CN103040740A - Ornidazole injection and preparation technology thereof - Google Patents

Abstract

The invention provides an ornidazole injection which comprises ornidazole, propylene glycol and water for injection, wherein the ornidazole can be well dissolved when the volume of the propylene glycol is 60%-70% of that of the injection. According to a preparation technology for the ornidazole injection, oxygen in the solution can be completely removed by utilizing carbon dioxide gas, and the saturated carbon dioxide gas in the injection can be used for not only reducing the oxidized by-product of the ornidazole injection, but also improving the heat stability of the ornidazole injection.

Description

A kind of ornidazole injection and preparation technology

Technical field

The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of ornidazole injection and preparation technology.

Background technology

Ornidazole (ornidazole, ONZ), chemical name: 1-(3-chloro-2-hydroxypropyl)-2-5-nitro imidazole.Ornidazole is third generation nitro glyoxaline antibiotic, and such antibiotic is used for anaerobic infection, and protozoon, trichomonacide etc.Be used for the treatment of by bacteroides fragilis, bacteroides disiens, ovum garden bacteroid, bacteroides thetaiotaomicron, bacteroides vulgatus, clostruidium, Eubacterium, dyspepsiacoccus and peptostreptococcus, helicobacter pylori, bacaeroides melaninogenicus, Fusobacterium, CO2 and bite the caused multi-infection diseases of responsive anaerobe such as knitting dimension bacterium, gingiva bacteroid; The serious ameba parasitosis for the treatment of digestive system is such as amebic dysentery, amebic liver abscess etc.

Ornidazole injection is the main dosage form of ornidazole medicine, clinical practice is extensive, but the ornidazole water solublity is bad, but dissolubility increases under acid condition, existing technique is with hydrochloric acid adjust pH to 1.8～2.3, but injection acidity causes too by force clinical patients to use the medium vessels zest stronger, and patient's toleration is relatively poor.

And, the ornidazole injection less stable, high temperature, oxidation can both produce by-product, particularly poor heat stability, and related substance amplification is larger behind the solution high temperature sterilize.

Therefore, improving the ornidazole injection pH value, improve ornidazole injection stability, is our problem anxious to be resolved.

Propylene glycol so that ornidazole is soluble in the water for injection, has had many disclosed reports as cosolvent, such as Chinese patent CN1686116A with propylene glycol as cosolvent so that ornidazole can be dissolved in the water for injection; Chinese patent CN102552127A has invented with ethanol and propylene glycol as cosolvent so that ornidazole can be dissolved in the water for injection; But all deep research is not carried out in the consumption of propylene glycol, do not have operability in the practice;

In order to promote the stability of ornidazole injection, Chinese patent CN102552127A thinks and can promote ornidazole injection stability with ethanol; Chinese patent CN101849937A adds dextran and promotes ornidazole injection stability in the ornidazole injection of propylene glycol as cosolvent, and using of having adds antioxidant and chelating agent method.But what these materials of adding had has zest to human body, has plenty of active substance, and the result of the test that has is unsatisfactory.

Summary of the invention

We find that ornidazole injection can be comprised of ornidazole, propylene glycol and water for injection.The volumetric usage of propylene glycol is 60% of injection volume～70 o'clock, can be molten clear, molten can crystallization after clear.Beneficial effect is seen experiment 1.

We also carry out vascular stimulation tests and hemolytic test to the ornidazole injection that contains 60% propylene glycol and the ornidazole injection that contains 70% propylene glycol, the volumetric usage of proof propylene glycol is 60% of injection volume～70 o'clock, and the ornidazole injection result of the test shows that ornidazole injection of the present invention is safe.Beneficial effect is seen experiment 2,3.

We find pleasantly surprisedly, before the injection embedding, injection passes into carbon dioxide to saturated: the injection embedding is filled with these 2 very simple processes of carbon dioxide to the ampoule while in the ampoule, can solve well the stability problem of ornidazole injection.

This be because: in the production of ornidazole injection, all be to be filled with simultaneously nitrogen at injection embedding to ampoule at present, this method can not drain the oxygen in ampoule space, more can not drain the oxygen that dissolves in the injection, so that ornidazole injection is unstable.

The method of our invention, at first, we have increased one procedure: solution enters vapor tight tank, evacuation drains air in the solution, like this, the oxygen that dissolves in the solution is drained, then pass into carbon dioxide to saturated, the dissolubility of carbon dioxide in propylene glycol and water can more be kept in the solution greater than general gas.

Simultaneously carbon dioxide is heavier, is heavier than air 1.53 times, the injection embedding to ampoule simultaneously, be filled with carbon dioxide in the ampoule, and be filled with nitrogen relatively, more can drain the oxygen in ampoule space.

The carbon dioxide that is full of in the injection has not only reduced the ornidazole injection oxidized byproduct, has also improved the heat stability of ornidazole injection.Good effect is seen experiment 4:

Experiment 1: the impact that propylene glycol solution concentration is dissolved ornidazole:

Conclusion: the volumetric usage of propylene glycol is 60% of injection volume～70 o'clock, can be molten clear, molten can crystallization after clear.

Experiment 2: ornidazole injection vascular stimulation tests research.

The ornidazole injection that contains 60% propylene glycol and the ornidazole injection that contains 70% propylene glycol are carried out vascular stimulation tests:

12 routine healthy new zealand rabbits are used in test, establish tested material and similar listing reference substance group, and 6/group, male and female half and half.Adopt the self-contrast method of picking up the ears about consubstantiality, the left side auricular vein gives tested material or similar listing reference substance ornidazole injection, administration concentration is 1.92mg/mL(and is equivalent to clinical vein drug administration by injection concentration), the administration volume is 10mL/kg, the about 3mL/ of injection speed minute, the right side gives isopyknic 0.9% sodium chloride injection and compares, and be administered once every day, totally 7 days.48 hours each groups are cutd open inspection 3 routine animals after the last administration, and remaining animal was cutd open inspection in 14 days after the last administration.During the administration and drug withdrawal after convalescent period, being showed no animal has abnormal response.The perusal result who cuts open the inspection animal be after the last administration 48 hours and 14 days each examples to cut open the left and right sides injection site rabbit ear blood vessel profile of examining animal more clear, rabbit ear thickness is even, is showed no obvious change; The microscopy result is that each routine animal left and right sides rabbit ear adnexa and cartilage structure are intact, and artery and vein vascular and surrounding tissue have no abnormal changes.In sum, under this experimental condition, tested material is that ornidazole injection ex hoc genus anne listing reference substance (administration concentration is 1.92mg/mL) is showed no the obvious irritation reaction to rabbit ear edge vein and surrounding tissue.The parallel comparison of result of the test of tested material ex hoc genus anne listing reference substance has no notable difference.

Experiment 3: ornidazole injection hemolytic Test Summary:

The ornidazole injection that contains 60% propylene glycol and the ornidazole injection that contains 70% propylene glycol are carried out the hemolytic test:

This medicine is carried out the external hemolytic experimental study of new zealand rabbit.

Test is established 4 groups, is respectively negative control group, positive controls, tested material group and similar listing reference substance group.Adopt in vitro administration, (administration concentration is 1.92mg/mL to add respectively the tested material of inequality or similar listing reference substance in each pipe that fills 2% erythrocyte suspension, be equivalent to the clinical vein administration concentration), drug liquid tube of each group is all in the haemolysis situation of 37 ℃ ± 0.5 ℃ incubation of calorstat 3 hours and each time point of perusal.Haemolysis and coacervation did not appear in the negative control pipe in 3 hours, full haemolysis namely appears in the positive control pipe in 15min, and each drug liquid tube of tested material and similar listing reference substance was showed no haemolysis or hemagglutination in 3 hours.In sum, under this experimental condition, the judgement tested material is that the hemolytic test of ornidazole injection ex hoc genus anne listing reference substance (1.92mg/mL) is all negative.The parallel comparison of result of the test of tested material ex hoc genus anne listing reference substance has no notable difference.

Experiment 4: comparative experiments

1. experiment purpose: to according to embodiment 1 preparation ornidazole injection and prescription according to embodiment 1, filling CO 2 gas not in the technique only relatively carries out in the stability that injection embedding to ampoule is filled with the ornidazole injection of nitrogen preparation simultaneously;

Ornidazole injection according to embodiment 1 preparation is decided to be sample 1;

Fill nitrogen technique, the ornidazole injection of preparation is decided to be sample 2; Sample 1,2 is carried out study on the stability.

2. investigation project and operational approach

Related substance checks: be filler with octadecylsilane chemically bonded silica, take methanol-water (20:80) as mobile phase, the detection wavelength is 318nm.It is an amount of to get 2-5-nitro imidazole reference substance, adds mobile phase dissolving and dilution and makes the solution that contains 0.2 μ g among every 1ml, and other got the need testing solution reflux 1 hour, let cool, get above-mentioned two kinds of solution 1:1 and mix as mixed solution, get 20 μ l injection liquid chromatographies, the record chromatogram.

3 test methods:

(1) test of sterilization fore-and-aft stability relatively sees the following form:

Conclusion: sample 1 is obviously stable than sample 2 before and after the sterilization.

(2): long-term stable experiment

With 2 batch samples, put under 60% ± 10%RH, 25 ℃ ± 2 ℃ the condition and place, and respectively at the 0th, 3,6,9,12, sampling at the end of month, detect by above-mentioned investigation project and method.The results are shown in following table:

Conclusion: through long-term stable experiment, sample 1 stability is very good, changes very littlely, and sample 2 stability can not show a candle to sample 1.

We have also invented the preparation method of ornidazole injection:

The propylene glycol of A. measuring recipe quantity is positioned in the Agitation Tank, is heated to 80 ℃, adds while stirring the ornidazole raw material of recipe quantity, makes fully dissolving;

B. inject water, with above-mentioned ornidazole-propylene glycol solution mix homogeneously, water gets ornidazole solution to recipe quantity 80%;

C. measure an amount of concentrated hydrochloric acid, make the pH value to 3.4 that hydrochloric acid solution is regulated ornidazole solution with the water for injection dilution;

D. add 0.1%(W/V) needle-use activated carbon, 80 ℃ of stirring and adsorbing 15 minutes, Φ 1.0 μ m microporous filter membrane filtered while hot are taken off charcoal;

E. the solution moisturizing after the decarburization gets midbody solution to full dose.Midbody solution is measured, pH value (3.3～3.5) and content etc.,

F solution enters vapor tight tank, and evacuation drains air in the solution, then passes into carbon dioxide to saturated;

G. qualified rear by Φ 0.22 μ m microporous filter membrane fine straining, filling CO 2 gas, embedding is to ampoule;

H.115 ℃ pressure sterilizing is 45 minutes.Finished product inspection, qualified rear packing.

The specific embodiment

Following embodiment is used for further narration the present invention, but does not impose any restrictions.

Embodiment 1: preparation ornidazole injection (5ml:0.25g)

Ornidazole	?	2.5kg
			Propylene glycol	?	35L
Water for injection	Add to	50L
			Make	?	10000

The propylene glycol of A. measuring recipe quantity is positioned in the Agitation Tank, is heated to 80 ℃, adds while stirring the ornidazole raw material of recipe quantity, makes fully dissolving;

B. inject water, with above-mentioned ornidazole-propylene glycol solution mix homogeneously, water gets ornidazole solution to recipe quantity 80%;

C. measure an amount of concentrated hydrochloric acid, make the pH value to 3.4 that hydrochloric acid solution is regulated ornidazole solution with the water for injection dilution;

D. add 0.1%(W/V) needle-use activated carbon, 80 ℃ of stirring and adsorbing 15 minutes, Φ 1.0 μ m microporous filter membrane filtered while hot are taken off charcoal;

E. the solution moisturizing after the decarburization gets midbody solution to full dose.Midbody solution is measured, pH value (3.3～3.5) and content etc.,

F solution enters vapor tight tank, and evacuation drains air in the solution, then passes into carbon dioxide to saturated;

G. qualified rear by Φ 0.22 μ m microporous filter membrane fine straining, filling CO 2 gas, embedding is to ampoule;

H.115 ℃ pressure sterilizing is 45 minutes.Finished product inspection, qualified rear packing.

Embodiment 2: preparation ornidazole injection (5ml:0.25g)

Ornidazole	?	2.5kg
			Propylene glycol	?	30L
Water for injection	Add to	50L
			Make	?	10000

Preparation technology is with embodiment 1.

Claims (5)

1. ornidazole injection, it is characterized in that: injection is comprised of ornidazole, propylene glycol and water for injection.

2. injection according to claim 1, it is characterized in that: the volumetric usage of propylene glycol is 60%～70% of injection volume.

3. injection according to claim 2, the preparation method of injection is: before the injection embedding, injection will pass into carbon dioxide to saturated.

4. injection according to claim 3, the preparation method of injection is: the injection embedding to ampoule simultaneously, be filled with carbon dioxide in the ampoule.

5. injection according to claim 4, the preparation method of injection is:

The propylene glycol of A. measuring recipe quantity is positioned in the Agitation Tank, is heated to 80 ℃, adds while stirring the ornidazole raw material of recipe quantity, makes fully dissolving;

B. inject water, with above-mentioned ornidazole-propylene glycol solution mix homogeneously, water gets ornidazole solution to recipe quantity 80%;

C. measure an amount of concentrated hydrochloric acid, make the pH value to 3.4 that hydrochloric acid solution is regulated ornidazole solution with the water for injection dilution;

D. add 0.1%(W/V) needle-use activated carbon, 80 ℃ of stirring and adsorbing 15 minutes, Φ 1.0 μ m microporous filter membrane filtered while hot are taken off charcoal;

E. the solution moisturizing after the decarburization gets midbody solution to full dose.Midbody solution is measured, pH value (3.3～3.5) and content;

F solution enters vapor tight tank, and evacuation drains air in the solution, then passes into carbon dioxide to saturated;

G. qualified rear by Φ 0.22 μ m microporous filter membrane fine straining, filling CO 2 gas, embedding is to ampoule;

H.115 ℃ pressure sterilizing is 45 minutes.Finished product inspection, qualified rear packing.