CN101816650A - Ornidazole-sodium chloride combination and preparation method thereof - Google Patents
Ornidazole-sodium chloride combination and preparation method thereof Download PDFInfo
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- CN101816650A CN101816650A CN 201010177459 CN201010177459A CN101816650A CN 101816650 A CN101816650 A CN 101816650A CN 201010177459 CN201010177459 CN 201010177459 CN 201010177459 A CN201010177459 A CN 201010177459A CN 101816650 A CN101816650 A CN 101816650A
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Abstract
The invention relates to an ornidazole-sodium chloride combination which is prepared from the following components according to the prescription: 5.0g of ornidazole, 8.5g of sodium chloride, a right amount of hydrochloric acid, and 1000 ml of water for injection. The preparation method of the combination comprises the following steps: dissolving the ornidazole and the sodium chloride in 1000ml of the water for injection, adding activated carbon with needle uses (0.05g/100ml) according to the proportion, decoloring by stirring at 25-50 DEG C for 20-30 minutes, standing for 15 minutes, filtering, adding the hydrochloric acid to adjust the pH to 4.5, sampling to measure the pH value and the content, fine-filtering by utilizing a sintered funnel and a microporous filtering film after conforming to the requirements, carrying out clarity detection, encapsulating after being qualified, and sterilizing at high temperature.
Description
Technical field
The present invention relates to a kind of medicine that is applied to the nitro imidazole derivatives in the medical technical field, especially a kind of ornidazole and sodium chloride combination and preparation method thereof.
Background technology
It is that CN1768742A, denomination of invention are the application for a patent for invention description of " intravenous administration formulation of ornidazole and preparation method " that Chinese patent literature discloses a kind of notification number.This description has emphasized that painstakingly the preparation of its preparation is divided into a., b, four steps of c., d., and its prescription is " take by weighing the ornidazole and the adjuvant of recipe quantity, add 35 ℃～55 ℃ waters for injection of part ".According to the observation, still having certain limitation as intravenous administration formulation aspect the clinical efficacy of anti-broad spectrum fungus infection, its preferred scheme still is short of.
Summary of the invention
The objective of the invention is to provide the preparation method of a kind of ornidazole and sodium chloride combination and preparation said composition, in the hope of solving medicine with ornidazole and sodium chloride combination in requirements for clinical application.
For this reason, the technical scheme that the present invention solves described problem is: a kind of ornidazole and sodium chloride combination, and its preparation prescription amount: ornidazole 5.0g, sodium chloride 8.5g, hydrochloric acid is an amount of, and water for injection adds to 1000ml.
The preparation method of its preparation is: get ornidazole and sodium chloride and be dissolved in the 1000ml water for injection, add needle-use activated carbon (0.05g/100ml) by the dosing amount, in 25-50 ℃ with interior stirring decolouring 20-30min, leave standstill 15min, filter, add hydrochloric acid and transfer about pH to 4.5, sampling and measuring pH value and content, meet the requirements after the microporous filter membrane fine straining, through clarity embedding after the assay was approved, high temperature sterilize gets final product again.
Compared to existing technology, the ornidazole that the present invention relates to the good effect of sodium chloride combination is: the parallel comparative study of clinical randomized, double-blind, this kind treatment is by clinical efficacy and the safety and the contrast of tinidazole injection of anaerobic infection diseases such as the surgery due to the anaerobe, gynecological, the total effective rate of anaerobe resistant is respectively 100% and 98.5% (P＞0.05), and bacteria clearance is 100%.The main clinic symptoms heating improvement time is subjected to the examination group slightly faster than matched group, but no difference of science of statistics (P＞0.05).Two groups of adverse reaction rates are respectively 13.8% and 21.5%, and the untoward reaction of ornidazole group is less than Both tinidazole, but difference does not have significance (P＞0.05).Be the novel nitro imidazole derivatives of a kind of third generation after metronidazole, tinidazole, little because of its side effect, characteristics such as evident in efficacy have been widely used in treatment and have infected the various diseases that causes by anaerobe, ameba, Giardia, trichomonacide
[1-4]
The specific embodiment
The present invention relates to a kind of ornidazole and sodium chloride combination, its preparation prescription amount: ornidazole 5.0g, sodium chloride 8.5g, hydrochloric acid is an amount of, and water for injection adds to 1000ml.
The preparation method of its preparation is: get ornidazole and sodium chloride (be respectively recipe quantity 1～1.07,1～1.05 times) and be dissolved in the 1000ml water for injection, add needle-use activated carbon (0.05g/100ml) by the dosing amount, in 25-50 ℃ with interior stirring decolouring 20-30min, leave standstill 15min, filter, add hydrochloric acid and transfer about pH to 4.5, sampling and measuring pH value and content, meet the requirements after the microporous filter membrane fine straining, through clarity embedding after the assay was approved, high temperature sterilize gets final product again.
Specifically, prescription of the present invention is according to being:
It is 0.5～1.5g that Czech's pharmacopeia is recommended consumption, and pre-test result shows that the ornidazole aqueous solution is stable under solutions of weak acidity, for reducing the zest of ornidazole sodium chloride injection to blood vessel, so the development specification is the injection that 100ml contains ornidazole 0.5g.
The human plasma osmotic pressure is about 313mOsm/kgH2O, is normal range at 280～330mOsm/kgH2O generally.The osmotic pressure sum that the osmotic pressure that ornidazole produces in ornidazole sodium chloride injection and sodium chloride produce should be consistent with the human plasma osmotic pressure, calculates according to Van't Hoff (Vant-Hoff) formula should add sodium chloride 8.5 among every 1000ml and restrain, and it reached etc. ooze.
The optimum principle of its process conditions of preparation method that the present invention relates to is:
1, pH value is selected:
The pH value that will contain the mixed liquid of 0.5%ONZ and 0.85%NaCl under same temperature transfers to 3.0,3.5,4.0,4.5,5.0,5.5,6.0, fill is in the 100ml infusion bottle respectively, high temperature sterilize is investigated the variation of ornidazole, pH and 2-methyl-5-nitro imidazoles, the results are shown in Table 1.
I in the table 1, "+" expression increase, and "-" expression reduces.
Ii, ONZ% sterilization is preceding in 100%.
By above table 1 as can be seen, under the environment of pH4.5, ornidazole sodium chloride injection is more stable.
2, the selection of activated carbon dosage and operating condition
With being diluted to recipe quantity after the ornidazole of recipe quantity, the water for injection dissolving of sodium chloride with about 800ml, investigate by following scheme, detect color and luster, pH, ONZ% and bacterial endotoxin before and after its decolouring.
Following table 2 is to investigate the factor and the level of decolorization condition, wherein, and A: activated carbon dosage (g/100ml) B: bleaching time (min) C: bleaching temperature (℃) the D:pH value.
A B C D
1 0.05 20 25 3.5
2 0.10 30 50 4.5
3 0.20 40 75 5.5
4 0.30 - - -
Above table 2 testing result shows that the color and luster of pilot sample all is shallower than yellow green 2
#Standard color solution, the variation of pH value is all less than 0.40 pH unit, the content and the bacterial endotoxin of ornidazole see Table 3, as seen from table, after adding 0.05g/100ml active carbon stirred decolouring 20min, it is saturated that its adsorbance has been tending towards, and bacterial endotoxin meets the requirements, so decolorization condition is defined as activated carbon dosage 0.05g/100ml, bleaching time 20-30min, Ph is near 4.5.
Table 3 decolouring scheme and result
Trial-manufacture of sample of the present invention:
By preparation technology with the 5 times of amounts of writing out a prescription feed intake trial-production three batch samples, testing result sees Table 4
Table 4 sample detection result
"-" expression in the above table 4 meets the requirements.
The stability of formulation factors influencing that the present invention relates to:
1, strong illumination test placed the light cupboard 10 days with three batch samples, made its surperficial intensity of illumination reach 4500 ± 500Lx, in the 5th day, the 10th day sample analysis of test, and relatively with 0 o'clock analysis result, and its test item and the results are shown in Table 5-6
Table 5-6 exposure experiments to light data
Ornidazole sodium chloride injection illumination degrading product has three kinds, and one is a 2-methyl-5-nitro imidazoles, and its content is far above other two unknown peaks.Above-mentioned exposure experiments to light shows the prolongation with light application time, and 2-methyl-5-nitro imidazoles content is raising, so this product needs lucifuge when depositing.
2, hot test places the calorstat 10 days of constant temperature to 60 ℃ and 40 ℃ respectively with sample, sample analysis behind the 5th day, the 10th day of test, and with 0 o'clock analysis result relatively, investigate and the results are shown in Table 5, table 6.
40 ℃ of test datas of table 5
60 ℃ of test datas of table 6
Result of the test shows that this product is relatively stable at 40 ℃ of duration of test, and under 60 ℃ of hot conditionss poor stability, it is very fast that catabolite 2-methyl-5-nitro imidazoles increases, so should avoid depositing in the hot environment more than 60 ℃.
3, low-temperature test places constant temperature to the electric refrigerator of (4 ± 2) ℃ 10 days three batches of pilot samples, sample analysis behind the 5th day, the 10th day of test, and analysis result is relatively investigated and be the results are shown in Table 7 during with 0 day.
Table 7 low-temperature test data
Result of the test shows, this product is stable in low temperature environment, and every index changes very little, and duration of test does not see that solids separates out yet, so can leave in the low temperature environment.
The scale-up of the preparation that the present invention relates to
Feed intake for 200 times by recipe quantity, manufacture experimently three batch samples (20090404-20090406) according to preparation technology, assay sees Table 8
Table 8 scale-up result
Result of the test shows that this prescription and technology are more stable, manufactures experimently with meeting former continuous three batches of crude drug of declaring the crude drug quality standard according to this, and products made thereby meets the prescription of injection.So the former ornidazole crude drug quality standard of declaring can satisfy the injecting drug use requirement.
The test of pesticide effectiveness result of the medicine that the present invention relates to:
1, minimum inhibitory concentration
A. use ornidazole and metronidazole (doubling dilution) in test tube, trichomonas vaginitis and endameeba histolytica to be carried out the test of pesticide effectiveness, minimum inhibitory concentration data following (parenthetic numeral is 95% fiducial limit):
Annotate:
*Testing institute's value in 37 ℃ through 48 hours, is the geometrical mean of three tests;
*37 ℃ of 24 hours gained test datas.
B. the antibacterial effect test of being made in test tube of ornidazole and metronidazole shows that the minimum inhibitory concentration of ornidazole and metronidazole equals minimum control concentration (test data is 37 ℃ of 24 hours result of the tests).
C. use metronidazole (M), ornidazole (O), tinidazole (T) that 114 kinds of anaerobism bacterial strains have been carried out minimal inhibitory concentration (MTC) and Minimum Bactericidal.
For anaerobe, the bacteriostasis and sterilization ability of ornidazole and tinidazole is higher than metronidazole.The ornidazole Mlc is 3.1 μ g/ml, and bacteriocidal concentration is 6.3 μ g/ml.
2, antimicrobial drug effect result of the test in the animal body
A. use ornidazole and metronidazole drug efficacy study to the test of mice trichomonacide.Half with
90% effective dose is (ED relatively
50With ED
90), a dosage oral medication repeats four tests (mg/kg), (parenthetic numeral is 95% fiducial limit).
Test A: in the CPCM medium
Test B: in trichomonacide medium CM161
B. the drug efficacy study of the Leber ameba parasitosis of Gold hamster being tested with ornidazole and metronidazole.ED
50With ED
90Value, the dose oral medication repeats five tests (mg/kg), (parenthetic numeral is 95% fiducial limit).
C. the drug efficacy study of rat Blinddarm ameba parasitosis being tested with ornidazole and metronidazole, dose oral medication triplicate test (mg/kg), (parenthetic numeral is 95% fiducial limit).
D. mice gas gangrene test, dose oral medication triplicate test (mg/kg), (parenthetic numeral is 95% fiducial limit).
From ED
50Be worth especially ED
90Being worth as can be seen, the ornidazole drug effect is better than metronidazole.
The intravenous pharmacokinetic of the dose of the preparation that the present invention relates to:
Ornidazole concentration level and pharmacokinetic parameter in the blood plasma of intravenous injection (dose 1000mg) back
Measured value or mean parameter ± standard deviation scope
Maximum (15 minutes) levels (mg/l) 24 ± 5.2 33.3-18.2
Final measured value (24 hours) levels (mg/l) 6.3 ± 1.4 7.7-3.2
Eliminate phase half-life (tl/2 β) h 14.1 ± 2.7 19.8-10.2
Elimination factor (CL) is 47 ± 2.7 66-34 (ml/min)
Apparent volume of distribution (V
1(l/kg) 0.9 ± 0.13 1.05-0.59
The clinical efficacy of the preparation that the present invention relates to compares:
(A) overall clinical efficacy compares,
Each hospital's anti anaerobic bacteria infection is subjected between the examination group and clinical efficacy such as table 9 between matched group, analyzes there was no significant difference (P＞0.05) through Ridit.Analyzed through Ridit by clinical efficacy, also there was no significant difference (P＞0.05).
Each clinical center medicine anaerobe resistant clinical efficacy of table 9 relatively
Wherein, the percentage rate of total effective rate=(recovery from illness+produce effects);
Ridit check: compare P＞0.05 between each clinical center; Compare P＞0.05 between group
(B) each section's clinical efficacy relatively
Be subjected to examination group and matched group anaerobe resistant curative effect through the Ridit statistical test, two groups of there was no significant differences (P＞0.05).Be subjected to examination group and matched group anaerobe resistant cure rate to be respectively 89.2% and 92.3%, the anaerobe resistant total effective rate is respectively 100% and 98.5%, through X
2Check there are no significant difference (P＞0.05) sees Table 10.
Table 10 surgery and gynecological clinic curative effect are relatively
Through X
2Check * P＜0.05; * P＜0.01
(C) bacteriology's curative effect relatively
Two groups of anaerobe positive cases are totally 106 examples, and bacterial positive rate is 80% (104/130).Anaerobe removing situation sees the following form.Being subjected to the preceding anaerobe positive case of examination group treatment is 57 examples, and the anaerobe positive rate is 87.7% (57/65), and it is 57 examples that treatment back anaerobe the moon changes case, and the anaerobe negative conversion rate is 100% (57/57).The anaerobe positive case was 49 examples before matched group was controlled, and the anaerobe positive rate is 75.3% (49/65), and controlling the cloudy commentaries on classics of back anaerobe case is 49 examples, and the anaerobe negative conversion rate is 100% (49/49).Two groups of anaerobe clearance rate (being 100%) are there was no significant difference (P=1) relatively, shows bacteriology's therapeutic equivalence of two medicines.
Anaerobe elimination situation relatively
Through X
2Check, P＞0.05
(D), medicine MIC measures
The high-rise semi-solid strain transferred species of preserving of the unit of participating in the experiment respectively to isolation medium, is made anaerobism routinely and cultivated, obtain pure culture.Adopt the agar doubling dilution to measure MIC, scope is 0.1ug-100ug/ml.Be divided into from having measured 107 strain anaerobe, ornidazole MIC scope is≤0.1-25ug/ml MIC
500.4ug/ml, MIC
903.2ug/ml, see the following form 11.The ornidazole MIC of ornidazole MIC measured value and bibliographical information is close.Reference material demonstration tinidazole MIC and ornidazole difference are very little
[6], consistent with this clinical trial bacteriology efficacy result.
Table 11 bacterial species (strain number) and ornidazole MIC scope
Annotate: the above person of 10 strains has all added up MIC
50And MIC
90, because of the strain number less, only for reference;
The safety research of the medicine that the present invention relates to:
1, toxicologic study
(1). acute toxicity test
With the homemade ornidazole of the present invention Kunming kind white mice has been cooked acute toxicity test, LD through pharmaceutical college of Xian Medical Univ Pharmacology Lab
50(mg/kg) measurement result is for irritating stomach: 1645 ± 147; Lumbar injection: 1027 ± 170; The Fourth Military Medical University clinical pharmacology clinical pharmacy research center with its Cmax (1.5%) and maximum volume (30ml/kg) to Kunming kind white mice through the tail intravenously administrable, none death as a result, the maximum dosage-feeding of mouse tail vein injection are 450mg/kg (30ml/kg).
(2). long term toxicity test
Rat 400mg/kg/day successive administration 2 years does not have influence to the life-span of rat, does not cause the infringement of serious function and form.
Canis familiaris L. 70-100mg/kg/day successive administration had toleration preferably in 1 year, high dose 250mg/kg/day successive administration causes neurotoxic symptom (ataxia to occur since the 17th day, cold, moderate tremble and sialorrhea, body weight begin to reduce), this is the general character of nitro imidazole derivatives, but in the evening that the neurotoxic symptom that ornidazole causes occurs, metronidazole 250mg/kg/day neurotoxic symptom then just occurred to the Canis familiaris L. administration continuously at the 5th day.
(3). through The Fourth Military Medical University's clinical pharmacology clinical pharmacy research center test, the ornidazole sodium chloride injection of the present invention's trial-production does not have sensitization, no blood vessel zest, no haemolysis.
(4). mutagenicity test
Ornidazole has mutagenicity to various bacterial strains, but the lymphocyte of personnel selection or mouse test (micronucleus test, dominant lethal test) prove that ornidazole to the not influence of mammiferous chromosome, does not have mutagenicity.
(5). tertogenicity test
Young youngster is fairly good to the toleration of ornidazole to young youngster and term in rat, mice, the rabbit high dose administration tire, does not especially find teratogenecity.
(6). carcinogenic test
Ornidazole reaches the ornidazole that studies have shown that in 2 years to rat 400mg/kg/day does not have carcinogenesis.
2, human body safety test
1. to human body, every day, oral 1.5g ornidazole serve on 5 days, and toleration is very good, did not find that taking this medicine impacts hemopoietic, liver, renal function, and electrocardiogram and electroencephalogram do not show any obvious change.
2. the slight side effect that 73 once oral 1.5g ornidazoles of patient are caused is as follows: tired 28.77%, dizzy 47.95%, bitter taste 4.11%, feel sick 2.74%, other symptom (vomiting, diarrhoea, constipation, thirsty, perspire, itch) 6.85% has no side effect 9.59%.Each 0.5g, every day, the secondary oral medication discovered that to 2085 patients 256 examples have side effect (accounting for 12.2%), wherein dizziness 4.7%, gastrointestinal upset 2.8%, none routine dangerous property.
Claims (2)
1. ornidazole and sodium chloride combination is characterized in that its preparation prescription amount: ornidazole 5.0g, and sodium chloride 8.5g, hydrochloric acid is an amount of, and water for injection adds to 1000ml.
2. the preparation method of ornidazole and sodium chloride combination, it is characterized in that, get ornidazole and sodium chloride and be dissolved in the 1000ml water for injection, add needle-use activated carbon (0.05g/100ml) by the dosing amount, in 25-50 ℃ with interior stirring decolouring 20-30min, leave standstill 15min, filter, add hydrochloric acid and transfer pH to 4.5 sampling and measuring pH value and content, meet the requirements after sintered filter funnel and microporous filter membrane fine straining, through clarity embedding after the assay was approved, high temperature sterilize gets final product again.
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Cited By (1)
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1768742A (en) * | 2004-11-05 | 2006-05-10 | 南京圣和药业有限公司 | Intravenous formulation of ornidazole and its preparation method |
| CN1332662C (en) * | 2005-04-29 | 2007-08-22 | 南京圣和药业有限公司 | Levo ornidazole vein administration agent and its preparation method |
-
2010
- 2010-05-20 CN CN 201010177459 patent/CN101816650A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1768742A (en) * | 2004-11-05 | 2006-05-10 | 南京圣和药业有限公司 | Intravenous formulation of ornidazole and its preparation method |
| CN1332662C (en) * | 2005-04-29 | 2007-08-22 | 南京圣和药业有限公司 | Levo ornidazole vein administration agent and its preparation method |
Cited By (1)
| 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 |
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Application publication date: 20100901 |