CN102908307A - Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof - Google Patents
Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof Download PDFInfo
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- CN102908307A CN102908307A CN2011102202964A CN201110220296A CN102908307A CN 102908307 A CN102908307 A CN 102908307A CN 2011102202964 A CN2011102202964 A CN 2011102202964A CN 201110220296 A CN201110220296 A CN 201110220296A CN 102908307 A CN102908307 A CN 102908307A
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Abstract
The invention relates to a dronedarone hydrochloride pharmaceutical composition for injection and a preparation method thereof. The pharmaceutical composition comprises amorphous dronedarone hydrochloride, sodium chloride and cysteine hydrochloride, is prepared to 1000 parts and is prepared from 213-426g of the amorphous dronedarone hydrochloride, 90-180g of the sodium chloride, 1-3g of the cysteine hydrochloride, 2-6g of sodium hydrogen phosphate, appropriate amount of pH (potential of hydrogen) modifier and 10-20L of water for injection by means of sterilization. The preparation method of the pharmaceutical composition includes the steps of preparing the dronedarone hydrochloride to be amorphous form for standby; taking the water for injection of the amount in the prescription and adding the raw materials of the amount in the prescription into the water for injection to be dissolved completely; and decarburizing, filtering, supplementing the water for injection to the full amount, uniformly mixing, regulating the pH value, performing fine filtration, filling, sterilizing, performing light inspection, packaging and storing. The dronedarone hydrochloride pharmaceutical composition is simple in prescription, excellent in stability and suitable for long-term storage and industrial mass production.
Description
Technical field
The present invention relates to field of medicaments, relate to specifically a kind of injection dronedarone hydrochloride pharmaceutical composition and preparation method thereof.
Background technology
Dronedarone
English name: Dronedarone
Chemical name: 2-normal-butyl-3-[4-(3-di-n-butyl-amino sick oxygen base) benzoyl]-5-methyl sulfanilamide benzofuran
Molecular formula: C
31H
44N
2O
5S
Molecular weight: 556.765
Dronedarone is the derivant of a kind of structure and the similar benzofuran of amiodarone, but has removed the iodine atom, to reduce the organ toxicity of its propiodal; Increase mesyl in benzofuran one side, reduced lipotropy, shortened the half-life of medicine with this, and reduced the tissue accumulation effect of medicine.Its fundamental characteristics and amiodarone are similar, also possess some New Characteristics simultaneously.Existing experiment shows, the elimination half-life of dronedarone is 24h, and the elimination half-life of amiodarone is 30～50d.Because the first pass effect of liver, the bioavailability of dronedarone only has 15%～20%, but can improve 2～3 times of blood drug level with food with clothes.About 6 dronedarone is removed through kidney, therefore its plasma concentration is not subjected to renal function.
US20040044070 discloses the injection of dronedarone hydrochloride.This invention has added beta-cyclodextrin derivative in buffer system (the pH value scope is 3-5), thereby has improved the dissolubility of effective ingredient, but the method for the dissolubility of this raising dronedarone hydrochloride, complicate fabrication process, and stability may be relatively poor.
WO9858643 discloses a kind of solid composite medicament that contains benzofuran derivatives, it finds poloxamer class phenanthrene ion type surfactant and dronedarone or its hydrochlorate, this active component is kept among the pH neutral 6-7 and can not separate out precipitation, improve the bioavailability of dronedarone hydrochloride.
CN10152154A discloses a kind of micronized dronedarone or its pharmaceutically acceptable salt of containing, surfactant and as the hydrophilic polymer of cosolvent.
Application in combination of oral medication is studied the inventor to dronedarone hydrochloride, yet beyond thoughtly be, because the principal agent physicochemical property causes dronedarone hydrochloride to be difficult to stripping, dronedarone hydrochloride dissolubility in water-bearing media is very low, be pH value dependent form, scope at pH value 3-5 has maxima solubility, and dissolubility is very low in the scope of pH value 6-7.
The objective of the invention is in order to solve the problems such as poor stability in the dronedarone hydrochloride aqueous solution, easily oxidation, indissoluble, by raw material is carried out unformedization processing, free oxygen in solution in the eliminant pendular ring border, increase special antioxidant and pH adjusting agent, thereby a kind of dronedarone hydrochloride injection formulation is provided, and said preparation has guaranteed that medicine is in production process and the stability between the storage life.
Summary of the invention
Purpose of the present invention just is according to existing adjuvant and working condition, guaranteeing to have lower production cost and simple preparation technology, be suitable under the prerequisite of large-scale industrial production, being necessary to work out a kind of suitable prescription forms and preparation technology, can produce injection dronedarone hydrochloride pharmaceutical composition, make for the dronedarone hydrochloride pharmaceutical composition to have good bioavailability and stability of drug products.
Advantage of the present invention and effect are that production method is simple, and cost is low, and the preparation that makes can reach effective blood drug concentration very soon after taking medicine.
The object of the present invention is to provide a kind of injection dronedarone hydrochloride pharmaceutical composition and preparation method thereof, it can overcome the deficiency of prior art, efficiently solve dronedarone hydrochloride and dissolve difficult problem, by adding special antioxidant, efficiently solve the problem of this pharmaceutical composition poor stability.
Purpose of the present invention provides a kind of injection dronedarone hydrochloride pharmaceutical composition, it is characterized in that, the prescription of making 1000 is composed as follows:
Purpose of the present invention provides a kind of injection dronedarone hydrochloride pharmaceutical composition in addition, it is characterized in that, main ingredient consists of in the described injection dronedarone hydrochloride:
1000 of injection dronedarone hydrochloride sheet unit prescriptions, wherein:
Another object of the present invention provides the preparation method of injection dronedarone hydrochloride pharmaceutical composition, and this preparation method comprises the steps:
1) prepare: adopt spray-dired mode to be prepared into unformed form dronedarone hydrochloride, for subsequent use;
2) get recipe quantity water for injection 70%, temperature is at 50-70 ℃, adds cysteine hydrochloride, sodium hydrogen phosphate, the sodium chloride of recipe quantity, be stirred to dissolving after, add again the dronedarone hydrochloride of recipe quantity in the solution, be stirred to dissolve complete;
3) to 2) in add the 0.05-0.1% medicinal charcoal of medicine liquid volume, stir fully after, placed 15-30 minute;
4) with 3) adopt plate filter to filter, the supplementary injection water is to full dose, and mix homogeneously records original ph, according to original ph, regulates the pH value scope at 3.0-4.5 with 4% sodium hydroxide solution and 10% hydrochloric acid solution;
5) control in: carry out the intermediate products check;
6) fine straining: adopt 0.22 μ m, 0.45 μ m microporous filter membrane fine straining qualified to visible foreign matters medicinal liquid;
7) fill: the loading amount that medicinal liquid props up by 10.5ml/ or 20.6ml/ props up is distinguished fill in ampoule;
8) sterilization: 121 ℃ of pressure sterilizings 15 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
Injection dronedarone hydrochloride pharmaceutical composition of the present invention is characterized in that, is packaged in the low borosilicate glass ampoule.
Traditional dronedarone hydrochloride injection, to poor stability, easily degraded, quality can't guarantee.
Among the present invention, through the screening of tens of times test recipes and the summary of test data, optimized its recipe quantity, not only solved poor stability, slightly solubility problem, and constant product quality.
The inventor finds through a large amount of experimental study, when the dronedarone hydrochloride pharmaceutical composition is above-mentioned prescription, and described injection the best in quality, stability is best.
Another aspect of the present invention provides the preparation method of dronedarone hydrochloride injection of the present invention, and the method is simple, prepared dronedarone hydrochloride injection good stability.
Below by conceptual design and prescription screening explanation the present invention.
At first, solve dronedarone hydrochloride indissoluble problem, in the documents and materials, in injection, add some cosolvents, can effectively improve its solubility problem, interpolation 1,2-PD arranged, the cosolvents such as polyoxyethylene sorbitan monoleate, because the adjuvant that injection adds is fewer, the safety meeting of clinical application improves greatly, and we consider raw material is adopted physics mode, pulverize, control its particle diameter and investigate its dissolution time and solution temperature.
The selection of raw material particle size
Respectively dronedarone hydrochloride pulverized 200 mesh sieves (particle diameter is at 75 μ m ± 4.1 μ m), be crushed to particle diameter less than 10 μ m, made formulation concentrations solution, observed the dissolving situation:
As seen from the experiment: because raw material particle size is excessive, dissolving slowly; Raw material through being crushed to particle diameter less than 10 μ m after, dissolving is very fast, still select with raw material pulverizing to particle diameter less than 10 μ m.
Because the chemical constitution of dronedarone hydrochloride causes its easy oxidation, poor stability, still select different antioxidants, to its compatibility test of carrying out major ingredient and adjuvant, the adjuvant of investigating is as follows:
At first, we carry out compatibility test to raw material and adjuvant, choosing dronedarone hydrochloride mixes in certain 10: 1 ratios with adjuvant sodium sulfite, sodium pyrosulfite, cysteine hydrochloride respectively, make the solution of drug level, test method according to influence factor in the medicine stability guideline, respectively under 4500LX ± 500LX illumination condition, in the calorstat of 60 ℃ of high temperature and the calorstat of 25 ℃ of relative humiditys 92.5% ± 5% (KNO3 saturated solution) placed 72 hours, investigate appearance character and related substance, the results are shown in following table:
Shown by above result of the test, dronedarone hydrochloride, dronedarone hydrochloride are mixed by a certain percentage with antioxidant, the solution that is mixed with formulation concentrations places under influence factor's condition and placed 72 hours, and dronedarone hydrochloride is the most stable with the solution that is mixed with formulation concentrations after the cysteine hydrochloride certain proportion mixes.
On the relevant basis of studying to the supplementary material compatibility, the prescription of the following several reasonables of design is in order to launch screening and optimization.
Antioxidant consumption screening: according to supplementary material compatibility test result of study, investigate the antioxidant consumption of variable concentrations, on the impact of its related substance:
| Supplementary material | Prescription 3 | Prescription 4 |
| Dronedarone hydrochloride | 426g | 426g |
| Sodium chloride | 180g | 180g |
| Cysteine hydrochloride | 1.5g | 3g |
| Sodium hydrogen phosphate | 6g | 6g |
| Water for injection | Add to 20L | Add to 20L |
Preparation technology:
1) prepare: adopt spray-dired mode to be prepared into unformed form dronedarone hydrochloride, for subsequent use;
2) get recipe quantity water for injection 70%, temperature is at 50-70 ℃, adds cysteine hydrochloride, the sodium chloride of recipe quantity, be stirred to dissolving after, add again the dronedarone hydrochloride of recipe quantity in the solution, be stirred to dissolve complete;
3) to 2) in add 0.1% medicinal charcoal of medicine liquid volume, stir fully after, placed 15 minutes;
4) with 3) adopt plate filter to filter, the supplementary injection water is to full dose, and mix homogeneously records original ph, according to original ph, regulates the pH value scope at 3.0-4.5 with 4% sodium hydroxide solution and 10% hydrochloric acid solution;
5) control in: carry out the intermediate products check;
6) fine straining: adopt 0.22 μ m, 0.45 μ m microporous filter membrane fine straining qualified to visible foreign matters medicinal liquid;
7) fill: the loading amount that medicinal liquid props up by 20.6ml/ is distinguished fill in ampoule;
8) sterilization: 121 ℃ of pressure sterilizings 15 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
Each investigates the project measurement result
| Detection | Prescription 1 | Prescription 2 |
| Character | Achromatism and clarity solution | Achromatism and clarity solution |
| Related substance before the sterilization | 0.25％ | 0.22％ |
| PH value before the sterilization | 3.5 | 3.5 |
| Related substance after the sterilization | 0.57％ | 0.32％ |
| PH value after the sterilization | 3.5 | 3.5 |
By above result of the test as can be known: pH value is basicly stable before and after 2 sterilizations of prescription 1-prescription; Related substance is basically identical after prescription 2 and prescription 3 sterilizations, and diversity is little, is better than writing out a prescription 1, still in the large production scale of prescription simulation, with 10,000 every batch, amplify and produce 3 batches.
Specification: 20ml:426mg (embodiment 1)
Specification 10ml:213mg (embodiment 2)
Through evidence: product formulation and technology simple possible.Be packaged in 40 ℃ ± 2 ℃ through six batches of products with listing, placed under the accelerated test condition of relative humidity 75% ± 5% 6 months and the long term test condition was placed 6 months, the result shows, quality is more stable to meet production requirement.
Product of the present invention is the sterile water solution of dronedarone hydrochloride, and sterilising conditions is very crucial, should reach sterilization effect, can not destroy solution again, and the inventor investigates sterilising conditions, and 121 ℃ of pressure sterilizings 15 minutes, safety was best.
Compared with prior art, the present invention has following advantage:
1) new dronedarone hydrochloride compositions provided by the present invention has thoroughly solved the slightly solubility problem of dronedarone hydrochloride.
2) salt dronedarone hydrochloride injection provided by the present invention is for the market risk of the yield that improves this product, reduction product, and better being applied to clinical treatment has very large help.
3) new dronedarone hydrochloride compositions provided by the present invention proves constant product quality through industrialized great production and study on the stability, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
4) preparation method of new dronedarone hydrochloride compositions provided by the present invention, the method is simple, prepared dronedarone hydrochloride injection good stability.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
The dronedarone hydrochloride injection prepares 1000, wherein:
Preparation technology:
1) prepare: adopt spray-dired mode to be prepared into unformed form dronedarone hydrochloride, for subsequent use;
2) get recipe quantity water for injection 70%, temperature is at 50-70 ℃, adds cysteine hydrochloride, sodium hydrogen phosphate, the sodium chloride of recipe quantity, be stirred to dissolving after, add again the dronedarone hydrochloride of recipe quantity in the solution, be stirred to dissolve complete;
3) to 2) in add the 0.05-0.1% medicinal charcoal of medicine liquid volume, stir fully after, placed 15-30 minute;
4) with 3) adopt plate filter to filter, the supplementary injection water is to full dose, and mix homogeneously records original ph, according to original ph, regulates the pH value scope at 3.0-4.5 with 4% sodium hydroxide solution and 10% hydrochloric acid solution;
5) control in: carry out the intermediate products check;
6) fine straining: adopt 0.22 μ m, 0.45 μ m microporous filter membrane fine straining qualified to visible foreign matters medicinal liquid;
7) fill: the loading amount that medicinal liquid props up by 10.5ml/ or 20.6ml/ props up is distinguished fill in ampoule;
8) sterilization: 121 ℃ of pressure sterilizings 15 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
Embodiment 2
The dronedarone hydrochloride injection prepares 1000, wherein:
Preparation technology: with embodiment 1.
Test example 1
Freezing-thawing test result
Under-10 ℃～20 ℃ conditions 2 days, then under 40 ℃ ± 2 ℃ acceleration environments, investigate 2 days, through three circulations, sampling detects, and each investigates the indices of project without significant change.
Freezing-thawing test result
The result shows, then embodiment 1, embodiment 2 under-10 ℃～20 ℃ conditions 2 days investigate 2 days under 40 ℃ ± 2 ℃ acceleration environments, and through three circulations, sampling detects, and each investigates the indices of project without significant change.
Test example 2
Long-term stable experiment
Above result of the test shows: embodiment 1, embodiment 2 placed 6 months in the long term test condition, and each investigates the indices of project without significant change, had preferably stability, and embodiment 1, embodiment 2 all are better than comparative example 1.
Claims (3)
1. dronedarone hydrochloride pharmaceutical composition of an injection and preparation method thereof, it is characterized in that, this pharmaceutical composition is comprised of unformed dronedarone hydrochloride, sodium chloride and cysteine hydrochloride, and described pharmaceutical composition prepares 1000, is comprised of following proportioning weight:
2. dronedarone hydrochloride pharmaceutical composition of an injection and preparation method thereof, it is characterized in that, this pharmaceutical composition is comprised of unformed dronedarone hydrochloride, sodium chloride and cysteine hydrochloride, and described pharmaceutical composition prepares 1000, is comprised of following proportioning weight::
3. the preparation method of the dronedarone hydrochloride pharmaceutical composition of claim 1 or 2 described a kind of injections is characterized in that, this preparation method comprises the steps:
1) prepare: adopt spray-dired mode to be prepared into unformed form dronedarone hydrochloride, for subsequent use;
2) get recipe quantity water for injection 70%, temperature is at 50-70 ℃, adds cysteine hydrochloride, sodium hydrogen phosphate, the sodium chloride of recipe quantity, be stirred to dissolving after, add again the dronedarone hydrochloride of recipe quantity in the solution, be stirred to dissolve complete;
3) to 2) in add the 0.05-0.1% medicinal charcoal of medicine liquid volume, stir fully after, placed 15-30 minute;
4) with 3) adopt plate filter to filter, the supplementary injection water is to full dose, and mix homogeneously records original ph, according to original ph, regulates the pH value scope at 3.0-4.5 with 4% sodium hydroxide solution and 10% hydrochloric acid solution;
5) control in: carry out the intermediate products check;
6) fine straining: adopt 0.22 μ m, 0.45 μ m microporous filter membrane fine straining qualified to visible foreign matters medicinal liquid;
7) fill: the loading amount that medicinal liquid props up by 10.5ml/ or 20.6ml/ props up is distinguished fill in ampoule;
8) sterilization: 121 ℃ of pressure sterilizings 15 minutes;
9) lamp inspection: carry out the visible foreign matters inspection;
10) packing warehouse-in.
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| CN2011102202964A CN102908307A (en) | 2011-08-03 | 2011-08-03 | Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof |
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| CN2011102202964A CN102908307A (en) | 2011-08-03 | 2011-08-03 | Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115702878A (en) * | 2021-08-16 | 2023-02-17 | 上海博志研新药物技术有限公司 | Dronedarone hydrochloride injection composition, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1301177A (en) * | 1998-05-15 | 2001-06-27 | 若素制药株式会社 | Anti-inflammatory eye drops |
| CN1479610A (en) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | Drondearone pharmaceutical composition for external gastrointestinal-tract administration |
| CN101766641A (en) * | 2010-01-20 | 2010-07-07 | 北京凯因科技股份有限公司 | Compound glycyrrhizin injection preparation |
| CN102078307A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Medicine composition of dronedarone hydrochloride solid dispersion and preparation method thereof |
-
2011
- 2011-08-03 CN CN2011102202964A patent/CN102908307A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301177A (en) * | 1998-05-15 | 2001-06-27 | 若素制药株式会社 | Anti-inflammatory eye drops |
| CN1479610A (en) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | Drondearone pharmaceutical composition for external gastrointestinal-tract administration |
| CN102078307A (en) * | 2009-12-01 | 2011-06-01 | 严洁 | Medicine composition of dronedarone hydrochloride solid dispersion and preparation method thereof |
| CN101766641A (en) * | 2010-01-20 | 2010-07-07 | 北京凯因科技股份有限公司 | Compound glycyrrhizin injection preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115702878A (en) * | 2021-08-16 | 2023-02-17 | 上海博志研新药物技术有限公司 | Dronedarone hydrochloride injection composition, preparation method and application thereof |
| CN115702878B (en) * | 2021-08-16 | 2024-05-10 | 上海云晟研新生物科技有限公司 | Dronedarone hydrochloride injection composition, preparation method and application thereof |
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Application publication date: 20130206 |