yellow crystalline powder is left-handed aspartate of levofloxacin or levofloxacin glutamate, Glu;
B. mixing routinely with various excipient substances above-mentioned salt respectively, pharmaceutical methods is mixed and made into various pharmaceutical dosage forms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005101252462A CN1785193A (en) | 2005-11-21 | 2005-11-21 | Amino acid (-) ofloxacin water soluble salt |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005101252462A CN1785193A (en) | 2005-11-21 | 2005-11-21 | Amino acid (-) ofloxacin water soluble salt |
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| Publication Number | Publication Date |
|---|---|
| CN1785193A true CN1785193A (en) | 2006-06-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005101252462A Pending CN1785193A (en) | 2005-11-21 | 2005-11-21 | Amino acid (-) ofloxacin water soluble salt |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009136408A1 (en) * | 2008-04-09 | 2009-11-12 | Institute Of Life Sciences | Synergistic pharmaceutical cocrystals |
-
2005
- 2005-11-21 CN CNA2005101252462A patent/CN1785193A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009136408A1 (en) * | 2008-04-09 | 2009-11-12 | Institute Of Life Sciences | Synergistic pharmaceutical cocrystals |
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Open date: 20060614 |