CN1973839B - Nizatidine injection - Google Patents
Nizatidine injection Download PDFInfo
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- CN1973839B CN1973839B CN200610022545A CN200610022545A CN1973839B CN 1973839 B CN1973839 B CN 1973839B CN 200610022545 A CN200610022545 A CN 200610022545A CN 200610022545 A CN200610022545 A CN 200610022545A CN 1973839 B CN1973839 B CN 1973839B
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- injection
- nizatidine
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Abstract
The nizatidine injection contains nizatidine in 10-100 mg/ml, stabilizer in 5-80 vol% and at least one of pharmaceutically acceptable solubilizer and/or cosolvent in 0-5 vol%, except solvent including water for injection, with the stabilizer being at least one of ethanol, propylene glycol, glycerin and other lower alcohol. Test shows that the injection has high stability and safety in production and clinical application.
Description
Technical field
The present invention relates to a kind of injection type medicine, specifically being a kind of Nizatidine injection, is the medicine that a kind of H2 of having receptor antagonism and can be used for treats and/or prevents optimum active gastric ulcer, active duodenal ulcer, esophagitis (comprising erosion and ulcerative oesophagitis) and relevant with GERD disease such as heartburn.
Background technology
As the report of U.S. Pat 4375547, the nizatidine of structure can have good pharmaceutical active shown in the formula (I).It is as a kind of medicine with H2 receptor antagonism, can be used for treating and/or preventing optimum active gastric ulcer, active duodenal ulcer, esophagitis (comprising erosion and ulcerative oesophagitis) and relevant with GERD disease such as heartburn.At present, the intravenously administrable of nizatidine is mainly used in emergency cases such as hemorrhagic gastric ulcer.
Be not difficult to find out that by formula (I) structure nizatidine is one and contains amino thiazole compound, so it is extremely unstable in aqueous solution, also very easily produces a large amount of impurity even at room temperature place, and brings hidden danger for the safety of medication.Although the report of existing Nizatidine freeze-dried powder injection, because its cost and price is higher relatively, becoming influences its widely used unfavorable factor.
Summary of the invention
Given this, the present invention will provide a kind of Nizatidine injection for addressing the above problem, and it can be had fine qualities and stability.
Nizatidine injection of the present invention is to contain nizatidine 10～100mg in a kind of every milliliter of injection, wherein is preferably every milliliter and contains 10～35mg, is preferably 15～30mg, more preferably 20～25mg.In the injection except that containing the nizatidine composition, also contain volume ratio simultaneously and be 5%～80% stabilizing agent and by weight/volume and be 0～5% pharmaceutically acceptable injection solubilizing agent or cosolvent, Chang Yong nonionic surfactant for example, all the other are the solvent composition that comprises water for injection.Wherein, said stabilizing agent composition generally can be at C commonly used
1-3Select in the low-grade alkane alcohol, for example can select at least a in the compositions such as ethanol, propylene glycol, glycerol and formal glycerine for use.These stabilizing agents use as the nonaqueous solvent in the injection except that can be used as auxiliary composition use simultaneously.Can be used as the injection nonaqueous solvent except that above-mentioned composition, also comprise aminated compounds as dimethyl acetylamide etc., or comprise ketone compounds, or as comprise the polyhydric alcohol polymer etc. of Macrogol 200, Liquid Macrogol etc. as N-methyl-2-pyrrolidone, N-butyl-2-pyrrolidone etc.Wherein preferred nonaqueous solvent is ethanol and/or propylene glycol, and these nonaqueous solvents are the solvent of low-k, help slowing down the decomposition of nizatidine.
Above-mentioned said pharmaceutically injection acceptable solubilizing agent or cosolvent, can help improving the dissolubility of nizatidine, can be preferred especially as poloxamer, soil temperature, span, the nonionic surfactant that polysorbate etc. are commonly used. test shows, content height according to nizatidine in the injection, consumption as the surfactant of hydrotropy and/or solubilising can be done suitable adjustment, generally can increasing and increase with nizatidine content. the content of nizatidine is lower than every milliliter 25 milligram hour in injection, even can not use said surfactant composition, can guarantee that still nizatidine has satisfied dissolubility.
When needed, for example when the content of nizatidine in injection is higher, said stabilizing agent composition and the surfactant composition with solubilising and/or hydrotropy effect can also be used simultaneously.
Test shows, the pH value of the above-mentioned injection of the present invention is controlled in 6.5～9.5 the scope and all can obtains satisfactory stability, and wherein preferred pH scope is 7.0～8.5, and more preferred pH scope is 7.0～7.5.
The preparation of the above-mentioned injection of the present invention can be adopted usual manner, for example nizatidine can be dissolved in the mixed solvent of forming by cosolvent and/or solubilizing agent and water for injection, non-water-soluble matchmaker, the decolorizing with activated carbon of adding 0.15～0.3%, filter, regulate suitable pH value, fixed molten, behind the corresponding membrane filtration as 0.45um, 0.22um etc., embedding is in ampoule again.
During clinical use, above-mentioned injection of the present invention (for example being equivalent to nizatidine 300mg) can with slowly intravenous drip behind the conventional transfusion of the 150ml compatibility, in order to treat and/or prevent optimum active gastric ulcer, active duodenal ulcer, esophagitis (comprising erosion and ulcerative oesophagitis) and relevant with GERD disease such as heartburn.
The specific embodiment by the following examples is described in further detail foregoing of the present invention again, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
The specific embodiment
Embodiment 1
Getting propylene glycol 1600ml and ethanol 200ml mixes with 2000ml water for injection, add nizatidine 100g stirring and make dissolving, the pin activated carbon that adds 0.15% (w/v), the back insulation that stirs is placed, and removes by filter activated carbon, and solution is transferred pH7.0～7.5 with 10% hydrochloric acid, add injection water to 4000 milliliter, after using 0.45um and the aseptic filtration of 0.22um filter membrane more respectively, embedding in ampoule, every 4ml.
Embodiment 2
Getting poloxamer 12g is dissolved in the 800ml water for injection, add 800ml propylene glycol and ethanol 100ml, add nizatidine 100g under stirring and make dissolving, add the pin activated carbon of 0.2% (w/v), back insulation placement stirs, remove by filter activated carbon, solution transfers pH 7.0～7.5 to add injection water to 2000 milliliter with 10% hydrochloric acid, and behind the 0.45um membrane filtration, embedding is in ampoule, every 2ml, 100 ℃ of sterilizations in 30 minutes.
Embodiment 3
Getting propylene glycol 1600ml and ethanol 200ml mixes with 2000ml water for injection, add nizatidine 100g stirring and make dissolving, the pin activated carbon that adds 0.15% (w/v), the back insulation that stirs is placed, and removes by filter activated carbon, solution is transferred pH7.0～7.5 with 10% hydrochloric acid, add injection water to 4000 milliliter, behind the 0.45um membrane filtration, embedding is in ampoule, every 4ml, 100 ℃ of sterilizations in 30 minutes.
Embodiment 4
Getting glycerol 1000ml and ethanol 200ml mixes with 2000ml water for injection, add nizatidine 100g stirring and make dissolving, the pin activated carbon that adds 0.15% (w/v), the back insulation of stirring is placed, remove by filter activated carbon after, solution is with 10% hydrochloric acid accent pH7.0～7.5, add injection water to 4000 milliliter, after using 0.45um and the aseptic filtration of 0.22um filter membrane more respectively, embedding in ampoule, every 4ml.
Embodiment 5
Getting propylene glycol 1500ml mixes with 3000ml water for injection, add nizatidine 50g stirring and make dissolving, the pin activated carbon that adds 0.1% (w/v), the back insulation that stirs is placed, and removes by filter activated carbon, and solution is transferred pH7.0～7.5 with 10% hydrochloric acid, add injection water to 5000 milliliter, after using 0.45um and the aseptic filtration of 0.22um filter membrane more respectively, embedding in ampoule, every 5ml.
Embodiment 6
Getting poloxamer 15g is dissolved in the 1000ml water for injection, after adding 500ml Polyethylene Glycol-200 and ethanol 200ml mix homogeneously, add nizatidine 100g stirring and make dissolving, add the pin activated carbon of 0.2% (w/v), the back insulation that stirs is placed, after removing by filter activated carbon, solution is transferred pH7.0～7.5 with 10% hydrochloric acid, adds injection water to 2000 milliliter, behind the 0.45um membrane filtration, embedding in ampoule, every 2ml, 100 ℃ 30 minutes the sterilization.
Embodiment 7
Getting 5g soil temperature-80 is dissolved in the 1500ml water for injection, after adding 300ml Polyethylene Glycol-300 mix homogeneously, add nizatidine 100g stirring and make dissolving, add the pin activated carbon of 0.15% (w/v), the back insulation that stirs is placed, after removing by filter activated carbon, solution is transferred pH7.0～7.5 with 10% hydrochloric acid, adds injection water to 2000 milliliter, behind the 0.45um membrane filtration, embedding in ampoule, every 2ml, 100 ℃ 30 minutes the sterilization.
Embodiment 8
Getting the 25g poloxamer is dissolved in the 1000ml water for injection, after adding N-methyl-2-pyrrolidone 300ml and ethanol 200ml mix homogeneously, add nizatidine 200g stirring and make dissolving, add the pin activated carbon of 0.15% (w/v), the back insulation that stirs is placed, after removing by filter activated carbon, solution is transferred pH7.0～7.5 with 10% hydrochloric acid, adds injection water to 2000 milliliter, behind the 0.45um membrane filtration, embedding in ampoule, every 2ml, 100 ℃ 30 minutes the sterilization.
Embodiment 9 (contrast injection)
Getting poloxamer 12g is dissolved in the 3800ml water for injection, stirring down, adding nizatidine 100g makes dissolving, the pin activated carbon that adds 0.15% (w/v), the back insulation that stirs is placed, remove by filter activated carbon, solution transfers pH 7.0～7.5 to add injection water to 4000 milliliter with 10% hydrochloric acid, behind 0.45um and 0.22um filter membrane degerming membrane filtration, embedding in ampoule, every 4ml.Do not add stabilizing agent in this example, purpose is to carry out the stability contrast with aforementioned each routine sample.
About the test of the relevant stability of Nizatidine injection of the present invention and safety research as follows.
One, stability test
The HPLC method of method reference " American Pharmacopeia " the 28th edition (USP28) that detects:
Chromatographic column: octadecylsilane chemically bonded silica is a filler
Mobile phase: methanol-0.05mol/L ammonium acetate buffer=24: 76
Detector: UV
Elution process: gradient elution
The contrast injection of getting embodiment 1 and embodiment 9 is that sample (wherein the content of stabilizing agent propylene glycol is respectively 40% and 0%) carries out stable contrast test, according to " " crude drug and the preparation stability test direction principle " of Chinese pharmacopoeia version appendix in 2005 XIX C also carried out with reference to " detection method " of American Pharmacopeia, and the result is as shown in table 1.
Table 1 stability test result
Two, safety testing
Owing to contain propylene glycol in the composition of the present invention, ethanol, organic solvents such as glycerol, there are certain hemolytic, zest and hypersensitive possibility, therefore, method with reference to " chemical drugs zest, anaphylaxis and hemolytic investigative technique guideline " (print and distribute in March, 2005) of national drug food Surveillance Authority is tested, and the result is summarized as follows:
1. hemolytic test
Test method: get Sanguis Leporis seu oryctolagi, go fiber to wash and make 2% red cell suspension with normal saline.
Be subjected to test product: the sample that embodiment 1 is prepared
Get 7 of clean tube, wherein 5 is the test sample pipe, remains 2 and is respectively negative control and positive control.Add 2% red cell suspension and each reagent in each test tube successively and be subjected to test product, place 37 ℃ ± 0.5 ℃ calorstat to carry out incubation behind the mixing immediately, beginning was observed once every 15 minutes, after 1 hour, observed once every 1 hour, observed 3 hours.Observational technique adopts observation method of naked eye and spectrophotography respectively.
Result of the test: adopt observation method of naked eye and spectrophotography to detect respectively, show that all being tried Nizatidine injection does not exert an influence to the erythrocyte physiological status, can inject use.
2. local irritation test
Be subjected to test product: the sample that embodiment 1 is prepared
Experimental animal: only get new zealand rabbit 2.0～2.5kg6, male and female are usefulness all, is divided into 2 groups at random, and 3 every group, the A group was observed as the administration phase, and the B group was observed as convalescent period.
Administering mode: all adopt consubstantiality left and right sides self matching type: after left ear auricular vein instillation 0.2% is subjected to test product 50ml, auris dextra auricular vein instillation normal saline 50ml, instil about every group of each 20min of medicinal liquid and finish, continuous drip 3 days. administration concentration is with clinical identical, dosage is about 8 times of clinical application amount, clinical usual amounts: 300mg/ day, concentration: 0.2%, be that standard body weight is calculated with 50kg.
The result observes: (1) administration phase: the forward and backward and administration of each administration finishes 24～72 hours perusal auricular vein blood vessels in back and whole body situation, behind the medicine 72 hours with 3% pentobarbital liquid (30mg/kg) ip injecting anesthetic A treated animal, draw medicine ears ear edge, 12% formalin solution soaks, HE dyeing, do histopathologic examination, be subjected to the blood vessel part of reagent effect whether zest is arranged with judgement.(2) convalescent period: B group continuation observation raising is drawn medicine ears ear edge with above-mentioned method after 15 days and is done histopathologic examination to understand the degree of reversibility of reagent to the effect of blood vessel local irritation.
Compared by reagent thing animal groups and normal saline group auricular vein vascular pathological histological examination result each, make the inflammation of medicine-feeding part, irritant reaction degree evaluations such as tissue degeneratiaon and necrosis, and the degree of reversibility of irritative response is commented after the drug withdrawal.
Result of the test: observation method of naked eye and auricular vein vascular pathological histological examination result show that all Nizatidine injection is to rabbit blood vessel nonirritant.
3. sensitivity test
Be subjected to test product: the sample that embodiment 1 is prepared
Experimental animal: 16 of healthy male Britain kind (English) Cavia porcelluss of one-level, body weight 290～320g.Be divided into four groups at random by body weight, 4 every group, be respectively negative control, positive control, low dosage and high dose group.
Medicine grouping: negative control: normal saline 0.5ml/ only; Positive control: 0.4% bovine serum albumin 2mg/, promptly about 0.5ml/ only; Nizatidine injection low dose group: 9.6mg/kg promptly is subjected to the about 0.015ml/kg of test product (about 0.5ml/ only) with 0.625%, is clinical maximal dose (480mg/ day is that standard body weight is calculated with 50kg); Nizatidine injection high dose group: 19.2mg/kg promptly is subjected to the about 0.015ml/kg of test product (about 0.5ml/ only) with 1.25%, is 2 times of clinical maximal dose.
Medication: use ip sensitization instead 3 times after adopting twice of sole of the foot iv sensitization, the next day 1 time, totally 5 times.The interval is 10 days after the 5th sensitization, adopts sole of the foot iv approach once to excite, and booster dose is 4 times of priming dose, that is: negative control: normal saline 1.0ml/ only; Positive control: 0.8% bovine serum albumin 1ml/ is (about 8mg/ only) only; Nizatidine injection hangs down the agent group: 1.25% is subjected to the about 0.03ml/kg of test product (about 1ml/ only); The high agent group of Nizatidine injection: 2.5% is subjected to the about 0.03ml/kg of test product stock solution (about 1ml/ only).
The result observes: during the sensitization, observe the symptom of every animal every day.For the first time, last sensitization and excite the body weight of measuring every group every animal the same day.
When exciting, to 30 minutes, press the reaction that " symptoms of allergic " observes every animal in detail, the appearance of symptom and extinction time after the intravenous injection.The longest observation 3 hours.In the maximum of symptoms of allergic score value, judge its irritated degree by whole body sensitization evaluation criterion.
Ordinary circumstance is observed, and does not observe other abnormal responses during the sensitization, and the laboratory animal body weight changes no significant difference (P＞0.1) between each is organized during the t check whole test.During the sensitization on the same group the weight of animals do not have significant change (P＞0.1), sensitization finishes to duration of exciting weight increase obviously (P＜0.1).The result is as shown in table 2.
The weight of animals situation of change during the table 2 Nizatidine injection hypersensitive test
Anaphylaxis is observed, and excites the beginning in about 2～4 minutes of the positive treated animal in back unpeaceful, and rapid breathing, dyspnea are arranged gradually, shows instability of gait in about about 10 minutes, pants etc., recovery in 1 hour about half.Negative group and each administration group all do not have above-mentioned reaction.
Conclusion (of pressure testing): Nizatidine injection animal after the whole body administration does not cause anaphylactic reaction.
Above-mentioned test shows that stability and the safety of Nizatidine injection medicine provided by the invention in clinical use all is enough gratifying.
Claims (9)
1. Nizatidine injection, it is characterized in that containing in every milliliter of injection 10～100 milligrams of nizatidines, and to contain volume ratio be 5%～80% stabilizing agent, with by weight/volume be at least a in 0～5% pharmaceutically acceptable injection solubilizing agent or the cosolvent, all the other are water for injection or nonaqueous solvent composition, and said stabilizing agent is C
1-3At least a in lower alkanols composition and the formal glycerine, the pH value of injection is 6.5～9.5.
2. Nizatidine injection as claimed in claim 1 is characterized in that the C in the said stabilizing agent
1-3The lower alkanols composition is at least a in ethanol, propylene glycol, the glycerol.
3. Nizatidine injection as claimed in claim 1 is characterized in that said solubilizing agent or cosolvent are poloxamer, tween or span.
4. Nizatidine injection as claimed in claim 1 is characterized in that the content of nizatidine in the said injection is lower than every milliliter 25 milligram hour, does not contain solubilizing agent or cosolvent composition.
5. Nizatidine injection as claimed in claim 1 is characterized in that said stabilizing agent composition and said injection solubilizing agent or cosolvent composition use simultaneously.
6. Nizatidine injection as claimed in claim 1 is characterized in that as the nonaqueous solvent of said injection solvent composition ethanol, propylene glycol, glycerol, formal glycerine, dimethyl acetylamide, ketone compounds or polyhydric alcohol polymer being arranged.
7. Nizatidine injection as claimed in claim 6 is characterized in that said injection nonaqueous solvent is at least a in ethanol or the propylene glycol.
8. as the described Nizatidine injection of one of claim 1 to 7, the pH value that it is characterized in that said injection is 7.0～8.5.
9. Nizatidine injection as claimed in claim 8, the pH value that it is characterized in that said injection is 7.0～7.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610022545A CN1973839B (en) | 2006-12-19 | 2006-12-19 | Nizatidine injection |
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| CN200610022545A CN1973839B (en) | 2006-12-19 | 2006-12-19 | Nizatidine injection |
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| CN1973839A CN1973839A (en) | 2007-06-06 |
| CN1973839B true CN1973839B (en) | 2010-05-12 |
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| CN200610022545A Expired - Fee Related CN1973839B (en) | 2006-12-19 | 2006-12-19 | Nizatidine injection |
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| CN104415336B (en) * | 2013-08-28 | 2019-05-03 | 沈阳药科大学 | The composition and its application in pharmaceutical preparation that poloxamer plays phenomenon covered with clouds can be eliminated |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771942A (en) * | 2005-09-30 | 2006-05-17 | 周卓和 | Nizatidine injection and its prepn |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1771942A (en) * | 2005-09-30 | 2006-05-17 | 周卓和 | Nizatidine injection and its prepn |
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| Title |
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| JP特开平11－193233A 1999.07.21 |
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