CN101849937A - Medicament compound of ornidazole and dextran and preparation method thereof - Google Patents
Medicament compound of ornidazole and dextran and preparation method thereof Download PDFInfo
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- CN101849937A CN101849937A CN200910019771A CN200910019771A CN101849937A CN 101849937 A CN101849937 A CN 101849937A CN 200910019771 A CN200910019771 A CN 200910019771A CN 200910019771 A CN200910019771 A CN 200910019771A CN 101849937 A CN101849937 A CN 101849937A
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Abstract
The invention belongs to the technical field of medicines, and discloses a medicament compound of ornidazole and dextran and a preparation method thereof. The weight ratio of the compound of ornidazole and dextran is 1:0.05-0.3, and the compound also contains other addictives. In the invention, the compound has the advantages of stable characteristics as well as safe and effective clinical medication, and is used for preparing medicaments for treating anaerobe and antiprotozoal infection.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to the pharmaceutical composition and the preparation method of ornidazole and dextran.
2, background technology
Ornidazole is a nitro imidazole derivatives, is third generation nitro imidazole derivatives behind metronidazole, is the medicine that a kind of powerful anaerobe resistant and protozoacide infect, and curative effect is higher, and the course of treatment is shorter, and toleration is better, and it is wider to distribute in the body.The anti-microbial effect of ornidazole is to be reduced into amino by the nitro in its molecule in oxygen-free environment, or interacts by the formation and the cell component of free radical, thereby causes the death of microorganism.Can be widely used in the various diseases that treatment is caused by infection such as anaerobe, ameba, merchant infusorian, trichomonacides.It is common clinical that anaerobe and protozoacide infect, and the sickness rate height, has a very wide distribution, and comprises abdominal infection, pelvic infection, oral cavity infection, surgical infection, brain infection, septicemia, bacterium blood disorder, amebic dysentery, amebic liver abscess etc.
Ornidazole (α-(chloromethyl)-2-methyl-5-nitro imidazoles-1-ethanol) is white or little yellow crystalline powder, odorless, bitter in the mouth, meet photochromic gradual change Huang, easily molten in ethanol, molten in the water part omitted, what be subject to light, heat, alkali condition influences the generation hydrolysis, generate epoxide, further generate glycol again, in clinical use, have potential safety hazard.Chinese patent 200410092247,200510068419,200510094489,200610086416 etc. discloses the injection of ornidazole, 200510102377 disclose the injectable powder of ornidazole, what have also adds the stability that antioxidant or metal chelating agent strengthen ornidazole, but does not tackle the problem at its root.So, be badly in need of a kind of ornidazole injection liquid of good stability.
3, summary of the invention
The object of the present invention is to provide a kind of stable in properties, safe, controlled ornidazole and the pharmaceutical composition of dextran.
The pharmaceutical composition of ornidazole of the present invention and dextran is characterized in that, the weight ratio of the two is 1: 0.05～0.3, preferred 1: 0.1～0.2.
Dextran (Dextran) is that the glucose polymer exquisiteness that sucrose is produced after leuconostoc mesenteroide L.M-1226 (Leuconostoc mesenteroides) fermentation forms.Because polymeric glucose molecule number difference, produce the product of different polymerization degree, be divided into high molecular dextran, medium molecular dextran, low molecular dextran and Dextran 10, as dextran 5 (molecular weight is 4500-5500), Dextran 10 (molecular weight is 9000-1100), Dextran-20 (molecular weight is 16000-24000), Dextran 40 (molecular weight is 32000-42000), macrodex (molecular weight is 64000-76000), Dextran 10 0 (molecular weight is 90000-110000), and molecular weight and intrinsic viscosity increase along with the increase of the degree of polymerization.
With ornidazole and dextran use in conjunction, have following effect in the pharmaceutical composition of the present invention:
Contain hydroxyl in the ornidazole molecular structure, store or use in, what be subject to light, heat, alkali condition influences the generation hydrolysis, generates epoxide, further generates glycol again, has potential safety hazard in clinical use.Dextran is the macromolecule glucose polymer, contain a large amount of hydroxyls in the molecular structure, with the ornidazole use in conjunction, can be cross-linked to form stabilising system with hydrogen bond between the hydroxyl in dextran and the ornidazole molecular structure, can effectively prevent in storage process because the degraded that factors such as light, heat cause, and the degree of polymerization of dextran is big more, and crosslinked action is obvious more, and preparation stability is good more; The dextran high molecular polymer is interweaved in aqueous solution and is connected to form grid structure, and ornidazole is distributed in this network structure, has avoided intermolecular polymerization, has strengthened the safety of medicine, has improved storage-stable.
The pharmaceutical composition of ornidazole of the present invention and dextran also contains additives, comprises organic solvent, antioxidant and pH regulator agent.
Described organic solvent is selected from one or more in propylene glycol, ethanol, Polyethylene Glycol, the glycerol, preferred propylene glycol, more preferably 1,2-propylene glycol.
Described antioxidant is selected from one or more in sodium citrate, sodium sulfite, sodium sulfite, disodiumedetate, the sodium pyrosulfite, preferred disodiumedetate.
Described pH regulator agent is selected from one or more in citric acid, tartaric acid, maleic acid, malic acid, succinic acid, methanesulfonic acid, lactic acid, acetic acid, sodium bicarbonate, sodium carbonate, ammonia, sodium hydroxide, hydrochloric acid, sulphuric acid, the phosphoric acid, preferred hydrochloric acid or sodium hydroxide.
Pharmaceutical composition of the present invention can be made pharmaceutically acceptable arbitrary dosage form, preferred injection.
The present invention is the preparation method of claimed medicine composition injection of the present invention also:
1) measures water for injection adding hydrochloric acid and stir, add the ornidazole stirring and make dissolving, suck dense preparing tank;
2) propylene glycol is added dense preparing tank, add dextran then, stirring and dissolving, heating is dissolved principal agent fully;
3) with an amount of water for injection dissolving disodiumedetate, add dense preparing tank, stir evenly;
4) add needle-use activated carbon, heating stirs, and absorption is taken off charcoal to thinning tank with microporous filter membrane pressure filtration while hot, stirs, and regulates pH value, and benefit adds to the full amount of water for injection;
5) check intermediate color, pH value, content etc., qualified after, use the microporous filter membrane fine straining;
6) embedding, flowing steam sterilization;
7) lamp inspection, quality examine entirely qualified after, the packing, the warehouse-in.
The advantage of pharmaceutical composition of the present invention is:
1) can be cross-linked to form stabilising system with hydrogen bond between the hydroxyl on dextran and the ornidazole molecular structure, make ornidazole injection liquid stable in properties in storage and use, medication is accurate, makes clinical application more safe and effective;
2) preparation technology is simple, with low cost.
Below example further specifies beneficial effect of the present invention by experiment, but should not be construed as limitation of the present invention.
The screening of experimental example 1 dextran
The injection that the dextran of test sample ornidazole and different polymerization degree (comprising dextran 5, Dextran 10, Dextran-20, Dextran 40, macrodex and Dextran 10 0) is made, proportioning: 1: 0.1, preparation method was referring to embodiment.
Experimental technique places test sample respectively in illumination experimental box (intensity of illumination 4500Lx) and the calorstat (40 ℃ of constant temperature), places 10 days, the 5th day and sampling detection in the 10th day.
The content of investigation project effective ingredient ornidazole, the content of related substance.
It is an amount of that [related substance] gets test sample, adds mobile phase and be diluted to the contrast solution that contains 5 μ g among the need testing solution that contains 500 μ g among every 1mL and the every 1mL, measures according to the chromatographic condition under the assay item.Get contrast solution 20 μ L and inject chromatograph of liquid, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10～20% of full scale; Get each 20 μ L of need testing solution and contrast solution again, inject chromatograph of liquid respectively, the record chromatogram is to 2 times of main constituent peak retention time, in the chromatogram of need testing solution as show impurity peaks, measure each impurity peak area and, must not be greater than the main peak area (1.0%) of contrast solution
[assay] measured according to high performance liquid chromatography (two appendix VI of Chinese Pharmacopoeia version in 2005 D).
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are filler, with methanol-water-glacial acetic acid (30: 70: 0.2) is mobile phase, flow velocity is 1.0mL/min, the detection wavelength is 310nm, theoretical cam curve is calculated by the ornidazole peak and is not less than 2500, and the separating degree of ornidazole and main impurity peaks should be not less than 3.
The algoscopy precision is measured test sample 1mL, puts in the 100mL measuring bottle, adds mobile phase and is diluted to scale, shakes up, and precision is measured 1mL, puts in the 10mL measuring bottle, adds mobile phase and is diluted to scale, shakes up, and gets 20 μ L and injects chromatograph of liquid, and the record chromatogram is measured peak area; Other learns from else's experience, and to be dried to the ornidazole reference substance of constant weight an amount of for 60 ℃ of vacuum decompressions, accurately claims surely, adds the mobile phase dissolving and quantitatively be diluted to the solution that contains 50 μ g among the 1mL, measures with method, calculates, promptly.
Experimental result sees Table 1 and table 2.
Table 1 illumination experimental result
The thermally-stabilised experimental result of table 2
By table 1, table 2 experimental result as seen, under intensity of illumination 4500Lx or 40 ℃ of conditions of high temperature, placed 5 days and 10 days, the content of the injection that ornidazole and dextran 5, Dextran 10 are made obviously descends, the content of the injection that ornidazole and Dextran-20, Dextran 40, macrodex or Dextran 10 0 are made descends little, illustrate that dextran can significantly improve the stability of ornidazole, and it is relevant with the degree of polymerization of dextran, the degree of polymerization is big more, crosslinked action is good more, and stability is strong more.Consider the feasibility of production cost and preparation, the injection of selecting Dextran-20, Dextran 40 or macrodex and ornidazole to make, stability is best.
The proportioning screening of experimental example 2 ornidazoles and dextran
The injection that the different proportionings with Dextran 40 of test sample ornidazole are made, preparation method is referring to embodiment.
Experimental technique places test sample respectively in illumination experimental box (intensity of illumination 4500Lx) and the calorstat (40 ℃ of constant temperature), places 10 days, the 5th day and sampling detection in the 10th day.
The content of investigation project effective ingredient ornidazole, the content of related substance, assay method is with experimental example 1.
Experimental result sees Table 3 and table 4.
Table 3 illumination experimental result
The thermally-stabilised experimental result of table 4
By table 3, table 4 experimental result as seen, placed 5 days and 10 days ornidazole: dextran 1 under intensity of illumination 4500Lx or 40 ℃ of conditions of high temperature: 0.01,1: 0.4 group, ornidazole content descends bigger, and impurity content raises bigger; Ornidazole: dextran is 1: 0.05,1: 0.1,1: 0.15,1: 0.2,1: 0.25,1: 0.3 group, ornidazole content and impurity content change less, stability to light and heat is all better, especially ornidazole: dextran is that 1: 0.1,1: 0.15,1: the 0.2 group of stability to light and heat is better, illustrate that dextran has significant role to the stability of enhancing ornidazole.
The stability study of experimental example 3 injection of the present invention
Test sample listing ornidazole injection liquid, commercial, 5mL/0.25g, SHANXI POWERDONE PHARMACEUTICAL.,LTD;
Experimental technique is test sample, is that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature, respectively at the 0th, 3,6 the end of month sampling and measuring.
The content of investigation project effective ingredient ornidazole, the content of related substance, assay method is with experimental example 1.
Experimental result sees Table 5.
Table 5 stability experiment is investigated
By table 5 as seen, be that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature, the active constituent content of embodiment of the invention prescription 1, prescription 2 and 3 injection of writing out a prescription descends to some extent; Listing ornidazole injection liquid was placed 3 months and 6 months content of effective all significantly descend.Embodiment of the invention prescription 1, prescription 2 and write out a prescription 3 injection and listing ornidazole injection liquid phase ratio, stability obviously improves.
By the experimental result of experimental example 1-3 as seen, the accelerated stability of the light stability of injection of the present invention, heat stability and 6 months ornidazole injection liquid that goes on the market all is significantly increased, and drug quality is more easy to control, and the clinical practice safety is higher.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.
Embodiment
Prescription 1:
Ornidazole 250g
Dextran 40 25g
1,2-propylene glycol 2500mL
0.1M the about 40mL of hydrochloric acid solution
EDTA-2Na 1g
Active carbon 5g
Water for injection adds to 5000mL
Be prepared into 1000 altogether
Prescription 2:
Ornidazole 500g
Dextran 40 50g
1,2-propylene glycol 5000mL
0.1M the about 80mL of hydrochloric acid solution
EDTA-2Na 2g
Active carbon 10g
Water for injection adds to 10000mL
Be prepared into 1000 altogether
Prescription 3:
Ornidazole 250g
Dextran 40 12.5g
1,2-propylene glycol 2500mL
0.1M the about 40mL of hydrochloric acid solution
EDTA-2Na 1g
Active carbon 5g
Water for injection adds to 5000mL
Be prepared into 1000 altogether
Prescription 4:
Ornidazole 500g
Dextran 40 25g
1,2-propylene glycol 5000mL
0.1M the about 80mL of hydrochloric acid solution
EDTA-2Na 2g
Active carbon 10g
Water for injection adds to 10000mL
Be prepared into 1000 altogether
Prescription 5:
Ornidazole 250g
Dextran 40 50g
1,2-propylene glycol 2500mL
0.1M the about 40mL of hydrochloric acid solution
EDTA-2Na 1g
Active carbon 5g
Water for injection adds to 5000mL
Be prepared into 1000 altogether
Prescription 6:
Ornidazole 500g
Dextran 40 100g
1,2-propylene glycol 5000mL
0.1M the about 80mL of hydrochloric acid solution
EDTA-2Na 2g
Active carbon 10g
Water for injection adds to 10000mL
Be prepared into 1000 altogether
Prescription 7:
Ornidazole 250g
Dextran 40 37.5g
1,2-propylene glycol 2500mL
0.1M the about 40mL of hydrochloric acid solution
EDTA-2Na 1g
Active carbon 5g
Water for injection adds to 5000mL
Be prepared into 1000 altogether
Prescription 8:
Ornidazole 500g
Dextran 40 75g
1,2-propylene glycol 5000mL
0.1M the about 80mL of hydrochloric acid solution
EDTA-2Na 2g
Active carbon 10g
Water for injection adds to 10000mL
Be prepared into 1000 altogether
Prescription 9:
Ornidazole 250g
Dextran 40 2.5g
1,2-propylene glycol 2500mL
0.1M the about 40mL of hydrochloric acid solution
EDTA-2Na 1g
Active carbon 5g
Water for injection adds to 5000mL
Be prepared into 1000 altogether
Prescription 10:
Ornidazole 500g
Dextran 40 5g
1,2-propylene glycol 5000mL
0.1M the about 80mL of hydrochloric acid solution
EDTA-2Na 2g
Active carbon 10g
Water for injection adds to 10000mL
Be prepared into 1000 altogether
Preparation technology:
1) the injection water of measuring recipe quantity 80% adds hydrochloric acid and stirs, and adds ornidazole and stirs and make dissolving, sucks dense preparing tank;
2) with 1 of recipe quantity, the 2-propylene glycol adds dense preparing tank, adds dextran then, and stirring and dissolving is heated to 82 ℃ principal agent is dissolved fully;
3) with an amount of water for injection dissolving disodiumedetate, add dense preparing tank, stir evenly;
4) add dosing amount 0.1% (W/V) needle-use activated carbon, stir, behind 82 ℃ of about 15min of standing adsorption, take off charcoal to thinning tank with 0.45 μ m microporous filter membrane pressure filtration while hot, stir, reconcile pH value to 2.0, benefit adds to the full amount of water for injection;
5) check intermediate color, pH value, content etc., qualified after, with 0.22 μ m microporous filter membrane fine straining;
6) embedding, 115 ℃ of flowing steam sterilization 30min (the 10mL:0.5g specification is 115 ℃ of flowing steam sterilization 45min);
7) lamp inspection, quality examine entirely qualified after, the packing, the warehouse-in.
Claims (10)
1. the pharmaceutical composition of ornidazole and dextran is characterized in that the weight ratio of the two is 1: 0.05～0.3.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the weight ratio of the two is 1: 0.1～0.2.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, also contains additives, comprises organic solvent, antioxidant and pH regulator agent.
4. pharmaceutical composition as claimed in claim 3 is characterized in that, organic solvent is a propylene glycol.
5. pharmaceutical composition as claimed in claim 3 is characterized in that, antioxidant is disodiumedetate.
6. the pharmaceutical composition shown in claim 3 is characterized in that, the pH regulator agent is hydrochloric acid or sodium hydroxide.
7. as the described pharmaceutical composition of the arbitrary claim of claim 1～6, it is characterized in that described dextran is Dextran-20, Dextran 40 or macrodex.
8. as the described pharmaceutical composition of the arbitrary claim of claim 1～6, it is characterized in that, can be made into pharmaceutically acceptable arbitrary dosage form.
9. as the described pharmaceutical composition of the arbitrary claim of claim 1～6, it is characterized in that, make injection.
10. the preparation method of injection as claimed in claim 9 is characterized in that, may further comprise the steps:
Measure water for injection adding hydrochloric acid and stir, add the ornidazole stirring and make dissolving, suck dense preparing tank;
Propylene glycol is added dense preparing tank, add dextran then, stirring and dissolving, heating is dissolved principal agent fully;
With an amount of water for injection dissolving disodiumedetate, add dense preparing tank, stir evenly;
Add needle-use activated carbon, heating stirs, and absorption is taken off charcoal to thinning tank with microporous filter membrane pressure filtration while hot, stirs, and regulates pH value, and benefit adds to the full amount of water for injection;
Check intermediate color, pH value, content, qualified after, use the microporous filter membrane fine straining;
Embedding, flowing steam sterilization;
Lamp inspection, quality examine entirely qualified after, the packing, the warehouse-in.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910019771A CN101849937A (en) | 2009-03-31 | 2009-03-31 | Medicament compound of ornidazole and dextran and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910019771A CN101849937A (en) | 2009-03-31 | 2009-03-31 | Medicament compound of ornidazole and dextran and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127379A (en) * | 2014-08-14 | 2014-11-05 | 珠海亿邦制药股份有限公司 | Ornidazole injection and preparation method thereof |
| CN104510702A (en) * | 2013-10-05 | 2015-04-15 | 长春海悦药业有限公司 | Ornidazole-containing pharmaceutical composition and preparation thereof |
-
2009
- 2009-03-31 CN CN200910019771A patent/CN101849937A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104510702A (en) * | 2013-10-05 | 2015-04-15 | 长春海悦药业有限公司 | Ornidazole-containing pharmaceutical composition and preparation thereof |
| CN104510702B (en) * | 2013-10-05 | 2017-09-12 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing Ornidazole and its preparation |
| CN104127379A (en) * | 2014-08-14 | 2014-11-05 | 珠海亿邦制药股份有限公司 | Ornidazole injection and preparation method thereof |
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Application publication date: 20101006 |