CN103054799A - Amiodarone hydrochloride injection emulsion and preparation method thereof - Google Patents
Amiodarone hydrochloride injection emulsion and preparation method thereof Download PDFInfo
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Abstract
The invention provides an amiodarone hydrochloride injection emulsion and a preparation method thereof. The amiodarone hydrochloride injection emulsion contains 0.05-0.5% of amiodarone hydrochloride, 10-30% of oil for injection, 0.5-5% of emulsifier, 2-8% of osmotic pressure modifier, and an approximate amount of pH regulator and water for injection, and also contains 0.001-0.01% of antioxidant and 0.01-0.1% of stabilizer. The preparation method comprises the following main steps of: heating an oil phase and an aqueous phase respectively; adding medicaments into the oil phase, and then adding the oil phase into the aqueous phase (or adding the aqueous phase into the oil phase); stirring to obtain initial emulsion; regulating the pH value; homogenizing the initial emulsion through a high-pressure homogenizer; and sterilizing through high temperature steam, thereby obtaining a finished product. The emulsion for injection is uniform in granularity, stable in quality and easy for industrial production, can be used for improving the in-vivo bioavailability of the medicaments, and avoiding toxic and side effects generated by a cosolvent in a general injection, so that the controllability and safety of the clinical medication are improved greatly.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to injectable emulsion of a kind of long-acting antiarrhythmic drug Amiodarone Hydrochloride and preparation method thereof.
Background technology
Amiodarone Hydrochloride be present clinical practice at most, antiarrhythmic drug the most widely, be take the pharmacological action of III class as main heart ion multichannel blocker, have the electric physiological action of I, II, IV class antiarrhythmic drug concurrently.Intravenous injection shows that the pharmacological action of I class, II class, IV class is very fast, and III class pharmacology onset time is longer, and is fairly obvious to the therapeutic effect of serious and fatal arrhythmia.At present commonly used have oral tablet, and in gastrointestinal absorption slowly and not exclusively, individual variation is large bioavailability is unstable but Amiodarone Hydrochloride is oral, and absolute bioavailability only has 50%, oral onset and remove all slowly, and it is oral to need a couple of days to onset several weeks.Under unsuitable oral administration and serious arrhythmia conditions, can in 30min, play a role behind the intravenously administrable, onset obviously speeds.
The Amiodarone Hydrochloride injection is gone on the market in U.S.A by Wyeth at first, and commodity are called Cordarone.Because the Amiodarone Hydrochloride raw material is water insoluble, in injection preparation, added a certain amount of cosolvent Tween 80 and benzyl alcohol, Chang Yi causes explosive hepatitis, hypotension, phlebitis and the neonate mortality toxic and side effects such as syndrome of suffocating.Publication number is the preparation that discloses the parenterai administration that contains Amiodarone Hydrochloride and sulfoalkyl ether-beta-cyclic dextrine in the patent document of US2003/0216353, can be so that the water solublity of medicine improves greatly with the technology of Amiodarone Hydrochloride enclose in cyclodextrin, but at present cyclodextrin adjuvant and clathrate safety in vivo thereof are understood still not deeply, its intravenous formulations exists certain nephrotoxicity and hemolytic with the consumption increase.Cyclodextrin inclusion compound can be accompanied by the reduction of medicinal effectiveness and reduce when increasing drug solubility, can't its regularity of distribution in vivo of Accurate Prediction etc.Because the cyclodextrin adjuvant mostly is the pharmaceutic adjuvant of synthetic, in synthetic process, has the by-product that is difficult to separate and generate simultaneously, increased the risk that produces toxic and side effects.For overcoming above problems, be necessary to develop a kind of Amiodarone Hydrochloride ejection preparation of novel, nontoxic secondary untoward reaction.
Lipomul has drug loading height, technique and quality controllable, ability is subjected to pressure sterilizing, the advantage that is suitable for industrialized great production, natural, safe, nontoxic, the good biocompatibility of the employed adjuvant refined phosphatide of Emulsion and soybean oil source, be more widely used as the carrier of intravenous drug, adopt the Emulsion packaging medicine can improve the stability of medicine, and can realize the function of targeting in the body.
Summary of the invention
The purpose of invention is to remove to use with an organic solvent cause in cosolvent Tween 80, benzyl alcohol and the technical process that side effect is arranged residual in the preparation, work out a kind of Amiodarone Hydrochloride injectable emulsion, in its drug effect of performance, reduce or avoid its side effect.The invention provides the Amiodarone Hydrochloride injectable emulsion that a kind of preparation technology is simple, zest is low, safety is good, with on the satisfying the market to the demand of Amiodarone Hydrochloride injection type.
The present invention seeks to be achieved through the following technical solutions:
A kind of Amiodarone Hydrochloride injectable emulsion, take Amiodarone Hydrochloride as the active drug composition, in every 1000ml injectable emulsion, contain by weight/the percent by volume meter: 0.05～0.5% Amiodarone Hydrochloride, 10～30% oil for injection, 0.5～5% emulsifying agent, 2～8% osmotic pressure regulator, an amount of pH adjusting agent, surplus is water for injection; Wherein, be preferably and contain by weight/percent by volume meter 0.1～0.3% Amiodarone Hydrochloride.
Described oil for injection is vegetable oil, and is selected from any one or a few the mixture in soybean oil, Oleum Arachidis hypogaeae semen, hydrogenated corn oil, Oleum Camelliae, Oleum sesami, safflower oil, Oleum Gossypii semen, Oleum Cocois C8/C10 triglyceride, the vegetable oil polyethyleneglycol glyceride.
Described emulsifying agent is fabaceous lecithin, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, serinephosphatide, lipositol, cephalin, hydrogenated phospholipid, 1, the mixture of any one or a few in the 2-DSPG; Wherein be preferably 1,2-DSPG and phosphatidylcholine or egg yolk lecithin according to 1: 1-1: the emulsifier combination that 3 weight ratio combination obtains.
Described osmotic pressure regulator is selected from any one in glycerol, sorbitol, xylitol, glucose, the sodium chloride.
PH adjusting agent in the described injectable emulsion, being preferably concentration is that 0.01～2M sodium hydroxide solution or concentration are the hydrochloric acid solution of 0.01～2M.
Can also contain 0.001～0.01% antioxidant in the described injectable emulsion; And be selected from disodium edetate, calcium disodium chelate, TGA, vitamin E, coenzyme Q10, propyl gallate, ascorbyl palmitate and the vitamin C any one.
Can also contain 0.01～0.1% stabilizing agent in the described injectable emulsion; And be selected from oleic acid, enuatrol, linoleic acid, linoleic acid sodium and the cholesterol any one.
The Emulsion average particle size range is 100～500nm in the described injectable emulsion, and pH is 4.0～9.0.
The preparation method of Amiodarone Hydrochloride injectable emulsion of the present invention comprises the following steps:
1. the preparation of oil phase: measure amiodarone, oil for injection and injection emulsifying agent by prescription, 50～80 ℃ of heated and stirred dissolvings, get oil phase;
2. the preparation of water: measure water for injection and selectable osmotic pressure regulator by prescription, 50～80 ℃ of heated and stirred dissolvings, get water;
3. optionally add stabilizing agent or antioxidant at oil phase or aqueous phase;
4. the preparation of Emulsion: above-mentioned oil phase and water are mixed under 50～80 ℃ of temperature, and with emulsification pretreatment or stirring and emulsifying 20～30 minutes, rotating speed was 8000～15000 rev/mins, makes oil phase and water mix homogeneously, gets colostrum.With the further emulsifying of high pressure homogenizer emulsifying method, regulating pH with pH adjusting agent is 4.0～9.0 with colostrum, and by the filtering with microporous membrane of 0.45 μ m, nitrogen is filled in packing, and high pressure steam sterilization gets the Amiodarone Hydrochloride injectable emulsion.
In the preparation method of Amiodarone Hydrochloride injectable emulsion of the present invention, also can be with emulsifiers dissolve at aqueous phase, namely concrete steps are:
1. the preparation of oil phase: measure amiodarone, oil for injection by prescription, 50～80 ℃ of heated and stirred dissolvings, get oil phase;
2. the preparation of water: measure water for injection by prescription, add the injection emulsifying agent of recipe quantity, then heated and stirred or ultrasonic or shear and make emulsifiers dissolve adds selectable osmotic pressure regulator, and the heated and stirred dissolving gets water;
3. optionally add stabilizing agent or antioxidant at oil phase or aqueous phase;
4. the preparation of Emulsion: above-mentioned oil phase and water are mixed under 50～80 ℃ of temperature, and with emulsification pretreatment or stirring and emulsifying 20～30 minutes, rotating speed was 8000～15000 rev/mins, makes oil phase and water mix homogeneously, gets colostrum.With the further emulsifying of high pressure homogenizer emulsifying method, regulating pH with pH adjusting agent is 4.0～9.0 with colostrum, and by the filtering with microporous membrane of 0.45 μ m, nitrogen is filled in packing, and high pressure steam sterilization gets acid hydrochloride salt amiodarone injectable emulsion.
Wherein step 4. mesohigh homogenizer emulsifying method pressure be 300～1000bar, be preferably 400～800bar; Temperature is 10～95 ℃, is preferably 50～80 ℃; Homogenization cycles is 3～10 times, is preferably 5～8 times; Sterilising conditions is 100～128 ℃ of sterilizations 2～30 minutes, is preferably 121 ℃ of sterilizations 15～30 minutes.
The Amiodarone Hydrochloride injectable emulsion that the present invention prepares gained is white or off-white color emulsion liquid, sometimes have opalescence to occur, the content of amiodarone in Emulsion is 0.5～5mg/ml, and mean diameter is 100～500nm, pH is 4.0～9.0, and all other indexs all meet the injectable emulsion requirement.
Utilize technical scheme of the present invention, particularly utilize emulsifier combination scheme preferably among the present invention, the Emulsion that can prepare different Amiodarone Hydrochloride content, described Emulsion can keep well stability in the suitable pH scope of injection, be better than adopting the Amiodarone Hydrochloride injection of cyclodextrin inclusion compound, avoided since cyclodextrin inclusion compound along with the prolongation effective ingredient of time is separated out from clathrate, water solublity reduces, unsettled defective; Got rid of simultaneously in the commercially available common amiodarone preparation because the caused toxic and side effects of adjuvant has reduced the zest of medicine to blood vessel, the pain when alleviating patient infusion has strengthened patient's compliance.Emulsion preparation process of the present invention is simple, is applicable to a large amount of preparations and suitability for industrialized production Amiodarone Hydrochloride injectable emulsion.Have no any document and open report about the Amiodarone Hydrochloride intravenous injection emulsion.
Description of drawings
Fig. 1 is particle diameter and the scattergram thereof of Amiodarone Hydrochloride injectable emulsion of the present invention.
The specific embodiment
The specific embodiment of form is described in further detail content of the present invention by the following examples.But should not be understood as scope of the present invention and only limit to following examples.All technical schemes that realizes based on content of the present invention all belong to scope of the present invention.Obviously, according to content of the present invention, according to ordinary skill knowledge and the customary means of this area, under the prerequisite that does not break away from basic fundamental thought of the present invention, can also make modification, replacement and the change of other various ways.
Embodiment 1
Prescription:
Amiodarone Hydrochloride 0.5g
Soybean oil 100g
Egg yolk lecithin 5g
Disodium edetate 0.01g
Oleic acid 0.1g
Glycerol 20g
Sodium hydroxide solution or hydrochloric acid solution are an amount of
Make 1000ml
Preparation technology:
(1) Amiodarone Hydrochloride 0.5g, soybean oil 100g, egg yolk lecithin 5g, oleic acid 0.1g, heating in water bath to 65 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 500ml, add glycerol 20g, disodium edetate 0.01g is heated to 65 ℃ of stirring and dissolving, gets water;
(3) with oil phase and water 65 ℃ of mixing, emulsification pretreatment 15 minutes (8000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, makes colostrum;
(4) with colostrum 5 (pressure 650bar of high pressure homogenizer homogenizing, 65 ℃ of temperature), regulating its pH with sodium hydroxide solution (0.1mol/L) is 8.5, filtering with microporous membrane by 0.45 μ m, packing, fill nitrogen, 121 ℃ of sterilizations of rotary hot pressing sterilization 15 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 350nm, 90% particle diameter aggregate-value is no more than 500nm, and pH is 6.70, and Amiodarone Hydrochloride content is 98.4% of labelled amount, and all other indexs all meet the requirement of vein breast.
Embodiment 2
Prescription:
Amiodarone Hydrochloride 1g
Oleum Arachidis hypogaeae semen 150g
Phosphatidylcholine 10g
1,2-DSPG 30g
Sorbitol 40g
Enuatrol 0.03g
Vitamin E 0.3g
Sodium hydroxide solution or hydrochloric acid solution are an amount of
Make 1000ml
Preparation technology:
(1) get Amiodarone Hydrochloride 1g, Oleum Arachidis hypogaeae semen 150g, heating in water bath to 55 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 600ml, add phosphatidylcholine 10g, 1,2-DSPG 30g, sorbitol 40g is heated to 55 ℃ of stirring and dissolving, gets water;
(3) with oil phase and water 55 ℃ of mixing, emulsification pretreatment 15 minutes (10000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, regulating its pH with sodium hydroxide solution (0.1mol/L) is 11.0, makes colostrum;
(4) with colostrum high pressure homogenizer homogenizing 6 times (pressure 600bar, 55 ℃ of temperature), by 0.45 μ m
Filtering with microporous membrane, nitrogen is filled in packing, 121 ℃ of sterilizations of rotary hot pressing sterilization 20 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 365nm, 90% particle diameter aggregate-value is no more than 520nm, and pH is 7.0, and amiodarone content is 99.2% of labelled amount, and all other indexs all meet the requirement of vein breast.
Embodiment 3
Prescription:
Amiodarone Hydrochloride 3g
Hydrogenated corn oil 200g
Egg yolk lecithin 25g
1,2-DSPG 25g
Calcium disodium chelate 0.05g
Oleic acid 0.5g
Xylitol 30g
Sodium hydroxide solution or hydrochloric acid solution are an amount of
Make 1000ml
Preparation technology:
(1) get Amiodarone Hydrochloride 3g, hydrogenated corn oil 200g, egg yolk lecithin 25g, 1,2-DSPG 25g, oleic acid 0.5g, heating in water bath to 75 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 800ml, add xylitol 30g, calcium disodium chelate 0.05g is heated to 75 ℃ of stirring and dissolving, gets water;
(3) with oil phase and water 75 ℃ of mixing, emulsification pretreatment 20 minutes (10000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, makes colostrum;
(4) with colostrum 8 (pressure 550bar of high pressure homogenizer homogenizing, 75 ℃ of temperature), regulating its pH with sodium hydroxide solution (0.1mol/L) is 8.0, filtering with microporous membrane by 0.45 μ m, packing, fill nitrogen, 121 ℃ of sterilizations of rotary hot pressing sterilization 30 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 400nm, 90% particle diameter aggregate-value is no more than 600nm, and pH is 7.20, and amiodarone content is 97.6% of labelled amount, and all other indexs all meet the requirement of vein breast.
Embodiment 4
Prescription:
Amiodarone Hydrochloride 5g
Oleum sesami 300g
Cephalin 50g
Cholesterol 1g
Glucose 80g
Make 1000ml
Preparation technology:
(1) get Amiodarone Hydrochloride 5g, Oleum sesami 300g, coenzyme Q10 0.1g, heating in water bath to 60 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 700ml, add cephalin 50g, glucose 80g, cholesterol 1g is heated to 60 ℃ of stirring and dissolving, gets water;
(3) with oil phase and water 60 ℃ of mixing, emulsification pretreatment 30 minutes (7000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, makes colostrum;
(4) with colostrum high pressure homogenizer homogenizing 5 times (pressure 650bar, 65 ℃ of temperature), by the filtering with microporous membrane of 0.45 μ m, nitrogen is filled in packing, and 121 ℃ of sterilizations of rotary hot pressing sterilization 15 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 355nm, 90% particle diameter aggregate-value is no more than 520nm, and pH is 6.50, and amiodarone content is 97.8% of labelled amount, and all other indexs all meet the requirement of vein breast.
Embodiment 5
Prescription:
Amiodarone Hydrochloride 2g
Soybean oil 150g
Ovum Gallus domesticus Flavus lecithin 10g
Glycerol 50g
Sodium hydroxide solution or hydrochloric acid solution are an amount of
Make 1000ml
Preparation technology:
(1) get Amiodarone Hydrochloride 2g, soybean oil 150g, Ovum Gallus domesticus Flavus lecithin 10g,, heating in water bath to 85 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 800ml, add glycerol 50g, be heated to 85 ℃ of stirring and dissolving, get water;
(3) with oil phase and water 85 ℃ of mixing, emulsification pretreatment 20 minutes (6000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, makes colostrum;
(4) with colostrum 7 (pressure 600bar of high pressure homogenizer homogenizing, 85 ℃ of temperature), regulating its pH with sodium hydroxide solution (0.1mol/L) is 7.5, filtering with microporous membrane by 0.45 μ m, packing, fill nitrogen, 121 ℃ of sterilizations of rotary hot pressing sterilization 30 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 370nm, 90% particle diameter aggregate-value is no more than 540nm, and pH is 6.80, and amiodarone content is 101.1% of labelled amount, and all other indexs all meet the requirement of vein breast.
Embodiment 6
Prescription:
Amiodarone Hydrochloride 4g
Oleum Gossypii semen 250g
PHOSPHATIDYL ETHANOLAMINE 30g
Vitamin C 0.07
Oleic acid 0.7
Mannitol 70g
Sodium hydroxide solution or hydrochloric acid solution are an amount of
Make 1000ml
Preparation technology:
(1) get Amiodarone Hydrochloride 4g, Oleum Gossypii semen 250g, oleic acid 0.7g, heating in water bath to 75 ℃, stirring and dissolving gets oil phase;
(2) measure water for injection 600ml, add mannitol 70g, PHOSPHATIDYL ETHANOLAMINE 30g, vitamin C 0.07g is heated to 75 ℃ of stirring and dissolving, gets water;
(3) with oil phase and water 75 ℃ of mixing, emulsification pretreatment 30 minutes (12000 rev/mins of rotating speeds) makes oil phase and water mix homogeneously, makes colostrum;
(4) with colostrum 8 (pressure 550bar of high pressure homogenizer homogenizing, 75 ℃ of temperature), regulating its pH with sodium hydroxide solution (0.1mol/L) is 7.0, filtering with microporous membrane by 0.45 μ m, packing, fill nitrogen, 121 ℃ of sterilizations of rotary hot pressing sterilization 15 minutes get the Amiodarone Hydrochloride injectable emulsion.
This Emulsion mean diameter 400nm, 90% particle diameter aggregate-value is no more than 580nm, and pH is 6.50, and amiodarone content is 98.9% of labelled amount, and all other indexs all meet the requirement of vein breast.
Test example
Test example 1: the mensuration of diameter of aspirin particle
Particle diameter and distribution to Amiodarone Hydrochloride injectable emulsion of the present invention are measured, concrete grammar is as follows: the Amiodarone Hydrochloride injectable emulsion of getting the present invention preparation is with static evaporat light scattering particle size analyzer (LS13320, Beckman Coulter, the U.S.) measure, Emulsion particle diameter and the distribution results thereof of gained are seen Fig. 1.
As seen from Figure 1, the size of the Amiodarone Hydrochloride injectable emulsion of gained meets normal distribution.Average particle
The footpath is less than 350nm, and 90% particle diameter is less than 500nm.This measurement result meets the related request of used for intravenous injection Emulsion.
Test example 2: stability experiment
According to Chinese Pharmacopoeia 2010 editions, investigate Amiodarone Hydrochloride injectable emulsion of the present invention and commercially available Amiodarone hydrochloride injection (trade name: Cordarone) 25 ℃ ± 2 ℃ of room temperatures, placed 18 months under relative humidity 60% ± 10% condition, in the sampling in 0,3,6,9,12,18 month of placing once, investigate the stable content of sample respectively.The result is as follows:
The sample Amiodarone Hydrochloride content %(month)
03 months 6 months 9 months 12 months 18 months
Embodiment 1 99.4 99.2 99.1 98.8 98.7 98.4
Embodiment 2 99.2 99.3 99.9 99.6 99.3 99.1
Embodiment 3 99.9 98.5 98.2 99.4 99.0 99.2
Embodiment 4 99.8 99.8 99.4 99.2 99.3 99.1
Embodiment 5 100.1 99.8 100.0 100.1 99.9 100.1
Embodiment 6 99.9 99.3 99.5 99.1 98.4 98.7
Commercially available product 99.7 98.6 97.2 96.6 94.9 94.4
By as seen from Table 1: according to the Amiodarone Hydrochloride injectable emulsion of the present invention's preparation, compare with the commercially available prod Amiodarone hydrochloride injection, Amiodarone Hydrochloride content can keep stablizing after room temperature was placed in 18 months, and stability is better than commercially available product.
Test example 3: vascular stimulation test
Choose 24 of rabbit, be divided at random 4 groups, every group each 6, two groups is commercially available product Amiodarone hydrochloride injection administration group, in addition two groups is the Amiodarone Hydrochloride injectable emulsion administration group that the present invention prepares, and all is further divided into single-dose group and multiple dosing group, every animals administer of single-dose group 1 time in two groups, multiple dosing group administration every day 1 time, successive administration 7 days.Four groups are all adopted the consubstantiality own control, and Amiodarone Hydrochloride injectable emulsion/Amiodarone hydrochloride injection (1.5mg/ml, 2ml/kg) auris dextra edge vein slowly instils, and control sides (left ear) waits the capacity normal saline.Regularly observe the variation of rabbit bilateral auricular vein after the administration.
Administration and viewing duration and observe when drawing materials, the result shows:
(1) the Amiodarone Hydrochloride injectable emulsion administration group of the present invention's preparation, rabbit auricular vein instillation position occurs there are no red and swollen and erythema.Histopathology is observed, and rabbit ear epidermal structure is normal, under the epidermis papillary layer and reticular layer without inflammatory cell ooze out, without hemorrhage, blood vessel is interior to be formed without thrombosis.
(2) commercially available product Amiodarone hydrochloride injection administration group, there are slight redness and erythema in single-dose man rabbit ear edge instillation position, and multiple dosing man rabbit ear edge instillation position occurs serious red and swollen, takes on a red color streak or the change of branch sample.Histopathology is observed, the generation hyperemia of single-dose rabbit ear blood vessel and edema, and the nodositas scleroma appears in multiple dosing rabbit ear epidermis, and papillary layer and reticular layer have a large amount of inflammatory cells to ooze out under the epidermis, have clot to form in the blood vessel.
Test example 4: hemolytic experiment
Owing to have a certain amount of cosolvent Tween 80 in the commercially available product Amiodarone hydrochloride injection, hemolytic can occur when consumption was excessive, therefore the Amiodarone Hydrochloride injectable emulsion of the present invention's preparation has been made following hemolytic experiment exam as its safety evaluatio foundation.
Get 21 in test tube, number 1～No. 7, add successively 2% red blood cell suspension 2.5ml, normal saline (1～No. 5 pipe, every pipe 2.0～2.5ml, No. 6 pipe 2.5ml, No. 7 pipe 0ml) behind the mixing, 1～No. 5 pipe adds respectively 0.1～0.5ml Amiodarone Hydrochloride injectable emulsion, manages negative contrast No. 6, No. 7 pipes are with the positive control of distilled water 2.5ml as complete hemolysis, parallel 3 pipes of every pipe shake up rear 37 ℃ of water bath with thermostatic control 4h, respectively at 0.5,1,2,3 and 4h haemolysis and the coagulation situation of observing each pipe.
The result shows 0.5～4h, and except the positive control pipe, all the other test tubes are showed no clear and bright redness, and erythrocyte all sinks supernatant liquid achromatism and clarity, erythrocyte energy Uniform Dispersion after jolting.Show concentration of the present invention be 1.5mg/ml Amiodarone Hydrochloride injectable emulsion without haemolysis, can for the injection.
Claims (9)
1. Amiodarone Hydrochloride injectable emulsion, take Amiodarone Hydrochloride as the active drug composition, it is characterized in that, in every 1000ml injectable emulsion, contain by weight/the percent by volume meter: 0.05～0.5% Amiodarone Hydrochloride, 10～30% oil for injection, 0.5～5% emulsifying agent, 2～8% osmotic pressure regulator, an amount of pH adjusting agent, surplus is water for injection; Wherein, be preferably and contain by weight/percent by volume meter 0.1～0.3% Amiodarone Hydrochloride.
2. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1, it is characterized in that, described oil for injection is vegetable oil, and is selected from any one or a few the mixture in soybean oil, Oleum Arachidis hypogaeae semen, hydrogenated corn oil, Oleum Camelliae, Oleum sesami, safflower oil, Oleum Gossypii semen, Oleum Cocois C8/C10 triglyceride, the vegetable oil polyethyleneglycol glyceride.
3. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1, it is characterized in that, described emulsifying agent is fabaceous lecithin, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, serinephosphatide, lipositol, cephalin, hydrogenated phospholipid, 1, the mixture of any one or a few in the 2-DSPG; Wherein be preferably 1,2-DSPG and phosphatidylcholine or egg yolk lecithin according to 1: 1-1: the emulsifier combination that 3 weight ratio combination obtains.
4. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1 is characterized in that described osmotic pressure regulator is selected from any one in glycerol, sorbitol, xylitol, glucose, the sodium chloride.
5. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1 is characterized in that, the pH adjusting agent in the described injectable emulsion, and being preferably concentration is that 0.01～2M sodium hydroxide solution or concentration are the hydrochloric acid solution of 0.01～2M.
6. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1 is characterized in that, can also contain 0.001～0.01% antioxidant in the described injectable emulsion; And be selected from disodium edetate, calcium disodium chelate, TGA, vitamin E, coenzyme Q10, propyl gallate, ascorbyl palmitate and the vitamin C any one.
7. a kind of Amiodarone Hydrochloride injectable emulsion according to claim 1 is characterized in that, can also contain 0.01～0.1% stabilizing agent in the described injectable emulsion; And be selected from oleic acid, enuatrol, linoleic acid, linoleic acid sodium and the cholesterol any one.
8. the described Amiodarone Hydrochloride injectable emulsion of any one in 7 according to claim 1 is characterized in that the Emulsion average particle size range is 100～500nm in the described injectable emulsion, and pH is 4.0～9.0.
9. the preparation method of an Amiodarone Hydrochloride injectable emulsion as claimed in claim 1 is characterized in that, may further comprise the steps:
(1) preparation of oil phase: measure Amiodarone Hydrochloride, oil for injection and emulsifying agent by prescription, 50～80 ℃ of heated and stirred dissolvings, get oil phase;
(2) preparation of water: measure water for injection and selectable osmotic pressure regulator, antioxidant by prescription, 50～80 ℃ of heated and stirred dissolvings, get water;
(3) preparation of Emulsion: above-mentioned oil phase and water are mixed under 50～80 ℃ of temperature, and with emulsification pretreatment or stirring and emulsifying 20～30 minutes, rotating speed was 8000～15000 rev/mins, makes oil phase and water mix homogeneously, gets colostrum;
(4) with colostrum with the further emulsifying of high pressure homogenizer emulsifying method, regulating pH with pH adjusting agent is 4.0～9.0, by the filtering with microporous membrane of 0.45 μ m, nitrogen is filled in packing, high pressure steam sterilization gets the Amiodarone Hydrochloride injectable emulsion.
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| CN201210382934.7A Active CN103054799B (en) | 2012-10-11 | 2012-10-11 | Amiodarone hydrochloride injection emulsion and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983681A (en) * | 2015-06-10 | 2015-10-21 | 上海市第一人民医院 | Preparation method of amiodarone lipidosome and application of amiodarone lipidosome |
| CN106137963A (en) * | 2016-07-27 | 2016-11-23 | 武汉科福新药有限责任公司 | Antiarrhythmic drug fat emulsion injection and preparation method thereof |
| CN115969833A (en) * | 2023-01-03 | 2023-04-18 | 上海上药第一生化药业有限公司 | Amiodarone medicinal composition, injection, preparation method thereof and injector containing amiodarone medicinal composition and injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2002026324A2 (en) * | 2000-09-27 | 2002-04-04 | Sonus Pharmaceuticals, Inc. | Tocol-based compositions containing amiodarone |
| WO2012033538A1 (en) * | 2010-09-10 | 2012-03-15 | Stable Solutions Llc | Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle |
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2012
- 2012-10-11 CN CN201210382934.7A patent/CN103054799B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002026324A2 (en) * | 2000-09-27 | 2002-04-04 | Sonus Pharmaceuticals, Inc. | Tocol-based compositions containing amiodarone |
| WO2012033538A1 (en) * | 2010-09-10 | 2012-03-15 | Stable Solutions Llc | Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle |
Non-Patent Citations (1)
| Title |
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| TOMOHISA NIIYA，ET.AL: "Intravenous Lipid Emulsion Sequesters Amiodarone in Plasma and Eliminates Its Hypotensive Action in Pigs", 《ANNALS OF EMERGENCY MEDICINE》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104983681A (en) * | 2015-06-10 | 2015-10-21 | 上海市第一人民医院 | Preparation method of amiodarone lipidosome and application of amiodarone lipidosome |
| CN106137963A (en) * | 2016-07-27 | 2016-11-23 | 武汉科福新药有限责任公司 | Antiarrhythmic drug fat emulsion injection and preparation method thereof |
| CN106137963B (en) * | 2016-07-27 | 2019-07-30 | 武汉科福新药有限责任公司 | Antiarrhythmic drug fat emulsion injection and preparation method thereof |
| CN115969833A (en) * | 2023-01-03 | 2023-04-18 | 上海上药第一生化药业有限公司 | Amiodarone medicinal composition, injection, preparation method thereof and injector containing amiodarone medicinal composition and injection |
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| CN103054799B (en) | 2015-04-08 |
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