CN105125507B - A kind of Esomeprazole sodium injection freezes compound powder and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of injection esomeprazole sodium freeze dry composition and preparation method thereof, said composition is mainly used in treating the enterogastric diseases such as scorching hot sense, erosive esophagitis caused by the Non-erosive gastroesophageal reflux of gastroesophageal reflux disease.The main ingredient of said composition is Esomeprazole sodium, sodium chloride, sodium hydroxide and calcio-disodium edetate, the preparation technology of fed intake, rushed using low temperature in preparation process nitrogen protection and low-temperature distillation low temperature parsing-desiccation.It is lyophilized into that type is attractive in appearance, product quality is stable, the content of impurity is few, solubility is good by freezing flour complexes made from this kind of prescription and preparation technology, reduce production cost, expanding production batch, facilitates clinical application, can obtain good economic benefit and social benefit.

Description

A kind of Esomeprazole sodium injection freezes compound powder and preparation method thereof

Technical field

The present invention relates to pharmaceutical technology field, more particularly to a kind of Esomeprazole sodium injection freeze compound powder and its Preparation method.

Background technology

Peptic ulcer refer to gastrointestinal mucosa by peptic digest liquid autodigestion and caused by exceed the tissue damage of muscular layer of mucosa, Gastral any position can be betided, wherein most commonly seen with stomach and duodenum, i.e. gastric ulcer and duodenal ulcer.Stomach Ulcer is one of common disease in population of China, frequently-occurring disease, and the mainly damage factor and mucous membrane with gastroduodenal mucous membrane occurs in it Loss of equilibrium is relevant between self-defense reparation factor.The protection mechanism of the gastroduodenal mucous membrane of normal person be enough to resist hydrochloric acid in gastric juice and The erosion of pepsin, but when hydrochloric acid in gastric juice and protease may occur for some link that some factors are compromised in protection mechanism Corrode itself mucous membrane and cause the formation of ulcer, when excessive gastric acid secretion may also considerably beyond the defence and repair of mucous membrane Cause ulcer.Helicobacter pylori and NSAIDs are to damage the most commonly encountered diseases that stomach and intestine protection mechanism causes ulcer to be fallen ill Cause, medicine, stress, hormone may also lead to the generation of ulcer, various psychological factors and bad dietary life habits can induce routed The appearance of ulcer.

In the forming process of DD, hydrochloric acid in gastric juice plays a crucial role in ulcer is formed, and gastroxia easily draws Send out such as peptic ulcer (including stress ulcer), GERD (including reflux esophagitis), gastrinoma, portion Divide the diseases such as functional dyspepsia FD.Stomach lining parietal cell secretes the final step proton pump of hydrochloric acid in gastric juice, and proton pump inhibitor makes to appoint Gastric acid secretion caused by what stimulation is blocked, and has stronger acid suppression effect, has in terms of gastric acid related disease is treated The effect of prominent.Being commonly used on Present clinical has the 1st generation proton pump inhibitor：Omeprazole, Lansoprazole, pantoprazole etc., the 2 generation preparations：There are Rabeprazole, esomeprazole etc., treatment of the proton pump inhibitor to acid-related disease is evident in efficacy, peace It is complete reliable, it is convenient to take, clinically obtain extensive popularization and application.

Entitled (S) -5- methoxyl groups -2- [[(the 4- methoxies of Esomeprazole sodium (Esomeprazole sodium) chemistry Base -3,5- dimethyl -2- pyridine radicals）Methyl] sulfinyl -1H- benzimidazoles) sodium.Injection Esomeprazole sodium is As when oral therapies do not apply to, the alternative medicine of GERD.On March 31st, 2005 FDA have approved Ah This application of sharp Kanggong department on injection Esomeprazole sodium, Chinese food Drug Administration in 2007 have approved Ah The import of this sharp Kanggong department esomeprazole sodium freeze-drying powder, the resistance to letter of its trade name, it is packed with 5ml bottles, when in use By add 5ml 0.9% sodium chloride solution into the bottle injection for intravenous using in the prescription of resistance to letter except containing main ingredient angstrom Outside Suo Meila azoles sodium, also containing auxiliary material natrium adetate and water for injection.Esomeprazole sodium can be used for gastroesophageal reflux induced disease Disease（GERD）The treatment of-erosive reflux esophagitis；The esophagitis patient cured prevents the long-term maintenance of recurrence from controlling Treat；GORD（GERD）Symptom control；Helicobacter pylori is eradicated with appropriate antimicrobial therapy drug combination, and And the healing duodenal ulcer related to helicobacter pylorus infection, prevent recurrent peptic ulcer with helicobacter pylori correlation.

Esomeprazole sodium, molecular formula：C17H18N3NaO3S, structural formula are as follows：

Esomeprazole sodium has a variety of patents, such as WO2008/149204A1, WO2003/89408A2, WO02006/ 1753A1, WO2009/47775A2, WO2009/40825, EP1515963A2, WO2006001755 A1, WO9828294 A1, The crystal formation patent such as US20070259921；Chinese patent CN201110152549.9 discloses a kind of Esomeprazole sodium lipid Body composition of medicine；Chinese patent CN200880108483.X, which is disclosed, to be related to containing esomeprazole free alkali or the U.S. drawing of Esso Azoles；Chinese patent CN201110030214.X is related to the combination of oral medication formulation for treating peptic ulcer；China The B of patent CN 102512382 relate to the lyophilized combination of Esomeprazole sodium and Esomeprazole sodium, mannitol, sodium hydroxide Thing.

Patent of the present invention further optimum organization thing prescription and preparation technology, improves production on the basis of lot of experiments Quality, the stability of product quality is ensured, maximum relevant material index is below 0.1%, and product stability was good, in 2 years Meet quality criteria requirements in the term of validity, ensure clinical therapeutic efficacy, and prescription is simple and easy to do, saves production cost, improves Production efficiency.

The content of the invention

Esomeprazole sodium freeze-dried composition is in long-term storing process or easily goes out its colour changed into yellow in hot conditions and has The quality problems such as material is exceeded, clarity is unqualified are closed, experiment shows that Esomeprazole sodium is more stable in the basic conditions, had It is unqualified to close the exceeded mainly oxidation impurities index of material.Regarding to the issue above and products characteristics, the lyophilized combination to this product Thing prescription enters and gone substantial amounts of experiment, by adding antioxidant, nitrogen charging air-isolation, low temperature dispensing, heightening the methods of pH value, Had good stability, be curative for effect, reliable in quality, the Esomeprazole sodium that technique is simple, large-scale production is feasible freeze combination Thing.

The present invention provides Esomeprazole sodium drug injection freeze-dried composition, and the freeze-dried composition contains esomeprazole Sodium, sodium chloride, calcio-disodium edetate, sodium hydroxide etc. form, and are a kind of pharmaceutical preparations of suitable drug administration by injection, are preferably Freeze drying powder injection, and when the injection is freeze drying powder injection, it is by Esomeprazole sodium, sodium chloride, Ca-EDTA Sodium, sodium hydroxide, add water for injection to prepare freeze-dried technique and be made.

The esomeprazole sodium pharmaceutical composition of the present invention, the composition of wherein composition are：Esomeprazole sodium, chlorine Change sodium, calcio-disodium edetate, sodium hydroxide and water for injection.

It is as follows to prepare the prescription of 1000：

40~90g of Esomeprazole sodium

20~40g of sodium chloride

0.5~5g of calcio-disodium edetate

The g of sodium hydroxide 5~20

2000~4000ml of water for injection

It is made 1000

The preferential composition of patent of the present invention is：Esomeprazole sodium：Sodium chloride：Calcio-disodium edetate：Hydrogen-oxygen Changeization sodium：Water for injection=40~90：20~40：0.5~5：5~20：2000~4000.

Preferably preparation method is：

（One）With the filling preparation method of liquid

（1）The sodium hydroxide of recipe quantity, Esomeprazole sodium, sodium chloride, calcio-disodium edetate are added to injection With in water, in 5~15 DEG C, stirring makes to be completely dissolved water for injection temperature；

（2）With 10-20% sodium hydroxide solution regulating liquid medicine liquid pH values to 10.5~12.0, benefit injects water to complete Amount；

（3）According to 0.05~0.4%g/ml of medicine liquid volume amount in the solution prepared, medical charcoal, stirring 15~45 are added After minute, carbon is removed with 0.45um stud filter filtration；

（4）With 2 0.2um polyether sulfone filter core aseptic filtration；

（4）Intermediates content and acidity assaying；

（5）According to intermediates content measurement result, loading amount is adjusted, it is filling, partly jump a queue；

（6）With liquid, adjust PH, except carbon filtering and aseptic filtration during a straight-through nitrogen carry out protection against oxidation.

（Two）Freeze drying process of preparing same

（1）Decoction after will be filling, which is positioned over, to be cooled in 5~10 DEG C of freeze drying box, is cooled to -35 DEG C~40 rapidly DEG C, insulation freezing 3~4 hours；

（2）Vacuumize, -5~-10 DEG C were warming up in 2~3 hours, the time for maintaining -5~-10 DEG C is 10~20 Hour；

（3）It was warming up to 15~25 DEG C in 1~2 hour, the time for maintaining 15~25 DEG C is more than 15~25 hours, to true Reciprocal of duty cycle change terminates to freeze when little；

（4）In cillin bottle inflated with nitrogen and roll lid sealing, produce injection Esomeprazole sodium composite freeze-dried powder.

The esomeprazole sodium pharmaceutical composition main ingredient of the present invention is Esomeprazole sodium, and auxiliary material is sodium chloride, ethylenediamine Tetraacethyl calcium sodium, dosage range are：42.5~85mg/ branch, preferably 42.5mg/ branch.

The active component Esomeprazole sodium of this freeze-dried composition is readily soluble in water, but the aqueous solution is unstable, particularly exists In neutral aqueous solution, easily there is the phenomenon of solution turned yellow, lyophilized products change also easily occur in the long-term placement process of freeze-dried composition Yellow phenomenon, and relevant material is exceeded, have impact on the quality of medicine and the security of clinical practice.In the process of preparating liquid Middle addition sodium hydroxide, improve the PH of decoction（10.5~12）Stabilization effectively can be played to decoction, solve product About material is exceeded and the problem of discoloration, ensure that the quality and stably of medicine in storage.

In order to optimize the molded appearance of product, strengthen the dissolubility of product, prescription experiment carried out mannitol, lactose, The excipients such as glucose are tested, although these excipients make moderate progress to quality index such as the outward appearance of product, dissolubilities, But the relevant material index of product increased in study on the stability experiment.By the application to sodium chloride in prescription, protect Hinder the stability of the relevant material index of product, further improve the quality index such as product appearance and dissolubility.

Showing in stability test research, Esomeprazole sodium is easily oxidized generation impurity under Metal Ions Conditions, Metal ion in production process in production equipment and pipeline is easily soluble in decoction, accelerates the oxidation reaction of product.To be effective Suppress the progress of oxidation reaction, the complexing of metal ion such as sodium ethylene diamine tetracetate, calcio-disodium edetate are added in prescription Agent.Calcium, the iron plasma being easily complexed in human body due to sodium ethylene diamine tetracetate in body fluid, it is possible to the physiological reaction of human body Have an impact, therefore quality of the calcio-disodium edetate as complexing agent stable prod is added in prescription.

Tiny particulate is combined into after medicament freeze-drying with excipients, the dissolving of the main composition of medicine is often influenceed, makes lyophilized products Easily there is the underproof problem of clarity when redissolving, the jelly of Esomeprazole sodium and calcio-disodium edetate in this composition Dry compound adds the sodium chloride of the main amount of composition medicine about 1/2 by lot of experiments there have been underproof phenomenon is redissolved, The specific surface area of the Water-solubility Material of particulate is added, also increases the sponginess of freeze-dried composition, improves the main composition of medicine Dissolubility, solve the problems, such as that Esomeprazole sodium is lyophilized and redissolve clarity.

Activated carbon is mainly used in the effect such as decolouring, pyrogen removal, removal of impurity in agent prescription is injected, and then improves the matter of product Amount and purity.The dosage of activated carbon is an important parameter in injection formulation and technology, if activated carbon dosage is too It is more, the active component in adsorbent solution can be caused, make the yield of its product reduce, if activated carbon dosage cannot ensure very little The quality of product.Suction-operated very little of the activated carbon to main ingredient Esomeprazole sodium is shown by experiment, according to different batches angstrom Suo Meila azoles color and endotoxin quality condition, are separately added into 0.05~0.4%（g/ml）Activated carbon can fully ensure that Esso The color and bacterial endotoxin index of azoles freeze-dried composition are drawn by U.S..

By carrying out qualitative analysis to the relevant material of Esomeprazole sodium, in Esomeprazole sodium solution state and lyophilized group Under conditions of compound is placed for a long time, product colour turns yellow, and relevant material raises, mainly the elevated Amplitude Ratio of oxidation product compared with Greatly, and with the rise of temperature, relevant material the quantity and the degree of its colour changed into yellow improved increases.In with liquid filling process Low temperature dispensing, while the oxygen content that nitrogen reduces decoction is filled with, nitrogen is filled with the cillin bottle of freeze-drying prods makes product and sky Air bound is from can effectively prevent the oxidation of product, reduce the generation of oxidation impurities.

The quality of refrigerating process and product has close relationship, and the selection of sublimation temperature directly influences the speed of distillation Degree, the formation of material combinations particulate, the formation about material and the wherein content of moisture content are influenceed, be the weight of product quality stability Cut factor.Temperature rises the too fast formation influenceed into porous matrix, underclad portion atrophy is occurred, influences the residual water of product The content divided, causes solubility, stability and clarity problem.When pressure difference pressure during distillation is too low, heat transfer is unfavorable for Heat transfer, rate of sublimation reduce on the contrary, influence drying effect.During parsing-desiccation, temperature is higher to be advantageous to steaming for moisture content, but Temperature is higher to easily cause generation of the product about material.The jelly of low-temperature distillation low temperature drying by substantial amounts of Orthogonal Experiment and Design Dry technique, makes the relevant material index of product reach optimal, while also reaches the technical indicator that product moisture content is less than 5%.

Embodiment

With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this Invention, only explanatory example.

Embodiment 1

Esomeprazole sodium 42.5g

Sodium chloride 20g

Calcio-disodium edetate 1.0g

Sodium hydroxide 7g

Water for injection 2L

It is made 1000

(1) it is with the filling preparation method of liquid：

（1）The sodium hydroxide of recipe quantity, Esomeprazole sodium, sodium chloride, calcio-disodium edetate are added to injection With in water, in 10 DEG C, stirring makes to be completely dissolved water for injection temperature；

（2）With 10% sodium hydroxide solution regulating liquid medicine liquid pH values to 11, benefit adds to the full amount of water for injection；

（3）According to the 0.1%g/ml of medicine liquid volume amount in the solution prepared, medical charcoal is added, is stirred 20 minutes

Afterwards, carbon is removed with 0.45um stud filter filtration；

（4）With 2 0.2um polyether sulfone filter core aseptic filtration；

（4）Intermediates content and acidity assaying；

（5）According to intermediates content measurement result, loading amount is adjusted, it is filling, partly jump a queue；

（6）With liquid, adjust PH, except carbon filtering and aseptic filtration during a straight-through nitrogen carry out protection against oxidation.

（Two）Freeze drying process of preparing same

（1）Decoction after will be filling, which is positioned over, to be cooled in 5 DEG C of freeze drying box, is cooled to -35 DEG C rapidly, insulation freezing 3 hours；

（2）Vacuumize, -10 DEG C were warming up in 2 hours, the time for maintaining -10 DEG C is 10 hours；

（3）20 DEG C were warming up in 1 hour, the time for maintaining 20 DEG C is more than 15 hours, when changing little to vacuum Terminate lyophilized；

（4）In cillin bottle inflated with nitrogen and roll lid sealing, produce injection Esomeprazole sodium composite freeze-dried powder.

Embodiment 2

Esomeprazole sodium 85g

Sodium chloride 40g

Calcio-disodium edetate 1.5g

Sodium hydroxide 15g

Water for injection 4L

It is made 1000

(1) it is with the filling preparation method of liquid：

（1）The sodium hydroxide of recipe quantity, Esomeprazole sodium, sodium chloride, calcio-disodium edetate are added to injection With in water, in 10 DEG C, stirring makes to be completely dissolved water for injection temperature；

（2）With 10% sodium hydroxide solution regulating liquid medicine liquid pH values to 11.5, benefit adds to the full amount of water for injection；

（3）According to the 0.15%g/ml of medicine liquid volume amount in the solution prepared, medical charcoal is added, is stirred 30 minutes

Afterwards, carbon is removed with 0.45um stud filter filtration；

（4）With 2 0.2um polyether sulfone filter core aseptic filtration；

（4）Intermediates content and acidity assaying；

（5）According to intermediates content measurement result, loading amount is adjusted, it is filling, partly jump a queue；

（6）With liquid, adjust PH, except carbon filtering and aseptic filtration during a straight-through nitrogen carry out protection against oxidation.

（Two）Freeze drying process of preparing same

（1）Decoction after will be filling, which is positioned over, to be cooled in 5 DEG C of freeze drying box, is cooled to -40 DEG C rapidly, insulation freezing 4 hours；

（2）Vacuumize, -5 DEG C were warming up in 3 hours, the time for maintaining -5 DEG C is 15 hours；

（3）25 DEG C were warming up in 2 hours, the time for maintaining 25 DEG C is more than 20 hours, when changing little to vacuum Terminate lyophilized；

（4）In cillin bottle inflated with nitrogen and roll lid sealing, produce injection Esomeprazole sodium composite freeze-dried powder.

Tested according to two annex XIXC stability test guidelines of Chinese Pharmacopoeia 2010 edition, to embodiment

Key index carries out influence factor experiment, accelerated test and long term test.To following primary quality measure character, alkali Degree（pH）, visible foreign matters, clarity, moisture content, the investigation of testing such as relevant material and content.

Test example 1

To influence factor high temperature（Temperature 60 C ± 2 DEG C）High humidity（RH75% 、RH92.5%）Illumination（Illumination 4500 ± 500LX）Result of the test.

Test example 2

Example is taken, is accelerated by listing packaging（The bar that temperature is 40 DEG C ± 2 DEG C, relative humidity is 75% ± 5% Under part）6 months and long-term（Under conditions of temperature is 25 DEG C ± 2 DEG C, relative humidity is 60% ± 10%）Experiment in 6 months is ground Study carefully.

Accelerated test（Temperature is 40 DEG C ± 2 DEG C, relative humidity is 75% ± 5%）6 months testing results

For a long time（Temperature is 25 DEG C ± 2 DEG C, relative humidity is 60% ± 10%）6 months testing results

Shown by experimental data, according to this product influence factor experiment investigation result, sample appearance does not change, and measure is each Index is placed 10 days, except relevant material has increased slightly under illumination condition without significant change under high temperature, high humidity, illumination condition Outside, other each indexs have no significant change.Accelerated test has been carried out by commercially available back and long term test is investigated, the results showed that this product Under the terms of packing, significant changes do not occur for indices, disclosure satisfy that medicine to storage, the requirement of traffic condition.

The Esomeprazole sodium freeze-drying composition for injection of the present invention, product quality is stable, impurity content is low, prescription letter Just, technique is clear and coherent, reduces production cost, improves production efficiency, also ensured product quality and clinical therapeutic efficacy, can Obtain significant Social benefit and economic benefit.

Claims (3)

1. a kind of injection esomeprazole sodium freeze dry composition, it is characterised in that the injection is freeze-dried powder, each component Weight ratio be Esomeprazole sodium：Sodium chloride：Calcio-disodium edetate：Hydroxide sodium：Water for injection=40~90： 20~40：0.1~5：5~20：2000~4000.

2. a kind of method that injection freeze-dried powder is prepared with composition described in claim 1, it is matched somebody with somebody, and liquid is filling to be characterised by having Body operating procedure is：

（1）The sodium hydroxide of recipe quantity, Esomeprazole sodium, sodium chloride, calcio-disodium edetate are added to water for injection In, in 5~15 DEG C, stirring makes to be completely dissolved water for injection temperature；

（2）With 10-20% sodium hydroxide solution regulating liquid medicine liquid pH values to 10.5~12.0, benefit adds to the full amount of water for injection；

（3）According to 0.05~0.4%g/ml of medicine liquid volume amount in the solution prepared, medical charcoal is added, stirs 15~45 points Clock

Afterwards, carbon is removed with 0.45um stud filter filtration；

（4）With 2 0.2um polyether sulfone filter core aseptic filtration, intermediates content and acidity assaying；

（5）According to intermediates content measurement result, loading amount is adjusted, it is filling, partly jump a queue；

（6）With liquid, adjust PH, except carbon filtering and aseptic filtration during a straight-through nitrogen carry out protection against oxidation.

3. a kind of method that injection freeze-dried powder is prepared with composition described in claim 1, it freezes and is characterised by specifically grasping It is as step：

（1）Decoction after will be filling, which is positioned over, to be cooled in 5~10 DEG C of freeze drying box, is cooled to -35 DEG C~40 DEG C rapidly, Insulation freezing 3~4 hours；

（2）Vacuumize, -5~-10 DEG C were warming up in 2~3 hours, maintain -5~-10 DEG C of time small for 10~20 When；

（3）15~25 DEG C were warming up in 1~2 hour, the time for maintaining 15~25 DEG C is more than 15~25 hours, to vacuum Terminate to freeze when changing little；

（4）In cillin bottle inflated with nitrogen and roll lid sealing, produce injection Esomeprazole sodium composite freeze-dried powder.