CN106176588A - Improve the preparation method of composition of Codeine Hydrochloride ejection preparation stability - Google Patents

Improve the preparation method of composition of Codeine Hydrochloride ejection preparation stability Download PDF

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Publication number
CN106176588A
CN106176588A CN201610646215.XA CN201610646215A CN106176588A CN 106176588 A CN106176588 A CN 106176588A CN 201610646215 A CN201610646215 A CN 201610646215A CN 106176588 A CN106176588 A CN 106176588A
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CN
China
Prior art keywords
codeine hydrochloride
benzoic acid
injection
deg
codeine
Prior art date
Application number
CN201610646215.XA
Other languages
Chinese (zh)
Inventor
李云娟
Original Assignee
成都佳迪璐莎生物科技有限公司
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Priority to CN201610646215.XA priority Critical patent/CN106176588A/en
Publication of CN106176588A publication Critical patent/CN106176588A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions

Abstract

The invention discloses the preparation method of composition improving Codeine Hydrochloride ejection preparation stability, comprise the steps: 1) weigh the extracting solution of Codeine Hydrochloride, benzoic acid and/or sodium benzoate;2) benzoic acid, PhCOONa solution are joined respectively;3), during the extracting solution of Codeine Hydrochloride 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) benzoic acid and/or the PhCOONa solution regulation pH value of gained filtrate configuration is .0~7.0, 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, Codeine Hydrochloride 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 Codeine Hydrochloride 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

Improve the preparation method of composition of Codeine Hydrochloride ejection preparation stability

Technical field

The invention belongs to pharmaceutical technology field, in particular it relates to improve the combination of Codeine Hydrochloride ejection preparation stability Thing preparation method.

Background technology

Codeine Hydrochloride is subordinate to codeine salt family, is a kind of oral administration solution.Its Main Ingredients and Appearance is codeine, can treat Because extracting from Semen Papaveris, the analgesic activity of this material is that in nature, other compounds are incomparable, thus is regarded always For releasing the maximally effective analgesic of severe pain.

Due to Codeine Hydrochloride dissolubility extreme difference in aqueous, therefore it is made into Codeine Hydrochloride hydrochlorate or hydrochloric acid Codeine phosphate is to increase its water solublity.Presently commercially available Codeine Hydrochloride injection mainly have Codeine Hydrochloride hydrochlorate, The phosphatic injection with small volume of Codeine Hydrochloride, and in Codeine Hydrochloride 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 Codeine Hydrochloride 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 compositions system improving Codeine Hydrochloride ejection preparation stability Preparation Method.This medicinal composition for injections employing benzoic acid, sodium benzoate are as pH adjusting agent, and are found by creative work When using benzoic acid, sodium benzoate as pH adjusting agent, medicinal liquid pH value is more stable, the more existing skill of Codeine Hydrochloride degradation material Art is substantially reduced, and in the case of avoiding using other to increase the cosolvent of clinical practice risk, salt has been satisfactorily addressed Acid codeine 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 the group improving Codeine Hydrochloride ejection preparation stability Compound preparation method, comprises the steps:

(1) extracting solution 2g~40g of Codeine Hydrochloride, benzoic acid and/or sodium benzoate 5mg~3g are weighed;

(2) benzoic acid, sodium benzoate are configured to the solution of 5mg/100ml~3g/100ml respectively, standby;

(3), during the extracting solution of Codeine Hydrochloride adds the water for injection 500ml of 30 DEG C~40 DEG C, stir to after being completely dissolved, add The activated carbon entered, described activated carbon dosage is 0.02g/100ml, stirs 15 minutes, filters decarburization;

(4) step (3) gained filtrate step (2) configures benzoic acid and/or PhCOONa solution regulation pH value be 5.0~ 7.0, 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.

In described step (1) benzoic acid consumption be 5mg~3g, sodium benzoate consumption be 5mg~3g.

Described step also includes osmotic pressure regulator 12.0g in (1).

Described osmotic pressure regulator is sodium chloride.

In such scheme, what addition benzoic acid and/or sodium benzoate referred to addition can be in benzoic acid, sodium benzoate Any one, or benzoic acid, sodium benzoate are with arbitrary proportion proportioning;In step (2), the benzoic acid of addition, sodium benzoate In one, then make a kind of solution, as included benzoic acid, sodium benzoate two kinds, be configured to solution for standby the most respectively;Hydrochloric acid can Treat because of extracting solution, 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 Codeine Hydrochloride medicine Penetrating in preparation, when using benzoic acid, sodium benzoate as pH adjusting agent, medicinal liquid pH value is more stable, Codeine Hydrochloride 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 Codeine Hydrochloride 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 Codeine Hydrochloride 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 Codeine Hydrochloride 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 sodium benzoate is used to adjust as pH Joint agent, and use benzoic 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 Codeine Hydrochloride ejection preparation stability preparation method of composition, comprise the steps: (1) weighting raw materials with Codeine Hydrochloride extracting solution amount of calculation 5g, sodium chloride 12.0g, benzoic acid 1.2g, sodium benzoate 2.0g;(2) benzoic acid, benzoic acid Sodium 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 the most molten Xie Hou, add 0.02%(g/ml) activated carbon, stir 15 minutes, filtration decarburization;(4) filtrate benzoic acid or sodium benzoate are molten Liquid regulation pH value is 5.0~7.0, 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:

Codeine Hydrochloride extracting solution 15g

Sodium chloride 12g

Benzoic acid 1. 2g

Sodium benzoate 2. g

Benzoic acid, sodium benzoate are configured to the solution of 10%~20% respectively, standby.Codeine Hydrochloride extracting solution adds less than 40 DEG C Water for injection 500ml in, stir to after being completely dissolved, add 0.02% activated carbon (i.e. activated carbon dosage is 0.02g/ 100ml), stir 15 minutes, filter decarburization.Filtrate benzoic acid or PhCOONa solution regulation pH value are 5.0~7.0, 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 Codeine Hydrochloride drug injection preparation stability Penetrate pharmaceutical composition to be prepared according to the following steps:

(1) weighting raw materials is with Codeine Hydrochloride amount of calculation 35g, benzoic acid 3g, sodium benzoate 3g;(2) benzoic acid, sodium benzoate 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 0.2%(g/ml) activated carbon, stir 15 minutes, filtration decarburization;(4) filtrate benzoic acid or PhCOONa solution are adjusted Joint pH value is 5.0~7.0, adds the water for injection of less than 40 DEG C to 1000ml;(5) medical filtration is to clarifying, fill, sterilizing, Obtain.

Composition and the content thereof of the concrete each component of the present embodiment are as follows:

Codeine Hydrochloride extracting solution 35g

Benzoic acid 3g

Sodium benzoate 3g

Benzoic acid, sodium benzoate are configured to the solution of 10%~20% respectively, standby.Acid hydrochloride salt codeine adds less than 40 DEG C In water for injection 500ml, stir to after being completely dissolved, add 0.02% activated carbon (i.e. activated carbon dosage is 0.02g/ 100ml), stir 15 minutes, filter decarburization.Filtrate benzoic acid or PhCOONa solution regulation pH value are 5.0~7.0, 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:

Codeine Hydrochloride injection stability comparative test

The visible foreign matters detection utilizing Codeine Hydrochloride 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 Codeine Hydrochloride Injection easily occurs the problems such as small particles, white block, solution are muddy in storage process.The hydrochloric acid obtained by the present invention is utilized to treat Because 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 Codeine Hydrochloride 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 Codeine Hydrochloride drug injection preparation of the present invention can improve Codeine Hydrochloride injection The clarity of liquid, particularly in the case of Codeine Hydrochloride injection period of storage is longer, it is possible to stable holding injection Visible foreign matters detection meets the regulation of drug standard, solves Codeine Hydrochloride 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 composition of Codeine Hydrochloride ejection preparation stability, it is characterised in that comprise the steps:
(1) extracting solution 2g~40g of Codeine Hydrochloride, benzoic acid and/or sodium benzoate 5mg~3g are weighed;
(2) benzoic acid, sodium benzoate are configured to the solution of 5mg/100ml~3g/100ml respectively, standby;
(3), during the extracting solution of Codeine Hydrochloride adds the water for injection 500ml of 30 DEG C~40 DEG C, stir to after being completely dissolved, add The activated carbon entered, described activated carbon dosage is 0.02g/100ml, stirs 15 minutes, filters decarburization;
(4) step (3) gained filtrate step (2) configures benzoic acid and/or PhCOONa solution regulation pH value be 5.0~ 7.0, 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 composition of raising Codeine Hydrochloride ejection preparation stability the most according to claim 1, its feature Be, in described step (1) benzoic acid consumption be 5mg~3g, sodium benzoate consumption be 5mg~3g.
The preparation method of composition of raising Codeine Hydrochloride ejection preparation stability the most according to claim 1, its feature Being, described step also includes osmotic pressure regulator 12.0g in (1).
The preparation method of composition of raising Codeine Hydrochloride ejection preparation stability the most according to claim 3, its feature Being, described osmotic pressure regulator is sodium chloride.
CN201610646215.XA 2016-08-09 2016-08-09 Improve the preparation method of composition of Codeine Hydrochloride ejection preparation stability CN106176588A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1767831A (en) * 2003-04-08 2006-05-03 普罗热尼奇制药公司 Pharmaceutical formulations containing methylnaltrexone
CN101347429A (en) * 2007-07-20 2009-01-21 重庆人本药物研究院;重庆植恩药业有限公司 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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1767831A (en) * 2003-04-08 2006-05-03 普罗热尼奇制药公司 Pharmaceutical formulations containing methylnaltrexone
CN101347429A (en) * 2007-07-20 2009-01-21 重庆人本药物研究院;重庆植恩药业有限公司 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)

* Cited by examiner, † Cited by third party
Title
刘锡钧: "盐酸可待因", 《实用药物指南》 *

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