CN101683320A - Olprinone hydrochloric parenteral solution and method for preparing same - Google Patents
Olprinone hydrochloric parenteral solution and method for preparing same Download PDFInfo
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- CN101683320A CN101683320A CN200810223370A CN200810223370A CN101683320A CN 101683320 A CN101683320 A CN 101683320A CN 200810223370 A CN200810223370 A CN 200810223370A CN 200810223370 A CN200810223370 A CN 200810223370A CN 101683320 A CN101683320 A CN 101683320A
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- olprinone
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Abstract
The invention discloses olprinone hydrochloric parenteral solution and a method for preparing the same. In the parenteral solution, water-soluble excipient and organic acids serve as pharmaceutical adjuvant. In the parenteral solution in the invention, fewer sorts of pharmaceutical adjuvant are used, the dosage of the pharmaceutical adjuvant organic acids is greatly reduced, and on the basis of guaranteeing the quality of the preparation, the safety of the preparation is greatly improved.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of Olprinone hydrochloric parenteral solution and preparation method thereof.
Background technology
Heart failure (Cardiac Dysfunction) claims congestive heart failure (CHF) again, is meant under the normal situation of venous return, reduces because former heart damage causes cardiac output, can not satisfy a kind of syndrome of tissue metabolism's needs.Clinically with pulmonary circulation and (or) body circulation blood stasis and tissue blood hypoperfusion be principal character.Can be divided into acute and chronic two kinds by the heart failure speed of development, with chronic in the majority.The heart failure therapy present situation: current acute and base therapy chronic congestive heart failure mainly is utilization catecholamines and cardiac glycoside medicine.Because the positive inotropic action of catecholamines medicament for expanding vascellum can not effectively separate with the increase heart rate function, and the arrhythmia of causing possibility is arranged, thereby is restricted in clinical practice.Cardiac glycoside is at present still for treating the main medicine of heart failure, have the whole body vasodilator to improve cardiac function with the reduction cardiac afterload later on and be used for treating heart failure, the medicine that has the demonstration of experiment and clinical data to have muscle strength reinforcing and the effect of reduction ventricular afterload simultaneously can more effectively improve cardiac pumping function.The phosphodiesterase iii inhibitor is such class medicine.
Olprinone is another cardiac tonic that has much potentiality, its positive inotropic action and vasorelaxation action reduce the front and back load of heart effectively, but myocardium keto consumption only has slight increase, olprinone improves cardiac index (CI) and reduces peripheral vascular resistance suitable with the milrinone degree, strong to large artery trunks diastolic pressure and pulmonary artery pressure effect than milrinone, under giving the therapeutic dose condition, do not find to cause ARR increasing the weight of in the zoopery.In the experimentation, the result shows long-acting, the direct positive inotropic action of Olprinone HCl performance in narcotism and clear-headed dog body, and presents the relevant enhancing myocardial contraction effect of dosage, and this composition is oral all effective with intravenously administrable.The experiment in vitro Olprinone HCl presents concentration dependent and strengthens the effect of Cavia porcellus papillary muscles of right ventricle tensity.In experimental dog and human experimentation, left chamber shrinks end pressure-volume or pressure volume relationship shows the positive inotropic regulating action.Significant positive inotropic action except in the anesthetized dog experiment also has slight positivity and regulates heart rate and hypotensive activity.Only show the slight heart rate function that increases in the experiment of waking state dog, it is isolating pointing out its effect of regulating myocardial contraction and heart rate.Intra-arterial (coronary artery or femoral artery) gives the same show dose dependency of olprinone increases regional flow's effect, but does not cause that other cardio-vascular parameters change, and points out its directly performance vasorelaxation action.
Medicine is when becoming preparation, because the reason of aspects such as physical chemistry, seldom useful raw material directly is prepared into preparation, therefore need to add pharmaceutic adjuvant, though the pharmaceutic adjuvant that adds relatively all is safe, the scientist thinks that still the kind and the weight of pharmaceutic adjuvant adding is few more, can increase the safety of preparation more, therefore, in the research process of preparations shaping, want strictness to grasp to the kind and the weight of pharmaceutic adjuvant.
Application number is that 200610113480.8 Chinese patents disclose the preparation Olprinone HCl injection and preparation is taken precautions against, though said preparation has solved the problem of preparations shaping to a certain extent, but do not take into full account the character of hydrochloric acid Ao Pulinong, it is not too suitable using the amount of pharmaceutic adjuvant and the weight of pharmaceutic adjuvant, therefore, a lot of medical workers for research more suitable Ao Pulinong injection prescription painstakingly.
Summary of the invention
For these reasons, we find in the experiment by science, do not need to add buffer solvent in hydrochloric acid Ao Pulinong preparations shaping, only use organic acid, and the organic acid consumption can significantly reduce, and just can prepare qualified Olprinone hydrochloric parenteral solution.
The application is achieved through the following technical solutions.
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
, one or both in pharmaceutic adjuvant water soluble excipient lactose, mannitol, sorbitol, xylitol, the maltose alcohol and glucose wherein.
Wherein the pharmaceutic adjuvant organic acid is citric acid, tartaric acid, stearic acid, glutamic acid, fumaric acid or maleic acid.
Wherein the pharmaceutic adjuvant organic acid is 0.002%-0.005% in the injection percent weight in volume.
Wherein the pharmaceutic adjuvant organic acid is 0.002%-0.003% in the injection percent weight in volume.
Wherein the pharmaceutic adjuvant organic acid is 0.00252% in the injection percent weight in volume.
Its preparation method is:
Water soluble excipient and organic acid are dissolved in the water for injection of full volumetric amount 50%, add the active carbon charcoal and take off, filter, the raw material Olprinone HCl is dissolved in 5% the glucose adjuvant solution, strong agitation makes dissolving.Add active carbon, stir, room temperature is placed, absorption, filter, regulate the pH value of medicinal liquid, the pH value scope is 3.0～5.0, adds water for injection again, stir,, under aseptic condition, use aperture 0.22 μ m filtering with microporous membrane machine the medicinal liquid fine straining with the medicinal liquid coarse filtration.Fill, sterilization, lamp inspection, packing dissolution
One, detection method
Olprinone HCl is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octyl silane group silica gel; Regulating pH value to 3.0 with potassium phosphate buffer [get triethylamine 2ml and add the 0.01mol potassium dihydrogen phosphate to 1000ml]-methanol (92: 8) with phosphoric acid is mobile phase; The detection wavelength is 215nm.Number of theoretical plate calculates by the Olprinone HCl peak should be not less than 2000.
Precision is measured in Olprinone HCl glucose injection 5ml to the 10ml measuring bottle, and thin up shakes up to scale, measures 20 μ l and injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the Olprinone HCl reference substance, accurate claims surely, is dissolved in water and dilutes and make the solution that contains 30 μ g Olprinone HCls among every 1ml approximately, measures with method.Go out this product by external standard method with calculated by peak area and contain C
14H
10N
4The amount of OHCl, and result and 1.063 multiplied each other promptly gets and contains C in the test sample
14H
10N
4OHClH
2The amount of O.
The glucose precision is measured Olprinone HCl glucose injection 2ml, put in the tool plug conical flask, precision adds iodine titration solution (0.1mol/l) 25ml, and jolting limit, limit dropping sodium volumetric solution (0.1mol/l) 50ml in the dark placed 30 minutes, add dilute sulfuric acid 5ml, with sodium thiosulfate volumetric solution (0.1mol/l) titration, during to nearly terminal point, add starch indicator solution 2ml, continue titration and disappear, and titrating result is proofreaied and correct with blank assay to blue.The iodine titration solution of every 1ml (0.1mol/L) is equivalent to 9.909mgC
6H
12O
6H
2O.
Two, preparation prescription research
1, the physicochemical properties of Olprinone HCl
Olprinone HCl is that white is to the off-white color crystalline powder.This product is easily molten in formic acid, molten in the dimethyl sulfoxine part omitted, at water, methanol, N, and slightly soluble in the dinethylformamide, soluble,very slightly in glacial acetic acid, pyridine.The character of Olprinone HCl glucose injection, this product colourless clear liquid.Olprinone HCl is dissolubility test measuring cell relaxing the bowels with purgatives of warm nature Olprinone HCl dissolubility in water in water, 3 milligrams of Olprinone HCls of dissolving in every ml water.This dissolubility can satisfy the demand of preparation.
2, stability experiment
Preparation 1.5mg/ml Olprinone HCl solution, use organic acid to regulate the pH value of Olprinone HCl solution, the injection pH value scope that can tolerate because of human body is 4.0～9.0, so the pH value of Olprinone HCl solution is adjusted to 3.00 from 4.65 respectively, 4.01,5.00,6.02,7.02,8.00,9.01, the solution of each pH value is at room temperature placed observation, pH value 7.0 as a result, 8.0,9.0 solution see have obvious white precipitate to separate out immediately, the solution of pH value 6.0 is also seen after 30 minutes has a small amount of white precipitate to separate out, illustrate that this pH value of solution value stabilization is limited in the slant acidity scope, promptly is lower than 6.0.According to this character, reference standard, the Olprinone HCl glucose injection should be 3.0～5.0.
Measuring 10 days solution pH value of above-mentioned room temperature placement is 3.01,4.02,5.02.PH value is no change almost.
3, the selection of solvent supplementary product kind
The interpolation water for injection dissolving of Olprinone HCl glucose injection solvent and adjuvant; Water soluble excipient is main adjuvant, and regulates osmotic pressure; The pH value of final preparation is maintained or be lower than 6.0 by pH value test, thus the clarity of may command Olprinone HCl.The pH of preparation can control by organic acid.
4, the adjuvant amount determines
The calculating of osmotic pressure: calculating the osmotic pressure that the prescription sample should have according to the prescription of Olprinone HCl glucose injection is 286.2mOsm, and this solution is isosmotic solution.
According to prescription preparation Olprinone HCl solution, measure its as a result osmotic pressure be 287mOsm, thereby determine the consumption of osmotic pressure regulator water soluble excipient.
5, prescription determines
With reference to prescription and prescription are determined this preparation prescription both at home and abroad.
Specification: 150ml: Olprinone HCl 9mg is (with C
14H
10N
4OHClH
2The O meter) with glucose 7.05g
6, prescription Study on influencing factors
Second batch full inspection qualified samples in the process certification test is carried out factors influencing.With appearance character, clarity, pH, content and related substance serves as to investigate, respectively 0 day (the complete inspection of sample day), measured in 5 days, 10 days, condition is as follows, the results are shown in Table 1, table 2, table 3.
Hot test: sample thief places 60 ℃ calorstat to place.
Low-temperature test: sample thief places 4 ℃ of homothermic refrigerators to place.
The strong illumination test: sample thief places YB-2 clarity detector under the 4500Lx light intensity.
Table 1: high temperature (60 ℃) result of the test
Table 2: low temperature (4 ℃) is investigated result of the test
Table 3: highlight test result (4500Lx)
Conclusion: pass through factors influencing, appearance character, clarity, pH value, content and the basic no change of related substance after 5,10 days are placed in irradiation under prescription high-temperature sample, low temperature, the high light condition, prescription meets the preparation requirement, preliminary definite prescription and preparation technology.
Three, preparation embodiment
Embodiment 1
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, mannitol.
Wherein the pharmaceutic adjuvant organic acid is a citric acid.
Embodiment 2
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient glucose, mannitol.
Wherein the pharmaceutic adjuvant organic acid is a tartaric acid.
Embodiment 3
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, xylitol.
Wherein the pharmaceutic adjuvant organic acid is a stearic acid.
Embodiment 4
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient maltose alcohol, lactose.
Wherein the pharmaceutic adjuvant organic acid is a glutamic acid.
Embodiment 5
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient sorbitol, xylitol.
Wherein the pharmaceutic adjuvant organic acid is a fumaric acid.
Embodiment 6
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, glucose.
Wherein the pharmaceutic adjuvant organic acid is a maleic acid.
Embodiment 7
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, mannitol.
Wherein the pharmaceutic adjuvant organic acid is that citric acid percent weight in volume in injection is 0.002%.
Embodiment 8
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient glucose, mannitol.
Wherein the pharmaceutic adjuvant organic acid is that tartaric acid percent weight in volume in injection is 0.005%.。
Embodiment 9
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, xylitol.
Wherein the pharmaceutic adjuvant organic acid is that stearic acid percent weight in volume in injection is 0.00252%.。
Embodiment 10
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient maltose alcohol, lactose.
Wherein the pharmaceutic adjuvant organic acid is that glutamic acid percent weight in volume in injection is 0.003%.。
Embodiment 11
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient sorbitol, xylitol.
Wherein the pharmaceutic adjuvant organic acid is that fumaric acid percent weight in volume in injection is 0.0024%.。
Embodiment 12
A kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, and the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
Wherein pharmaceutic adjuvant water soluble excipient lactose, glucose.
Wherein the pharmaceutic adjuvant organic acid is that maleic acid percent weight in volume in injection is 0.0047%.。
The weight of water soluble excipient is selected to select according to prior art among the foregoing description 1-12.
The foregoing description 1-12 preparation method is:
Water soluble excipient and organic acid are dissolved in the water for injection of full volumetric amount 50%, add the active carbon charcoal and take off, filter, the raw material Olprinone HCl is dissolved in 5% the glucose adjuvant solution, strong agitation makes dissolving.Add active carbon, stir, room temperature is placed, absorption, filter, regulate the pH value of medicinal liquid, the pH value scope is 3.0～5.0, adds water for injection again, stir,, under aseptic condition, use aperture 0.22 μ m filtering with microporous membrane machine the medicinal liquid fine straining with the medicinal liquid coarse filtration.Fill, sterilization, lamp inspection, packing are promptly.
Annotate: the present invention's concrete technical scheme required for protection is not limited to the concrete combination of the expressed technical scheme of the foregoing description.
Claims (7)
1, a kind of Olprinone hydrochloric parenteral solution comprises hydrochloric acid Ao Pulinong and pharmaceutic adjuvant, it is characterized in that the injection pharmaceutic adjuvant is water soluble excipient and organic acid.
2, a kind of Olprinone hydrochloric parenteral solution according to claim 1, wherein one or both in pharmaceutic adjuvant water soluble excipient lactose, mannitol, sorbitol, xylitol, the maltose alcohol and glucose.
3, a kind of Olprinone hydrochloric parenteral solution according to claim 1, wherein the pharmaceutic adjuvant organic acid is citric acid, tartaric acid, stearic acid, glutamic acid, fumaric acid or maleic acid.
4, according to claim 1 or 3 described a kind of Olprinone hydrochloric parenteral solutions, wherein the pharmaceutic adjuvant organic acid is 0.002%-0.005% in the injection percent weight in volume.
5, according to claim 1 or 3 described a kind of Olprinone hydrochloric parenteral solutions, wherein the pharmaceutic adjuvant organic acid is 0.002%-0.003% in the injection percent weight in volume.
6, according to claim 1 or 3 described a kind of Olprinone hydrochloric parenteral solutions, wherein the pharmaceutic adjuvant organic acid is 0.00252% in the injection percent weight in volume.
7, according to claim 1,2 or 3 described a kind of hydrochloric acid Puli's farming difficult to understand injection, its preparation method is:
Water soluble excipient and organic acid are dissolved in the water for injection of full volumetric amount 50%, add the active carbon charcoal and take off, filter, the raw material Olprinone HCl is dissolved in 5% the glucose adjuvant solution, strong agitation makes dissolving.Add active carbon, stir, room temperature is placed, absorption, filter, regulate the pH value of medicinal liquid, the pH value scope is 3.0～5.0, adds water for injection again, stir,, under aseptic condition, use aperture 0.22 μ m filtering with microporous membrane machine the medicinal liquid fine straining with the medicinal liquid coarse filtration.Fill, sterilization, lamp inspection, packing are promptly.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101919814A (en) * | 2010-08-02 | 2010-12-22 | 无锡万全医药技术有限公司 | Stable Olprinone HCl injection |
| CN104161756A (en) * | 2014-06-13 | 2014-11-26 | 河北智同医药控股集团有限公司 | Olprinone hydrochloride injection composition |
| CN108619090A (en) * | 2018-05-30 | 2018-10-09 | 河北爱尔海泰制药有限公司 | A kind of high stability Olprinone HCl injection composition |
-
2008
- 2008-09-27 CN CN200810223370A patent/CN101683320A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101919814A (en) * | 2010-08-02 | 2010-12-22 | 无锡万全医药技术有限公司 | Stable Olprinone HCl injection |
| CN104161756A (en) * | 2014-06-13 | 2014-11-26 | 河北智同医药控股集团有限公司 | Olprinone hydrochloride injection composition |
| CN108619090A (en) * | 2018-05-30 | 2018-10-09 | 河北爱尔海泰制药有限公司 | A kind of high stability Olprinone HCl injection composition |
| CN108619090B (en) * | 2018-05-30 | 2020-12-08 | 河北爱尔海泰制药有限公司 | High-stability olprinone hydrochloride injection composition |
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Open date: 20100331 |