CN106176590A - Improve the preparation method of quinidine sulfate ejection preparation stability composition - Google Patents
Improve the preparation method of quinidine sulfate ejection preparation stability composition Download PDFInfo
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- CN106176590A CN106176590A CN201610646227.2A CN201610646227A CN106176590A CN 106176590 A CN106176590 A CN 106176590A CN 201610646227 A CN201610646227 A CN 201610646227A CN 106176590 A CN106176590 A CN 106176590A
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- Prior art keywords
- quinidine sulfate
- injection
- malic acid
- preparation
- natrium malicum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
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Abstract
The invention discloses the preparation method improving quinidine sulfate ejection preparation stability composition, comprise the steps: 1) weigh quinidine sulfate, malic acid and/or natrium malicum；2) malic acid, natrium malicum solution are joined respectively；3), during quinidine sulfate adds the water for injection 500ml of 30 DEG C～40 DEG C, stir to after being completely dissolved, the activated carbon of addition, stirring, filter decarburization；4) malic acid and/or the natrium malicum solution regulation pH value of gained filtrate configuration is 4.0～6.0, addition water for injection to 1000ml；5) it is filtered until clear, fill, sterilizing, to obtain final product.The present invention can make this injection pH value more stable, quinidine sulfate degradation material relatively prior art is substantially reduced, in the case of avoiding using other to increase the cosolvent of clinical practice risk, improve the clarity of quinidine sulfate injection, can ensure that the visible foreign matters inspection of product meets the regulation of drug standard, it is simple to clinical application and popularization.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates to improve quinidine sulfate ejection preparation stability composition
Preparation method.
Background technology
Quinidine sulfate is mainly used in paroxysmal tachycardia, tremble in atrium, morning is won；Prevent ventricular tachycardia and to room
Room knot reciprocal tachycardia；Also can prevent Symptomatic supraventricular and ventricular premature contraction.
Due to quinidine sulfate dissolubility extreme difference in aqueous, therefore it is made into quinidine sulfate hydrochlorate or sulphuric acid
Quinidine phosphate is to increase its water solublity.Presently commercially available quinidine sulfate injection mainly have quinidine sulfate hydrochlorate,
The phosphatic injection with small volume of quinidine sulfate, and in quinidine sulfate extracting solution solution, add glucose or sodium chloride
The high-capacity injection made as osmotic pressure regulator.But when preparing above-mentioned injection, it is necessary to the pH value of medicinal liquid is regulated
To being suitable for the certain limit that human injection is administered, the pH value regulator that current document report uses is sodium hydroxide solution or makes
With hydrochloric acid solution, phosphoric acid solution, but use quinidine sulfate injection prepared by above-mentioned pH value regulator in long-term storage and winter
Easily separate out the precipitate such as tiny white point, white block, solution is muddy under season cryogenic conditions, cause the visible foreign matters check item of product not
Qualified.Prior art is to add polyoxyethylene sorbitan monoleate in the solution as cosolvent, small particles, white block, molten occurs solving product
The sedimentary problems such as liquid is muddy.But polyoxyethylene sorbitan monoleate is owing to having the effect of haemolysis and blood pressure lowering, and at storage and high temperature sterilize
During easily become sour, cause the injection clinical practice risk containing polyoxyethylene sorbitan monoleate higher, to clinical application and promote band
It is inconvenient to come.
Summary of the invention
The technical problem to be solved is to provide the system improving quinidine sulfate ejection preparation stability composition
Preparation Method.This medicinal composition for injections employing malic acid, natrium malicum are as pH adjusting agent, and are found by creative work
When using malic acid, natrium malicum as pH adjusting agent, medicinal liquid pH value is more stable, the more existing skill of quinidine sulfate degradation material
Art is substantially reduced, and in the case of avoiding using other to increase the cosolvent of clinical practice risk, sulfur has been satisfactorily addressed
Acid quinidine injection easily separates out tiny white point, white block, the problem of solution muddiness under the conditions of storage for a long time and winter low temperature.
The present invention solves the problems referred to above and be the technical scheme is that raising quinidine sulfate ejection preparation stability combination
The preparation method of thing, comprises the steps:
(1) quinidine sulfate 5g～100g, malic acid and/or natrium malicum 1mg～10mg are weighed；
(2) malic acid, natrium malicum are configured to the solution of 1g/100ml～10g/100ml respectively, standby；
(3), during quinidine sulfate adds the water for injection 500ml of 30 DEG C～40 DEG C, stir to after being completely dissolved, the activity of addition
Charcoal, described activated carbon dosage is 0.2g/100ml, stirs 15 minutes, filters decarburization；
(4) step (3) gained filtrate step (2) configures malic acid and/or natrium malicum solution regulation pH value be 6.0～
8.0, add the water for injection of less than 40 DEG C (30 DEG C～40 DEG C) to 1000ml；
(5) by step (4) gained medical filtration to clarification, fill, sterilizing, to obtain final product.
In described step (1) malic acid consumption be 1mg～2.0mg, natrium malicum consumption be 1mg～2.0mg.
Described step also includes osmotic pressure regulator 9.0g in (1).
Described osmotic pressure regulator is xylitol.
In such scheme, what addition malic acid and/or natrium malicum referred to addition can be in malic acid, natrium malicum
Any one, or malic acid, natrium malicum are with arbitrary proportion proportioning；In step (2), the malic acid of addition, natrium malicum
In one, then make a kind of solution, as included malic acid, natrium malicum two kinds, be configured to solution for standby the most respectively；Sulphuric acid Kui
Buddhist nun's fourth, the consumption of osmotic pressure regulator can use the consumption of prior art, adjust according to the consumption of prior art.
In sum, the invention has the beneficial effects as follows: the present invention, by experimental studies have found that, notes at quinidine sulfate medicine
Penetrating in preparation, when using malic acid, natrium malicum as pH adjusting agent, medicinal liquid pH value is more stable, quinidine sulfate degradation product
Matter relatively prior art is substantially reduced, in the case of avoiding using other to increase the cosolvent of clinical practice risk, satisfactory
Solve quinidine sulfate injection and use prior art products easily to separate out tiny white point, white block, molten in storage process
The problem that liquid is muddy, it is ensured that keeping that quinidine sulfate injection can be stable in storage process is different seen from injection
Analyte detection meets the regulation of drug standard, it is simple to clinical application and popularization.
The present invention passes through creative work, to the tiny white point separated out in quinidine sulfate injection, white block, solution muddiness
Reason be analyzed and study, determine that deposit is mainly raw material free alkali crystallize and a small amount of catabolite, occur above-mentioned
Reason may be relevant with the kind of acid used by the pH value of solution and pH adjusting agent, alkali.Therefore natrium malicum is used to adjust as pH
Joint agent, and use malic acid as pH value counter regulation agent, avoiding using the feelings of the cosolvent of other increase clinical practice risks
Under condition, to solve this product easily tiny white point of precipitation, white block, muddy asking of solution under the conditions of long-term storage and winter low temperature
Topic.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1:
Improve quinidine sulfate ejection preparation stability composition preparation method, comprise the steps: (1) weighting raw materials with
Quinidine sulfate extracting solution amount of calculation 25g, sodium chloride 7.0g, malic acid 2g, natrium malicum 4mg；(2) malic acid, natrium malicum
It is configured to the solution of 10%～20% respectively, standby；(3) adding in the water for injection 500ml of less than 40 DEG C, stirring is to being completely dissolved
After, add 0.02%(g/ml) activated carbon, stir 15 minutes, filtration decarburization；(4) filtrate malic acid or natrium malicum solution
Regulation pH value is 3.0～7.0, adds the water for injection of less than 40 DEG C to 1000ml；(5) medical filtration is to clarification, fill, goes out
Bacterium, to obtain final product.
Composition and the content thereof of the concrete each component of the present embodiment are as follows:
Quinidine sulfate extracting solution 25g
Sodium chloride 7.0g
Malic acid 2.0g
Natrium malicum 4.0g
Malic acid, natrium malicum are configured to the solution of 10%～20% respectively, standby.Quinidine sulfate extracting solution adds less than 40 DEG C
Water for injection 500ml in, stir to after being completely dissolved, add 0.15% activated carbon (i.e. activated carbon dosage is 0.2g/
100ml), stir 15 minutes, filter decarburization.Filtrate malic acid or natrium malicum solution regulation pH value are 4.0～6.0, add
The water for injection of less than 40 DEG C is to 1000ml.Medical filtration, to clarification, fill, sterilizing, to obtain final product.
Embodiment 2:
The present embodiment another embodiment, as follows, the note of above-mentioned raising quinidine sulfate drug injection preparation stability
Penetrate pharmaceutical composition to be prepared according to the following steps:
(1) weighting raw materials is with quinidine sulfate amount of calculation 70g, malic acid 3g, natrium malicum 6g；(2) malic acid, natrium malicum
It is configured to the solution of 10%～20% respectively, standby；(3) adding in the water for injection 500ml of less than 40 DEG C, stirring is to being completely dissolved
After, add 0.15%(g/ml) activated carbon, stir 15 minutes, filtration decarburization；(4) filtrate malic acid or natrium malicum solution
Regulation pH value is 4.0～6.0, adds the water for injection of less than 40 DEG C to 1000ml；(5) medical filtration is to clarification, fill, goes out
Bacterium, to obtain final product.
Composition and the content thereof of the concrete each component of the present embodiment are as follows:
Quinidine sulfate extracting solution 70g
Malic acid 3g
Natrium malicum 5g
Malic acid, natrium malicum are configured to the solution of 10%～20% respectively, standby.Hydrochloric acid quinidine sulfate adds less than 40 DEG C
In water for injection 500ml, stir to after being completely dissolved, add 0.15% activated carbon (i.e. activated carbon dosage is 0.15g/
100ml), stir 15 minutes, filter decarburization.Filtrate malic acid or natrium malicum solution regulation pH value are 4.0～6.0, add
The water for injection of less than 40 DEG C is to 1000ml.Medical filtration, to clarification, fill, sterilizing, to obtain final product.
Embodiment 3:
Quinidine sulfate injection stability comparative test
The visible foreign matters detection utilizing quinidine sulfate injection obtained by the present invention meets the regulation of drug standard, and molten
Liquid stability is fine, in the case of avoiding using other to increase the cosolvent of clinical practice risk, solves quinidine sulfate
Injection easily occurs the problems such as small particles, white block, solution are muddy in storage process.Utilize the sulphuric acid Kui Buddhist nun obtained by the present invention
Fourth injection is wanted according to the relevant of two annex Ⅺ Ⅹ C pharmaceutical preparation stability test guidelines of China's coastal port
Ask, investigated respectively to place to place for 24 months, 40 DEG C at 25 DEG C and within 6 months, 60 DEG C, placed 10 days, 0～5 DEG C of low temperature 20 days medicine of placement
Thing stability, result constant product quality at the conditions of the experiments described above, every Testing index all meets the rule of this product quality standard
Fixed.
The pharmacological results shows: utilize the stable quinidine sulfate injection obtained by the present invention without hemolytic, nothing
Anaphylaxis, nonirritant, meet the requirement of drug administration by injection.
According to the above results, the quinidine sulfate drug injection preparation of the present invention can improve quinidine sulfate injection
The clarity of liquid, particularly in the case of quinidine sulfate injection period of storage is longer, it is possible to stable holding injection
Visible foreign matters detection meets the regulation of drug standard, solves quinidine sulfate medicine and uses existing technical products when storage
Between longer in the case of the problem that small particles, white block, solution are muddy occurs, it is ensured that the visible foreign matters inspection of product meets medicine
The regulation of quality standard, it is simple to clinical application and popularization.
As it has been described above, just can preferably realize the present invention.
Claims (4)
1. improve the preparation method of quinidine sulfate ejection preparation stability composition, it is characterised in that comprise the steps:
(1) quinidine sulfate 5g～100g, malic acid and/or natrium malicum 1g～5g are weighed；
(2) malic acid, natrium malicum are configured to the solution of 1g/100ml～10g/100ml respectively, standby；
(3), during quinidine sulfate adds the water for injection 500ml of 30 DEG C～40 DEG C, stir to after being completely dissolved, the activity of addition
Charcoal, described activated carbon dosage is 0.15g/100ml, stirs 15 minutes, filters decarburization；
(4) step (3) gained filtrate step (2) configures malic acid and/or natrium malicum solution regulation pH value be 4.0～
6.0, add the water for injection of 30 DEG C～40 DEG C to 1000ml；
(5) by step (4) gained medical filtration to clarification, fill, sterilizing, to obtain final product.
The preparation method of raising quinidine sulfate ejection preparation stability composition the most according to claim 1, its feature
Be, in described step (1) malic acid consumption be 1g～5g, natrium malicum consumption be 1g～5g.
The preparation method of raising quinidine sulfate ejection preparation stability composition the most according to claim 1, its feature
Being, described step also includes osmotic pressure regulator 7.0g in (1).
The preparation method of raising quinidine sulfate ejection preparation stability composition the most according to claim 3, its feature
Being, described osmotic pressure regulator is sodium chloride.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610646227.2A CN106176590A (en) | 2016-08-09 | 2016-08-09 | Improve the preparation method of quinidine sulfate ejection preparation stability composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610646227.2A CN106176590A (en) | 2016-08-09 | 2016-08-09 | Improve the preparation method of quinidine sulfate ejection preparation stability composition |
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| CN106176590A true CN106176590A (en) | 2016-12-07 |
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| CN201610646227.2A Withdrawn CN106176590A (en) | 2016-08-09 | 2016-08-09 | Improve the preparation method of quinidine sulfate ejection preparation stability composition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347429A (en) * | 2007-07-20 | 2009-01-21 | 重庆人本药物研究院 | Stable tartaric acid ifenprodil injection and method of preparing the same |
| CN102008727A (en) * | 2010-12-07 | 2011-04-13 | 四川升和药业股份有限公司 | Injection-purpose medicine composition for improving stability of ligustrazine medicine injection formulation and preparation method of injection-purpose medicine composition |
-
2016
- 2016-08-09 CN CN201610646227.2A patent/CN106176590A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101347429A (en) * | 2007-07-20 | 2009-01-21 | 重庆人本药物研究院 | Stable tartaric acid ifenprodil injection and method of preparing the same |
| CN102008727A (en) * | 2010-12-07 | 2011-04-13 | 四川升和药业股份有限公司 | Injection-purpose medicine composition for improving stability of ligustrazine medicine injection formulation and preparation method of injection-purpose medicine composition |
Non-Patent Citations (1)
| Title |
|---|
| 中国药物大全编委会: "《中国药物大全》", 31 January 1998 * |
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Application publication date: 20161207 |
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