CN1923196A - Medicinal composition containing l-ornidazole and its application - Google Patents
Medicinal composition containing l-ornidazole and its application Download PDFInfo
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- CN1923196A CN1923196A CN 200610086416 CN200610086416A CN1923196A CN 1923196 A CN1923196 A CN 1923196A CN 200610086416 CN200610086416 CN 200610086416 CN 200610086416 A CN200610086416 A CN 200610086416A CN 1923196 A CN1923196 A CN 1923196A
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Abstract
The invention relates to a drug compound with levamisole. Wherein, said levamisole is acceptable salt and solvent; and the invention also provides an application to prepare anti-anaerobe affection drug. The content of levamisole or acceptable salt or solvent is 0.01-99%; and the best unit agent is 10-1000mg levamisole or acceptable salt or solvent, or 50-750mg, or 200-250mg.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and application in the preparation anti anaerobic bacteria infection medicine thereof that contains l-ornidazole, belong to medical technical field.
Background technology
Ornidazole (ornidazole), chemistry 2-methyl isophthalic acid by name-(3-chloro-2-hydroxypropyl)-3-nitro-1H-imidazoles is a good anaerobe resistant and protozoacidal 5-nitro glyoxaline antibiotic, sale and clinical practice is its raceme in the market.The method report for preparing the ornidazole optical enantiomer is less, and CN1212405 has reported from the raceme of ornidazole and utilized enzyme process to split the method that obtains optically pure ornidazole, but this method is unsuitable for suitability for industrialized production.
L-ornidazole is the present left body of marketed drug ornidazole, chemical name: S-(-)-1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitro imidazoles, and structural formula is:
Ornidazole is a nitro imidazole derivatives, and its mechanism of action may be: by the nitro in its molecule, be reduced into amino or the formation by free radical at oxygen-free environment, interact with cell component, thereby cause microbial death.
The racemization ornidazole finds that in clinical practice it has untoward reaction, for reducing the ornidazole untoward reaction, reduce or delay fastbacteria generation, improve its clinical efficacy, improve its pharmaco-kinetic properties, increase its stability, the inventor has obtained l-ornidazole, and it has been carried out the comparative study of safety and effectiveness.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition that contains l-ornidazole, this l-ornidazole is mainly acceptable salt and solvate thereof on the pharmaceutics.
Another object of the present invention is to provide the above-mentioned application of pharmaceutical composition in the preparation anti anaerobic bacteria infection medicine that contains l-ornidazole.
In the compositions of the present invention, acceptable salt or its solvate weight content are 0.01-99% on l-ornidazole or its pharmaceutics, wherein preferred per unit preparation (as every, every bottle, every bag) contains acceptable salt or solvate 10～1000mg on l-ornidazole and the pharmaceutics thereof, further preferred 50～750mg, more preferably 200～250mg.
The preparation method of ornidazole optical enantiomer is a raw material with 2-methyl-5-nitro imidazoles and S-(+)-epoxychloropropane or R-(-)-epoxychloropropane, in organic solvent and under the catalysis of Lewis acid, react, obtain S-(-)-ornidazole or R-(+)-ornidazole, its reaction scheme is as follows:
Specifically comprise the steps:
A) add 2-methyl-5-nitro imidazoles in organic solvent, under the catalysis of Lewis acid, add S-(+)-epoxychloropropane or R-(-)-epoxychloropropane, the control reacting liquid temperature is lower than 10 ℃, and the response time is 1.5-8 hour;
B) reaction is finished, and above-mentioned reactant liquor is added frozen water, is hydrolyzed, and reacting liquid temperature is no more than 30 ℃, stirs 0.5-2 hour, filters, and adds acid in the filtrate, transfers to pH to 0.5-2.0;
C) above-mentioned gained mixed liquor, filters to 3-4 with weak adjusting PH with base, and filtrate to 7.0-7.5, is told organic layer with weak adjusting PH with base, uses the desiccant drying, and evaporated under reduced pressure gets crude product;
D) above-mentioned gained crude product gets S-(-)-ornidazole or R-(+)-ornidazole with organic solvent or alcohol/aqueous solution recrystallization.Above-mentioned steps A) preferred 2-6 of the response time in hour, the preferred 0-10 of reaction temperature ℃.Above-mentioned steps B) pH preferably transfers to 1.0 in.
Above-mentioned organic solvent is ethyl acetate, chloroform or dichloromethane; Be preferably ethyl acetate.Above-mentioned Lewis acid is iron chloride, zinc chloride and aluminum chloride; Be preferably aluminum chloride.
Above-mentioned acid is concentrated hydrochloric acid or 50% sulphuric acid.Above-mentioned weak base is ammonia, sodium bicarbonate aqueous solution, triethylamine or diethylamine, is preferably ammonia.Above-mentioned desiccant is anhydrous sodium sulfate or anhydrous magnesium sulfate.
Step D) described organic solvent is a toluene; Alcohol/aqueous solution is preferably 40%-60% (V/V) ethanol water, more preferably 50% ethanol water.
Resulting ornidazole optical enantiomer optical purity can reach 99.5%.
Pharmaceutical composition of the present invention can be prepared as the gastrointestinal administration preparation, also can be prepared as the parenteral administration preparation.
Gastrointestinal administration preparation of the present invention can be tablet, dispersible tablet, capsule, granule, oral liquid, syrup, preferred tablet, dispersible tablet, capsule.
Parenteral administration preparation of the present invention can be infusion preparation, injection and injection powder pin, can also be the vagina administration preparation, preferred effervescent tablet of vagina administration preparation and suppository.
The preparation method of l-ornidazole infusion preparation and injection is acceptable salt or solvate on l-ornidazole and the pharmaceutics thereof to be mixed with water for injection contact, perhaps with the intravenously administrable acceptable auxiliary, after osmotic pressure regulator, organic solvent, solubilizing agent, pH value regulator mixing contact, contact with water for injection again, realize obtaining by following step:
A. l-ornidazole is added the dissolving of injection water, add the receivable carrier mixing of medicine, add the injection water to ormal weight;
B. regulate pH value;
C. filter;
D. embedding;
E. sterilization.
Described osmotic pressure regulator is selected from alkali metal salt, sodium chloride, potassium chloride, Borax, Chile saltpeter, the boric acid of glucose, glucose, perhaps their mixture.
Described organic solvent is selected from propylene glycol, glycerol, Polyethylene Glycol, ethanol, dimethyl sulfoxide etc., or the mixture of their arbitrary proportions.
Described solubilizing agent is selected from tween 80, sodium lauryl sulphate, poloxamer etc.
Described pH regulator agent is selected from hydrochloric acid, sodium hydroxide, citric acid, lactic acid, phosphate or citrate buffer.
Described caffolding agent is selected from sodium chloride, glucose, mannitol, lactose and gelatin hydrolysate etc.
The preparation method of the freeze-dried powder of l-ornidazole contains following a few step:
A. preparating liquid: l-ornidazole is added the dissolving of injection water, can add the receivable carrier mixing of medicine, add the injection water to ormal weight;
B. depyrogenation: in the medicinal liquid of step a, add the injection active carbon and filtered in 20 minutes in 60～70 ℃ of heating;
C. degerming: the filtrate of step b is carried out degerming with germ tight filter filter;
D. fill: carry out sterile filling with the control antibiotic bottle;
E. lyophilizing: under cryogenic vacuum, carry out lyophilization.
The pharmaceutical composition that the present invention mentions can be used for the treatment of responsive protozoa and anti anaerobic bacteria infection.
Compositions of the present invention has been carried out pharmacological toxicology research, estimates its safety and effectiveness.
The specific embodiment
Embodiment 1
Present embodiment is the preparation of l-ornidazole sheet (250mg/ sheet).
Get l-ornidazole 250g, starch 30g, 2%HPMC aqueous solution 80ml, carboxymethylstach sodium 15g, magnesium stearate 2g, according to following steps:
A, preparation 2%HPMC solution are an amount of, standby;
B, former, adjuvant is suitably dry crosses 100 mesh sieves respectively, and is standby;
C, take by weighing former, adjuvant by recipe quantity.Behind l-ornidazole, starch, carboxymethylstach sodium mix homogeneously, add 2%HPMC solution and make soft material, with 20 mesh sieve system wet granulars;
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add magnesium stearate, with 20 mesh sieve granulate; Measure content, it is heavy to calculate sheet;
E, select 10mm dimple form drift tabletting for use, make 1000.
F, product inspection, qualified after, packing warehouse-in.
Embodiment 2
This example is the preparation of l-ornidazole sheet (500mg/ sheet).
Get l-ornidazole 500g, lactose 30g, microcrystalline Cellulose 30g, 2%HPMC aqueous solution 160ml, carboxymethylstach sodium 30g, magnesium stearate 4g, be prepared according to the preparation method of embodiment 1,1000.
Embodiment 3
This example is the preparation of l-ornidazole dispersible tablet (250mg/ sheet).
Get following component:
L-ornidazole 250g
Pregelatinized Starch 50g
Microcrystalline Cellulose 50g
Carboxymethylstach sodium 20g
The about 90ml of 2%HPMC aqueous solution
Micropowder silica gel 20g
Stevia glucoside 18g
Magnesium stearate 2g
Be prepared according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, adjuvant is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, adjuvant by recipe quantity.Behind l-ornidazole, pregelatinized Starch, microcrystalline Cellulose, carboxymethylstach sodium, stevia glucoside mix homogeneously, add 2%HPMC solution and make soft material, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in 55 ℃ of dryings 3 hours, add micropowder silica gel, magnesium stearate, with 20 mesh sieve granulate.Measure content, it is heavy to calculate sheet.
E, select 11mm dimple form drift tabletting for use, 1000.
F, product inspection, qualified after, packing warehouse-in.
Embodiment 4
This example is the preparation of l-ornidazole dispersible tablet (50mg/ sheet).
Get following component:
L-ornidazole 50g
Pregelatinized Starch 10g
Microcrystalline Cellulose 10g
Carboxymethylstach sodium 4g
The about 18ml of 2%HPMC aqueous solution
Micropowder silica gel 4g
Sucrose 4g
Magnesium stearate 0.4g
Make 1000 according to the method for embodiment 3.
Embodiment 5
This example is the preparation of l-ornidazole capsule (250mg/ grain).
Get following component:
L-ornidazole 250g
Starch 30g
The about 80ml of 2%HPMC aqueous solution
Carboxymethylstach sodium 15g
Magnesium stearate 2g
Be prepared according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, adjuvant is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, adjuvant by recipe quantity.Behind l-ornidazole, starch, carboxymethylstach sodium mix homogeneously, add 2%HPMC solution system soft material, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add magnesium stearate, with 20 mesh sieve granulate.Measure content, calculate loading amount.
E, select 0# capsule shells fill granule for use, 1000 of capsules.
F, with capsule polishing, dedusting.
G, product inspection, qualified after, packing warehouse-in.
Embodiment 6
This example is the preparation of l-ornidazole capsule (125mg/ grain).
Get following component:
L-ornidazole 125g
Starch 15g
Lactose 15g
The about 40ml of 2%HPMC aqueous solution
Carboxymethylstach sodium 7.5g
Magnesium stearate 1g
Carry out according to following steps:
A, preparation 2%HPMC solution are an amount of, standby.
B, former, adjuvant is suitably dry crosses 100 mesh sieves respectively, and is standby.
C, take by weighing former, adjuvant by recipe quantity.Behind l-ornidazole, starch, lactose, carboxymethylstach sodium mix homogeneously, add 2%HPMC solution system soft material, with 20 mesh sieve system wet granulars.
D, wet granular cool after the drying slightly in about 3 hours of 55 ℃ of dryings, add magnesium stearate, with 20 mesh sieve granulate.Measure content, calculate loading amount.
E, select 2# capsule shells fill granule for use, 1000 of capsules.
F, with capsule polishing, dedusting.
G, product inspection, qualified after, packing warehouse-in.
Embodiment 7
This example is the preparation of l-ornidazole effervescent tablet (250mg/ sheet).
Get following component:
L-ornidazole 250g
Lactose 100g
Boric acid 92g
Sodium bicarbonate 120g
Hydroxypropyl cellulose 20g
Magnesium stearate 15g
Polyvidone 5g
95% ethanol 100ml
Carry out according to following steps:
A. supplementary material is sieved, standby;
B. polyvidone is dissolved in 95% ethanol, standby;
C. l-ornidazole, lactose, sodium bicarbonate are used 95% alcoholic solution system soft material of polyvidone, granulated;
D. c is obtained with hydroxypropyl cellulose, magnesium stearate mix homogeneously;
E. tabletting gets 1000.
Embodiment 8
This example is the preparation of l-ornidazole suppository (500mg/ piece).
Get following component:
L-ornidazole 500g
Vitamin E 1.5g
Lactic acid 30g
Semi-synthetic fatty acid glyceride (36 type) 860g
Carry out according to following steps:
1, the l-ornidazole crude drug is pulverized, it is standby to cross 100 mesh sieves;
2, take by weighing supplementary material by recipe quantity;
3, get 36 type semi-synthetic fatty acid glyceride, put heat fused in 55～60 ℃ of water-baths;
4, l-ornidazole fine powder, lactic acid, the vitamin E that will pulverize and cross 100 mesh sieves adds letter to 36 type semi-synthetic fatty acid glyceride of above-mentioned fusing, with adding with stirring to mix homogeneously, irritates mould, solidifies, and wipes the demoulding off;
5, measure content;
6, pack 1000 pieces of finished products.
Embodiment 9
This example is l-ornidazole glucose injection (100ml: preparation 250mg).
Get following component:
L-ornidazole 2.5g
Glucose 50g
0.1mol/L an amount of adjust pH to 3.5 of hydrochloric acid solution
Water for injection adds to 1000ml
Carry out according to following steps:
A, take by weighing the l-ornidazole of recipe quantity, add in the hot water for injection (70 ℃～80 ℃) that accounts for preparation total amount 50%, after the stirring and dissolving, add 0.05% active carbon by the concentrated solution amount, stir, insulation was left standstill 15 minutes, and sucking filtration takes off charcoal while hot.
B, take by weighing the glucose of recipe quantity, be dissolved in the water for injection that boils in right amount, make it into 50%～60% concentrated solution, add 0.05% active carbon, mixing, heated and boiled 15 minutes filters while hot and takes off charcoal.
C, above-mentioned l-ornidazole solution and the glucose solution that takes off behind the charcoal merged, add water for injection to 95% of amount of preparation, after stirring evenly, regulate medicinal liquid pH value to 3.5 in right amount with the 0.1mol/L hydrochloric acid solution, benefit adds to the full amount of water for injection, and stirs evenly.
D, detect intermediate color, clarity, pH value, content etc., qualified after, with polysulfones filter coarse filtration and the 0.22 μ m polysulfones filter fine straining of 0.45 μ m.
E, embedding, tamponade, rolled lid, 110 ℃ of pressure sterilizings 45 minutes, lamp inspection, entirely examine qualified, label, pack promptly; Specification: 100ml: l-ornidazole 0.25g and glucose 5g.
Embodiment 10
This example is l-ornidazole sodium chloride injection (100ml: preparation 250mg).
Get following component:
L-ornidazole 250g
Sodium chloride 825g
Citric acid 6.5g
Water for injection adds to 100L
Carry out according to following steps:
A, the l-ornidazole that takes by weighing recipe quantity, sodium chloride and citric acid.
B, main materials and auxiliary materials is dissolved in the water for injection (about 80 ℃) that accounts for preparation total amount 90%, stirs and to make dissolving fully.
C, adding 0.05% are stirred through 2 hours needle-use activated carbons of 120 ℃ of activation, leave standstill 15 minutes.
Behind d, the titanium rod filter filtering decarbonization with 0.6 μ m, benefit adds to the full amount of water for injection.
E, detect intermediate color, clarity, pH value, content etc., qualified after, with polysulfones filter coarse filtration and the 0.22 μ m polysulfones filter fine straining of 0.45 μ m.
F, 1000 bottles of embeddings, tamponade, rolled lid, 110 ℃ of pressure sterilizings 45 minutes, lamp inspection, entirely examine qualified, label, pack promptly.
Embodiment 11
This example is l-ornidazole sodium chloride injection (500ml: preparation 750mg).
Get following component:
L-ornidazole 750g
Sodium chloride 4125g
0.1mol/L hydrochloric acid is transferred pH 4.5
Water for injection adds to 500L
According to the method for embodiment 10, make 1000 bottles.
Embodiment 12
This example is the preparation of l-ornidazole injection (125mg/ props up).
Get following component:
L-ornidazole 125g
Propylene glycol 2.0L
0.1mol/L an amount of adjust pH to 3.5 of hydrochloric acid solution
Water for injection adds to 5L
Carry out according to following steps:
A. l-ornidazole is added the propylene glycol dissolving, regulate pH value, add the injection water to ormal weight;
B. add the injection active carbon in the medicinal liquid of step a filtered in 60～70 ℃ of heating in 20 minutes;
C. embedding is 1000;
D. pressure sterilizing.
Embodiment 13
This example is the preparation of l-ornidazole injection (250mg/ props up).
Get following component:
L-ornidazole 250g
Ethanol 2.5L
0.1mol/L an amount of adjust pH to 3.5 of hydrochloric acid solution
Water for injection adds to 5L
Carry out according to following steps:
A. l-ornidazole is added dissolve with ethanol, regulate pH value, add the injection water to ormal weight;
B. add the injection active carbon in the medicinal liquid of step a filtered in 60～70 ℃ of heating in 20 minutes;
C. embedding is 1000;
D. pressure sterilizing.
Embodiment 14
This example is the preparation of injection l-ornidazole freeze-dried powder (125mg/ props up).
Get following component:
L-ornidazole 125g
Mannitol 125g
0.1mol/L an amount of adjust pH to 2.5 of hydrochloric acid solution
Water for injection 3000mL
Carry out according to following steps:
A, preparating liquid: take by weighing recipe quantity l-ornidazole, mannitol, add injection water 2400mL, an amount of adjust pH to 2.5 of 0.1mol/L hydrochloric acid solution makes dissolving;
B, depyrogenation: add injection active carbon (activated carbon dosage be cumulative volume 0.1～0.3%) in the above-mentioned medicinal liquid,, filter, collect filtrate 60～70 ℃ of heating 20 minutes;
C, degerming: above-mentioned filtrate is carried out degerming by aseptic manipulation with germ tight filter filter, with 0.22 μ m microporous filter membrane;
1000 bottles of d, fills;
E, lyophilizing: pre-freeze below-40 ℃ 1.5～2 hours, under-25 ℃, 1.33Pa (0.01 holder) vacuum, distil then, remove after 90% at free moisture, after heat drying (maximum temperature must not above 30 ℃) treats that temperature curve and vacuum curve overlap respectively, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box.
F, seal and add aluminium lid.
Embodiment 15
This example is the preparation of injection l-ornidazole freeze-dried powder (250mg/ props up).
Get following component:
L-ornidazole 250g
Tween 80 120g
Mannitol 200g
0.1mol/L an amount of adjust pH to 2.5 of hydrochloric acid solution
Water for injection 6000mL
Carry out according to following steps:
A, preparating liquid: take by weighing recipe quantity l-ornidazole, tween 80, mannitol, add injection water 4800mL, an amount of adjust pH to 2.5 of 0.1mol/L hydrochloric acid solution makes dissolving.
B, depyrogenation: add injection active carbon (activated carbon dosage be cumulative volume 0.1～0.3%) in the above-mentioned medicinal liquid,, filter, collect filtrate 60～70 ℃ of heating 20 minutes.
C, degerming: above-mentioned filtrate is carried out degerming by aseptic manipulation with germ tight filter filter, with 0.22 μ m microporous filter membrane.
1000 bottles of d, fills;
E, lyophilizing: pre-freeze below-40 ℃ 1.5～2 hours, under-25 ℃, 1.33Pa (0.01 holder) vacuum, distil then, remove after 90% at free moisture, after heat drying (maximum temperature must not above 30 ℃) treats that temperature curve and vacuum curve overlap respectively, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box.
F, seal and add aluminium lid.
Embodiment 16
This example is the preparation of injection l-ornidazole powder pin (250mg/ props up): with l-ornidazole sterilized powder 250g direct packaging in hundred grades of clean areas, make 1000 bottles altogether, specification 0.25g/ bottle.
Experimental example 1
This example is the external antimicrobial research of the present invention.
Method: select the clinical separation anaerobe of 147 strains for use, adopt agar dilution to detect the minimal inhibitory concentration (MIC) of l-ornidazole and control drug racemization ornidazole, right ornidazole, metronidazole and tinidazole, adopt broth dilution method to detect minimal bactericidal concentration (MBC), and MBC and MIC are compared.
The results are shown in following table:
Table 1: l-ornidazole and contrast medicine are to MIC (μ g/ml) statistical result of 157 strain experimental bacteria
| The bacterium name | The bacterial strain number | MIC (μg/ml) | Tinidazole | Metronidazole | The racemization ornidazole | Right ornidazole | L-ornidazole |
| Bacteroid | 30 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.25-8.0 | 0.25 0.5 0.125-4.0 | 1.0 4.0 0.5-16 | 0.125 0.25 0.06-2.0 |
| Prey is irrigated bacterium | 26 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.125-16 | 0.5 1.0 0.125-16 | 0.25 0.5 0.125-8.0 | 1.0 4.0 0.5-32 | 0.125 0.25 0.06-4.0 |
| Veillonella | 20 | MIC 50 MIC 90The MIC scope | 0.25 0.5 0.25-4.0 | 0.5 0.5 0.125-4.0 | 0.25 0.5 0.25-2.0 | 0.5 1.0 0.5-8.0 | 0.125 0.25 0.06-1.0 |
| Peptostreptococcus | 20 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.25-8.0 | 0.25 0.5 0.125-4.0 | 1.0 2.0 1.0-16 | 0.125 0.25 0.06-2.0 |
| Fusobacterium | 20 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.25-8.0 | 0.5 1.0 0.125-8.0 | 0.25 0.5 0.125-4.0 | 0.5 2.0 0.5-16 | 0.125 0.25 0.06-2.0 |
| Clostridium | 31 | MIC 50 MIC 90The MIC scope | 0.5 1.0 0.125-8.0 | 0.5 1.0 0.125-8.0 | 1.0 2.0 0.25-4.0 | 2.0 8.0 0.5-16 | 0.5 1.0 0.06-2.0 |
| Propionibacterium | 5 | MIC 50 MIC 90The MIC scope | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 |
| Lactobacillus | 5 | MIC 50 MIC 90The MIC scope | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 | ＞256 ＞256 ＞256-＞256 |
| Add up to | 157 | MIC 50 MIC 90The MIC scope | 1.0 2.0 0.125-＞256 | 1.0 2.0 0.125-＞256 | 0.5 1.0 0.25-＞256 | 2.0 8.0 0.5-＞256 | 0.25 0.5 0.06-＞256 |
Table 2 l-ornidazole compares (μ g/ml) to the MIC and the MBC value of 60 strain experimental bacteria
| The bacterium name | The bacterial strain number | The MIC value | The MBC value | ||||
| MIC 50 | MIC 90 | The MIC scope | MBC 50 | MBC 90 | The MBC scope | ||
| Bacteroid | 10 | 0.125 | 0.5 | 0.06-0.5 | 0.5 | 1.0 | 0.125-1.0 |
| Prey is irrigated bacterium | 10 | 0.25 | 0.25 | 0.06-0.25 | 0.5 | 1.0 | 0.125-1.0 |
| Veillonella | 10 | 0.125 | 0.25 | 0.06-0.25 | 0.5 | 0.5 | 0.25-0.5 |
| Peptostreptococcus | 10 | 0.125 | 0.25 | 0.06-0.5 | 0.5 | 0.5 | 0.25-0.5 |
| Fusobacterium | 10 | 0.125 | 0.25 | 0.06-0.5 | 0.5 | 1.0 | 0.25-1.0 |
| Clostridium | 10 | 0.5 | 1.0 | 0.06-2.0 | 1.0 | 2.0 | 0.125-4.0 |
| Add up to | 60 | 0.25 | 0.5 | 0.06-2.0 | 0.5 | 1.0 | 0.125-4.0 |
Conclusion: the in-vitro antibacterial experimental result shows that l-ornidazole has stronger antibacterial action to clinical common anaerobe.And the MIC of l-ornidazole
50Value is hanged down 1,4,2 and 2 times than racemization ornidazole, right ornidazole, metronidazole, tinidazole respectively.L-ornidazole MBC
50Than MIC
50Low 1 times.
ED in the body
50Measure
Method: adopt Kunming kind white mice, with clinical separation bacteroides fragilis, peptostreptococcus and actinomyces pseudonecrophorus respectively infecting mouse prepare the abdominal cavity infection model, and carry out the endogenous protective experiment with the positive contrast medicine of racemization ornidazole.
The result:
Table 3 injection l-ornidazole and control drug are to the ED of infecting mouse
50And 95% fiducial limit
| Antibacterial | Bacterium number | Infection dosage (CFU/ml) | L-ornidazole | The racemization ornidazole | ||||
| MIC (μg/ml) | ED 50 (mg/kg) | ED 5095% fiducial limit (mg/kg) | MIC (μg/ml) | ED 50 (mg/kg) | ED 5095% fiducial limit (mg/kg) | |||
| Bacteroides fragilis peptostreptococcus actinomyces pseudonecrophorus | AN 21 AN 3 AN 109 | 3.5×10 8 8.0×10 7 2.5×10 8 | 0.25 0.5 0.125 | 6.5957 13.7692 9.1454 | 5.0619～8.5944 10.5655～17.9444 7.0507～11.8625 | 0.5 10 0.25 | 8.4695 20.5268 9.8251 | 6.4090～11.1925 15.4458～27.2793 7.4580～12.9433 |
Oral l-ornidazole of table 4 and control drug are to the ED of infecting mouse
50And 95% fiducial limit
| Antibacterial | Bacterium number | Infection dosage (CFU/ml) | L-ornidazole | The racemization ornidazole | ||||
| MIC (μg/ml) | ED 50 (mg/kg) | ED 5095% fiducial limit (mg/kg) | MIC (μg/ml) | ED 50 (mg/kg) | ED 5095% fiducial limit (mg/kg) | |||
| Bacteroides fragilis peptostreptococcus actinomyces pseudonecrophorus | AN 21 AN 3 AN 109 | 3.5×10 8 8.0×10 7 2.5×10 8 | 0.25 0.25 0.125 | 9.2386 15.8829 11.0329 | 6.9829～12.2231 12.1873～20.6991 8.3762～14.5322 | 0.5 0.5 0.25 | 11.1737 24.2069 11.6159 | 8.6002～14.5172 18.0868～32.3979 9.6955～16.4161 |
Conclusion: oral and injection l-ornidazole is to the ED of infecting mouse
50All be better than the racemization ornidazole, antibacterial effect is better than the racemization ornidazole.
Experimental example 2
This example is general pharmacology research.
Method: to mice, Beagle dog is laboratory animal, all gives l-ornidazole and racemization ornidazole to irritate two kinds of approach of harmonization of the stomach intravenously administrable, observes after the administration the unify influence of respiratory system of central nervous system, cardiovascular system.
The results are shown in following table:
Table 5 l-ornidazole general pharmacology result of study
| Animal | Route of administration | Dosage mg/kg | The result | |||||
| The central nervous system | Cardiovascular system | Respiratory system | ||||||
| There is/do not have influence | Symptom | There is/do not have influence | Symptom | There is/do not have influence | Symptom | |||
| Mice | Irritate stomach | 127 | -- | -- | / | / | / | / |
| 165 | + | Suppress | / | / | / | / | ||
| 215 | + | Suppress | / | / | / | / | ||
| Mice | Vein | 127 | -- | -- | / | / | / | / |
| 165 | + | Suppress | / | / | / | / | ||
| 215 | + | Suppress | / | / | / | / | ||
| Dog | Oral | 33 | / | / | -- | -- | -- | -- |
| 100 | / | / | -- | -- | -- | -- | ||
| 300 | / | / | -- | -- | -- | -- | ||
| Dog | Vein | 27 | / | / | -- | -- | -- | -- |
| 67.5 | / | / | -- | -- | -- | -- | ||
| 168.8 | / | / | -- | -- | -- | -- |
+ expression is influential;--expression does not have influence :/expression is not tested with this animal
Table 6 l-ornidazole and raceme ornidazole general pharmacology research comparative result
| Medicine | Experimental animal | Dosage mg/k g | Route of administration | The result | |||
| The spontaneous activity number of times | Sodium pentobarbital hypnosis time for falling asleep | Pentobarbital sodium hypnosis sleep time | The coordination exercise contributive rate | ||||
| Blank | Mice | 0 | Irritate stomach | 56.5±23.3 | 0±0 | 0±0 | 0 |
| Left side Austria azoles that disappears | 215 | 69.3±24.8 | 6.5±1.0 ** | 8.5±1.0 ** | 83 | ||
| Racemization Austria azoles that disappears | 215 | 75.0±21.4 | 7.1±1.0 ** | 8.3±1.6 ** | 100 | ||
| Blank | Mice | 0 | Vein | 93.1±33.3 | 0±0 | 0±0 | 0 |
| Left side Austria azoles that disappears | 215 | 113.0±29.8 | 4.1±0.9 ** | 9.9±2.0 ** | 75 | ||
| Racemization Austria azoles that disappears | 215 | 107.0±63.5 | 4.0±1.1 ** | 11.0±1.1 ** | 100 | ||
Conclusion: l-ornidazole is lower than the racemization ornidazole to central nervous system's inhibitory action, and l-ornidazole is unified respiratory system less than influence to cardiovascular system.
Studies on acute toxicity:
Method: with Kunming mouse and Beagle dog is experimental animal, and male and female half and half are irritated the harmonization of the stomach intravenous administration.
The results are shown in Table 7:
| Experimental animal | Be subjected to the reagent product | Route of administration | Solvent | Main result of study |
| Mice | L-ornidazole | Oral administration | 0.4%CMC | LD 50Value is 1610mg/kg. |
| Intravenously administrable | The 30%DMSO sodium chloride injection | LD 50Value is 615mg/kg. | ||
| The raceme ornidazole | Oral administration | 0.4%CMC | LD 50Value is 1494mg/kg. | |
| Intravenously administrable | The 30%DMSO sodium chloride injection | LD 50Value 555mg/kg. | ||
| Dog | L-ornidazole | Oral administration | 0.4%CMC | ALD is 3788～4545mg/kg. |
| Intravenously administrable | Sodium chloride injection | ALD is 1083～1300mg/kg. | ||
| The raceme ornidazole | Oral administration | 0.4%CMC | ALD is 2581～3226mg/kg. | |
| Intravenously administrable | Sodium chloride injection | ALD is 778～972mg/kg. |
Conclusion: l-ornidazole mouse vein and oral administration LD
50Value is higher than the raceme ornidazole, and l-ornidazole is higher than the raceme ornidazole to the maximum lethal dose of dog.Left side body single-dose safe in the raceme ornidazole.
Long term toxicity research
Method: with rat and Beagle dog is experimental animal, administration time 3 months, and two kinds of animals are all irritated the harmonization of the stomach intravenously administrable, the trial drug l-ornidazole.The results are shown in Table 8:
Table 8
| Medicine | Animal | Route of administration | Dosage mg/kg | The result |
| L-ornidazole | Rat | Irritate stomach | 500 | Experimental animal there is not obvious influence. |
| 1000 | Leukocyte raises, and erythrocyte, platelet descend, and main toxicity target organ is a testis. | |||
| 2000 | Leukocyte raises, and erythrocyte, platelet descend, and main toxicity target organ is a testis. | |||
| L-ornidazole | Rat | Vein | 150 | Experimental animal there is not obvious influence. |
| 300 | Leukocyte raises, and main toxicity target organ is a liver. | |||
| 600 | Leukocyte raises, and main toxicity target organ is a liver. | |||
| L-ornidazole | Dog | Oral | 50 | Experimental animal there is not obvious influence. |
| 100 | RBC, Hgb, Hc, Rc raise, and main toxicity target organ is a thymus. | |||
| 200 | RBC, Hgb, Hc, Rc raise, and main toxicity target organ is a thymus. | |||
| L-ornidazole | Dog | Vein | 50 | Experimental animal there is not obvious influence. |
| 90 | The rising of RBC, Hgb, Hc, Rc, TRI, CHO, BUN, the reduction of WBC, N, L, K+, main toxicity target organ is a thymus. | |||
| 162 | The rising of RBC, Hgb, Hc, Rc, TRI, CHO, BUN, the reduction of WBC, N, L, K+, main toxicity target organ is a thymus. |
Conclusion: irritated the harmonization of the stomach vein and give and the rat l-ornidazole in continuous 3 months, safe dose is respectively 500mg/kg and 150mg/kg (being equivalent to clinical plan 5.56 times and 1.67 times with dosage), gastric infusion toxicity target organ is a testis, and intravenously administrable toxicity target organ is a liver.Jar harmonization of the stomach vein was given and the dog l-ornidazole in continuous 3 months, and safe dose is 50mg/kg (being equivalent to clinical plan 1.87 times with dosage), and main toxicity target organ is a thymus.
Hemolytic, local excitation Journal of Sex Research
This product does not have stimulation to the injection of rabbit auricular vein.
In the hemolytic experiment of this product, haemolysis and agglutination do not appear.
With the healthy guinea pig is experimental animal, systemic anaphylaxis do not occur after injection this product.
The research shows that this product intravenously administrable is safe.
The animal pharmacokinetics research data
Method: experimental animal Beagle dog, route of administration is irritated harmonization of the stomach intravenous injection, trial drug l-ornidazole and raceme ornidazole, detection method HPLC method.The results are shown in following table:
Table 9:Beagle dog pharmacokinetics (oral) data
| Dosage | t 1/2 (h) | Cmax (μg/L) | Tmax (h) | CL mg/kg/h/(μ g/ml) | AUC (μ g/ml) Qiu | V d(L/kg) | |
| L-ornidazole | 26.7mg/kg | 8.77 | 29.02 | 2.25 | 0.062 | 433.04 | 0.78 |
| 80mg/kg | 8.06 | 80.66 | 1.95 | 0.072 | 1123.66 | 0.85 | |
| 240mg/kg | 8.13 | 233.50 | 3.80 | 0.060 | 4014.85 | 0.68 |
| The racemization ornidazole | 26.7mg/kg | 9.79 | 21.47 | 0.45 | 0.090 | 309.02 | 1.24 |
| 80mg/kg | 8.27 | 50.98 | 3.77 | 0.100 | 817.37 | 1.21 | |
| 240mg/kg | 7.86 | 153.87 | 3.49 | 0.109 | 2230.18 | 1.22 |
Table 10 Beagle dog pharmacokinetics (intravenous injection) data
| Dosage | t 1/2 (h) | CL mg/kg/h/(μg/ml) | AUC (μ g/ml) Qiu | V d(L/kg) | |
| L-ornidazole | 26.7mg/kg | 9.846 | 0.067 | 401.875 | 0.946 |
| 40mg/kg | 9.838 | 0.070 | 572.597 | 0.993 | |
| The racemization ornidazole | 26.7mg/kg | 8.36 | 0.083 | 321.47 | 1.002 |
| 40mg/kg | 7.72 | 0.101 | 405.70 | 1.093 |
Conclusion: l-ornidazole meets the one-compartment model that arranged lag time at the intravital dynamic process of dog, racemization does not take place in vivo yet, and the peak time of l-ornidazole is wanted a little higher than raceme ornidazole, and maximum plasma concentration is higher than the raceme ornidazole, prompting this product is rapid-action in vivo, and effect is strong.
Claims (11)
1, a kind of pharmaceutical composition that contains l-ornidazole is characterized in that, the active ingredient that described compositions contains is that acceptable salt or its solvate weight content are 0.01-99% on l-ornidazole or its pharmaceutics.
2, compositions according to claim 1 is characterized in that, described compositions is the parenteral administration preparation.
3, compositions according to claim 1 is characterized in that, is described compositions oral Preparation.
4, compositions according to claim 2 is characterized in that, described parenteral administration preparation is infusion preparation, injection, injection powder pin or vagina administration preparation, wherein preferred effervescent tablet of vagina administration preparation and suppository.
5, compositions according to claim 3 is characterized in that, described oral Preparation is tablet, dispersible tablet, capsule, granule or oral liquid, preferred tablet, dispersible tablet or capsule.
According to the described compositions of claim 1～5, it is characterized in that 6, described composite preparation per unit contains acceptable salt or its solvate 10～1000mg on l-ornidazole or its pharmaceutics, preferred 50～750mg, more preferably 200～250mg.
7, compositions according to claim 4, it is characterized in that, described infusion preparation or injection are acceptable salt or its solvate on l-ornidazole or its pharmaceutics to be mixed with water for injection contact, perhaps with the acceptable osmotic pressure regulator of intravenously administrable, organic solvent, pH value regulator, solubilizing agent and caffolding agent mix contact after, again with water for injection is mixed must.
8, compositions according to claim 4 is characterized in that, described powder ampoule agent for injection is by packing of solvent crystal sterilized powder or freeze-drying preparation.
9, compositions according to claim 4 is characterized in that, the preparation method of described infusion preparation or injection contains following steps:
A. l-ornidazole is added the dissolving of injection water, add the receivable carrier mixing of medicine, add the injection water to ormal weight;
B. regulate pH value;
C. embedding;
D. sterilization.
10, compositions according to claim 9 is characterized in that, described freeze-dried powder preparation method contains following steps:
A. preparating liquid: l-ornidazole is added the dissolving of injection water, can add the receivable carrier mixing of medicine, add the injection water to ormal weight;
B. depyrogenation: in the medicinal liquid of step a, add the injection active carbon and filtered in 20 minutes in 60～70 ℃ of heating;
C. degerming: the filtrate of step b is carried out degerming with germ tight filter filter;
D. fill: carry out sterile filling with the control antibiotic bottle;
E. lyophilizing: under cryogenic vacuum, carry out lyophilization.
11, the described application that contains the compositions of l-ornidazole at preparation responsive protozoa of treatment and anaerobic bacteria infection medicine of claim 1.
Priority Applications (1)
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|---|---|---|---|
| CN 200610086416 CN1923196A (en) | 2005-11-28 | 2006-06-19 | Medicinal composition containing l-ornidazole and its application |
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| CN200510115095.2 | 2005-11-28 | ||
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813622A (en) * | 2012-08-09 | 2012-12-12 | 西安万隆制药股份有限公司 | Ornidazole sodium chloride injection composition and preparation method thereof |
| CN104606187A (en) * | 2013-11-01 | 2015-05-13 | 南京圣和药业股份有限公司 | Levo ornidazole once-daily medicine dosage form |
-
2006
- 2006-06-19 CN CN 200610086416 patent/CN1923196A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102813622A (en) * | 2012-08-09 | 2012-12-12 | 西安万隆制药股份有限公司 | Ornidazole sodium chloride injection composition and preparation method thereof |
| CN104606187A (en) * | 2013-11-01 | 2015-05-13 | 南京圣和药业股份有限公司 | Levo ornidazole once-daily medicine dosage form |
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