CN107982261B - Esomeprazole sodium freeze-dried powder and preparation method thereof - Google Patents

Esomeprazole sodium freeze-dried powder and preparation method thereof Download PDF

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CN107982261B
CN107982261B CN201711235609.7A CN201711235609A CN107982261B CN 107982261 B CN107982261 B CN 107982261B CN 201711235609 A CN201711235609 A CN 201711235609A CN 107982261 B CN107982261 B CN 107982261B
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esomeprazole sodium
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CN107982261A (en
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王庆鹏
骆献丽
尚云飞
杨永霞
王玉拓
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LEPU PHARMACEUTICAL Co Ltd
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

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Abstract

An esomeprazole sodium freeze-dried powder and a preparation method thereof belong to the technical field of pharmaceutical preparations and comprise esomeprazole sodium, disodium hydrogen phosphate and sodium hydroxide, wherein the content of the esomeprazole sodium is 42.5 mg, the addition amount of the disodium hydrogen phosphate is 0.3-0.8% of the mass of the esomeprazole sodium, and the sodium hydroxide is a pH regulator, so that the pH value of the solution of the freeze-dried powder before freeze drying is 10.5-11.0. The invention of the technical scheme mainly comprises the following steps: the preparation has simple prescription, no excipients such as an excipient, an antioxidant and the like are added, and the disodium hydrogen phosphate can play the role of a complexing agent and the role of pH buffering, so that the stability of a finished preparation product is ensured. In the technical scheme of the invention, excessive feeding is not needed, and the fluctuation of the content of the main medicine components after the re-dissolution of the finished product is very small.

Description

Esomeprazole sodium freeze-dried powder and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to esomeprazole sodium freeze-dried powder and a preparation method thereof.
Background
Esomeprazole, also known as esomeprazole, is the S-isomer of omeprazole and is used clinically in "replacement therapy for gastroesophageal reflux disease when oral therapy is not appropriate" with esomeprazole sodium for injection. Esomeprazole is a proton pump inhibitor anti-ulcer drug, and the proton pump inhibitor is a drug for effectively treating ulcerative diseases by inhibiting H in gastric parietal cells+，K+-ATPase to effect inhibition of gastric acid secretion in the digestive tract. Digestive system diseases are one of common frequently encountered diseases, and due to the development of society, the rhythm of life is accelerated, the incidence rate of gastrointestinal diseases is also increased year by year, and the medicine market of the diseases is also steadily increased.
Esomeprazole is poor in stability, unstable to light, heat, oxygen and the like, and the stability in an aqueous solution is seriously dependent on the pH value and can be degraded along with the reduction of the pH value of the solution. Therefore, the selection of the auxiliary materials and the process of the esomeprazole lyophilized powder is very important, the process realizability in the production process is ensured, and the stable pH value of the lyophilized powder needs to be kept after redissolving, so that the safety and the effectiveness of the drug administration of a patient can be ensured.
In the document CN103301077A, edetate disodium is used for producing esomeprazole sodium freeze-dried powder, and the auxiliary material is injected into a human body to chelate calcium ions in the human body, so that the blood calcium concentration in the human body is reduced. In the document CN107213122A, ethanol-propylene glycol-polyethylene glycol 4000 is used as an auxiliary material in omeprazole lyophilized powder to improve the stability of the product, wherein the volume ratio of ethanol-propylene glycol-polyethylene glycol 4000 is 65:20: 15. However, polyethylene glycol 4000 is not suitable for injection: the drug evaluation center of the State food and drug administration headquarter has been published with references: polyethylene glycol (PEG) is a commonly used adjuvant and can be used in a variety of dosage forms. The molecular weight can be classified into PEG-200, PEG-400, PEG-600 and PEG-4000. Among them, low molecular weight products such as PEG-200, 400, 600, etc. can be used as solubilizer in injection, while large molecular weight products such as PEG-4000, 6000, etc. are used as matrix in ointment and suppository, and are not generally used as solubilizer in intravenous injection preparation. PEG-4000 is used as a solubilizer and an excipient in certain powder for injection, so that the requirement of meeting the injection is ignored, and potential safety hazards are possibly generated. In addition, according to the description of polyethylene glycol 4000 in the 'Chinese pharmacopoeia' 2015 edition, the product is white wax-filled solid flakes or granular powder, while the other two auxiliary materials, namely ethanol and propylene glycol, are in liquid state, and according to the 'volume ratio of ethanol-propylene glycol-polyethylene glycol 4000 described in the literature being 65:20: 15', the matching error of the combination of the liquid and the solid according to the volume is very large, and the actual production operation is not realistic. The esomeprazole sodium freeze-dried powder disclosed in the document CN102657622A uses various auxiliary materials such as an excipient, an antioxidant and the like, and the esomeprazole sodium freeze-dried powder directly enters the blood of a patient when in use, so that the more the types of the auxiliary materials are, the higher the safety risk is.
Disclosure of Invention
The invention aims to provide esomeprazole sodium freeze-dried powder which is simple in prescription composition, strong in production process operability and stable in product quality and a preparation method thereof.
Based on the purpose, the invention adopts the following technical scheme:
an esomeprazole sodium freeze-dried powder comprises esomeprazole sodium, disodium hydrogen phosphate and sodium hydroxide, wherein the addition amount of the disodium hydrogen phosphate is 0.3-0.8% of the mass of the esomeprazole sodium, and the sodium hydroxide is used as a pH regulator, so that the pH value of the solution of the freeze-dried powder before freeze-drying is 10.5-11.0.
Preferably, the prescription of the esomeprazole sodium freeze-dried powder is that the dose of the esomeprazole sodium is 42.5g, the dosage of the disodium hydrogen phosphate is 0.13-0.34g of the mass of the esomeprazole sodium, water for injection is added until the volume is 600 ~ 800mL, the pH value of the sodium hydroxide is adjusted to 10.5-11.0, the water for injection is fixed to 1000mL, and 1000 lyophilized powder injections are prepared.
The preparation method of the esomeprazole sodium freeze-dried powder comprises the following steps:
(1) cooling water for injection to 10-15 deg.C;
(2) adding 60-80% of injection water in the preparation volume into a preparation tank, adding the disodium hydrogen phosphate and the esomeprazole sodium in the formula amount, and stirring to completely dissolve the disodium hydrogen phosphate and the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to be between 10.5 and 11.0 by using a sodium hydroxide solution;
(4) adding 0.05-0.1% (w/v) of activated carbon into the liquid medicine obtained in the step (3), and stirring for 10 ~ 30 minutes;
(5) firstly, filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug;
(6) and (4) after freeze drying, obtaining the esomeprazole sodium freeze-dried powder.
Further, the freeze-drying process is as follows:
putting the split semi-finished product into a freeze-drying box;
Figure 100002_DEST_PATH_IMAGE002
pre-freezing: setting the temperature of a freeze-drying box to be reduced to minus 30 +/-1 ℃ from 10 ℃ at a constant speed for 1 hour, and then keeping the temperature at minus 30 +/-1 ℃ for 1 to 2 hours;
Figure 615486DEST_PATH_IMAGE003
primary drying: uniformly raising the temperature from minus 30 +/-1 ℃ to minus 15 ℃ for 0.5 to 1 hour, and keeping the temperature at minus 15 ℃ for 3 to 5 hours; uniformly raising the temperature from-15 ℃ to-5 ℃ for 1 hour, and keeping the temperature at-5 ℃ for 1-2 hours;
Figure 100002_DEST_PATH_IMAGE004
secondary drying: uniformly heating the mixture from-5 ℃ to 25 ℃, keeping the temperature for 1.5-2 hours, and drying the mixture at 25 ℃ for 2-3 hours to obtain the esomeprazole sodium freeze-dried powder.
Freeze-drying includes 3 stages of prefreezing, low temperature sublimation, and redrying. The first step of the freeze-drying process is pre-freezing, and after filling and loading into a freeze-drying box, the liquid medicine is completely frozen. After the liquid medicine is completely frozen in the second step, ice sublimates, water is continuously pumped away, and the product is continuously dried, which is a low-temperature sublimation stage. In order to achieve a good dry state, secondary drying should be performed in order to further remove the water remaining in the product. Only by selecting proper freeze-drying process can the product with qualified indexes be produced, and the production energy consumption is low. The product of the invention has the appearance of full and loose white block and low water content.
Further, the concentration of the sodium hydroxide solution is 0.1 mol/L.
The invention of the technical scheme mainly comprises the following steps: the preparation has simple prescription, no excipients such as an excipient, an antioxidant and the like are added, and the disodium hydrogen phosphate can play the role of a complexing agent and the role of pH buffering, so that the stability of a finished preparation product is ensured.
The invention avoids the problem of excessive feeding in preparation production: in the registration standard review instruction of the esomeprazole sodium for injection, the following are explicitly mentioned: the enterprise was charged at 104% of the indicated amount and the reason for this analysis was to offset the losses of the reconstitution process. The quality standard of the esomeprazole sodium for injection in the 'Chinese pharmacopoeia' 2015 edition is described as follows: the product is an aseptic freeze-dried product of esomeprazole sodium, the content of the esomeprazole sodium is 97.0-109.0% of the marked amount calculated according to the esomeprazole sodium, and the content range of the main drug is wider because the operation of excessive feeding is adopted. The dosage of the injection is more accurate than that of a common oral preparation, and the problems that the fluctuation of the content of main components is large after redissolution and the actual dosage of a patient is not accurate enough can be caused by excessive feeding. In the technical scheme of the invention, excessive feeding is not needed, and the fluctuation of the content of the main medicine components after the re-dissolution of the finished product is very small.
Detailed Description
The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples, and the present invention is not limited to these examples in any way.
Example 1
An esomeprazole sodium freeze-dried powder (1000 lyophilized powder injection) consists of the following components:
the preparation method comprises the following steps:
firstly, preparing a solution
(1) Cooling water for injection to 10 deg.C;
(2) adding 80% of injection water with the preparation volume into a preparation tank, adding the disodium hydrogen phosphate and the esomeprazole sodium with the prescription amount, and stirring to completely dissolve the disodium hydrogen phosphate and the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to 10.5 by using 0.1mol/L sodium hydroxide solution;
(4) adding 0.05% (g/mL) of activated carbon, and stirring for 15 minutes;
(5) firstly filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug.
Second, freeze-drying
Figure 582174DEST_PATH_IMAGE001
Putting the split semi-finished product into a freeze-drying box;
Figure 39700DEST_PATH_IMAGE002
prefreezing (cooling stage and cooling maintaining stage): setting the temperature of the freeze-drying box to be reduced from 10 ℃ to-30 ℃ at a constant speed for 1 hour, and then keeping the temperature at-30 ℃ for 1 hour;
primary drying: uniformly heating from-30 ℃ to-15 ℃, keeping for 0.5 hour when in use, and keeping for 3 hours at-15 ℃; the temperature is increased from minus 15 ℃ to minus 5 ℃ at a constant speed, the use time is 1 hour, and the temperature is kept at minus 5 ℃ for 1 hour;
Figure 798239DEST_PATH_IMAGE004
secondary drying: and finally setting the drying temperature to be 25 ℃, uniformly heating from-5 ℃ to 25 ℃, keeping the temperature for 1.5 hours, and drying at 25 ℃ for 3 hours to obtain the esomeprazole sodium freeze-dried powder.
Example 2
An esomeprazole sodium freeze-dried powder (1000 lyophilized powder injection) consists of the following components:
Figure 100002_DEST_PATH_IMAGE008
the preparation method comprises the following steps:
firstly, preparing a solution
(1) Cooling water for injection to 12 deg.C;
(2) adding 80% of injection water with the preparation volume into a preparation tank, adding the disodium hydrogen phosphate and the esomeprazole sodium with the prescription amount, and stirring to completely dissolve the disodium hydrogen phosphate and the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to 10.8 by using 0.1mol/L sodium hydroxide solution;
(4) adding 0.08% (g/mL) of activated carbon, and stirring for 15 minutes;
(5) firstly filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug.
Second, freeze-drying
Figure 127589DEST_PATH_IMAGE001
Putting the split semi-finished product into a freeze-drying box;
Figure 388806DEST_PATH_IMAGE002
prefreezing (cooling stage and cooling maintaining stage): setting the temperature of the freeze-drying box to be reduced to minus 30 +/-1 ℃ from 10 ℃ at a constant speed, using for 1 hour, and then keeping for 2 hours at minus 30 +/-1 ℃;
Figure 120001DEST_PATH_IMAGE003
primary drying: uniformly heating from minus 30 +/-1 ℃ to minus 15 ℃ for 0.5 hour, and keeping at minus 15 ℃ for 5 hours; the temperature is increased from minus 15 ℃ to minus 5 ℃ at a constant speed, the use time is 1 hour, and the temperature is kept at minus 5 ℃ for 2 hours;
Figure 175682DEST_PATH_IMAGE004
secondary drying: and finally setting the drying temperature to be 25 ℃, uniformly heating from-5 ℃ to 25 ℃, keeping the temperature for 2 hours, and drying at 25 ℃ for 3 hours to obtain the esomeprazole sodium freeze-dried powder.
Example 3
An esomeprazole sodium freeze-dried powder (1000 lyophilized powder injection) consists of the following components:
Figure DEST_PATH_IMAGE009
the preparation method comprises the following steps:
firstly, preparing a solution
(1) Cooling water for injection to 15 deg.C;
(2) adding 80% of injection water with the preparation volume into a preparation tank, adding the disodium hydrogen phosphate and the esomeprazole sodium with the prescription amount, and stirring to completely dissolve the disodium hydrogen phosphate and the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to 11.0 by using 0.1mol/L sodium hydroxide solution;
(4) adding 0.1% (g/mL) of activated carbon, and stirring for 15 minutes;
(5) firstly filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug.
Second, freeze-drying
Figure 54645DEST_PATH_IMAGE001
Putting the split semi-finished product into a freeze-drying box;
Figure 853974DEST_PATH_IMAGE002
prefreezing (cooling stage and cooling maintaining stage): setting the temperature of the freeze-drying box to be reduced from 10 ℃ to-31 ℃ at a constant speed for 1 hour, and then keeping the temperature at minus 30 ℃ plus or minus 1 ℃ for 1.5 hours;
Figure 442606DEST_PATH_IMAGE003
primary drying: uniformly heating from-31 ℃ to-15 ℃ for 0.5 hour, and keeping at-15 ℃ for 4 hours; the temperature is increased from minus 15 ℃ to minus 5 ℃ at a constant speed, the use time is 1 hour, and the temperature is kept at minus 5 ℃ for 2 hours;
Figure 934767DEST_PATH_IMAGE004
secondary drying: and finally, setting the drying temperature to be 25 ℃, uniformly raising the temperature from-5 ℃ to 25 ℃, using for 2 hours, and keeping the temperature at 25 ℃ for drying for 2 hours to obtain the esomeprazole sodium freeze-dried powder.
Comparative example
An esomeprazole sodium freeze-dried powder (1000 lyophilized powder injection) consists of the following components:
Figure DEST_PATH_IMAGE010
the preparation method comprises the following steps:
firstly, preparing a solution
(1) Cooling water for injection to 12 deg.C;
(2) adding 80% of injection water with the preparation volume into the preparation tank, adding the prescribed amount of esomeprazole sodium, and stirring to completely dissolve the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to 10.8 by using 0.1mol/L sodium hydroxide solution;
(3) adding 0.08% (g/mL) of activated carbon, and stirring for 15 minutes;
(4) firstly filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug.
Second, freeze-drying
Figure 671998DEST_PATH_IMAGE001
Putting the split semi-finished product into a freeze-drying box;
Figure 9439DEST_PATH_IMAGE002
prefreezing (cooling stage and cooling maintaining stage): setting the temperature of the freeze-drying box to be reduced to minus 30 +/-1 ℃ from 10 ℃ at a constant speed, using for 1 hour, and then keeping for 2 hours at minus 30 +/-1 ℃;
Figure 777543DEST_PATH_IMAGE003
primary drying: uniformly heating from minus 30 +/-1 ℃ to minus 15 ℃ for 0.5 hour, and keeping at minus 15 ℃ for 5 hours; the temperature is increased from minus 15 ℃ to minus 5 ℃ at a constant speed, the use time is 1 hour, and the temperature is kept at minus 5 ℃ for 2 hours;
secondary drying: and finally setting the drying temperature to be 25 ℃, uniformly heating from-5 ℃ to 25 ℃, keeping the temperature for 2 hours, and drying at 25 ℃ for 3 hours to obtain the esomeprazole sodium freeze-dried powder.
And (3) carrying out result detection according to a 'Chinese pharmacopoeia' 2015 edition: examples 1-3 and comparative example
Examples 1-3 test results:
Figure DEST_PATH_IMAGE011
comparative example detection results:
Figure DEST_PATH_IMAGE012
from the results of the tests of the above examples and comparative examples, it can be seen that: the disodium hydrogen phosphate plays a key role in the esomeprazole sodium freeze-dried powder, and if the disodium hydrogen phosphate is not added, the content is reduced to 93% after 6 months, so that the disodium hydrogen phosphate can play a role of a complexing agent and a pH buffering role in the whole preparation, and the stability of a finished preparation product is ensured.

Claims (2)

1. The esomeprazole sodium freeze-dried powder is characterized in that the prescription is that the dose of the esomeprazole sodium is 42.5g, the dosage of the disodium hydrogen phosphate is 0.13-0.34g, water for injection is added until the volume is 600 ~ 800mL, the pH value of the sodium hydroxide is adjusted to 10.5-11.0, the water for injection is constant volume until the volume is 1000mL, 1000 freeze-dried powder injections are prepared, and the preparation method comprises the following steps:
(1) cooling water for injection to 10-15 deg.C;
(2) adding 60-80% of injection water in the preparation volume into a preparation tank, adding the disodium hydrogen phosphate and the esomeprazole sodium in the formula amount, and stirring to completely dissolve the disodium hydrogen phosphate and the esomeprazole sodium;
(3) adjusting the pH value of the liquid medicine to be between 10.5 and 11.0 by using a sodium hydroxide solution;
(4) adding 0.05-0.1% (w/v) of activated carbon into the liquid medicine obtained in the step (3), and stirring for 10 ~ 30 minutes;
(5) firstly, filtering and decarburizing by a filter membrane of 0.8 mu m, adding water for injection to full amount, then filtering by the filter membrane of 0.22 mu m, filling and adding a half plug;
(6) after freeze drying, the esomeprazole sodium freeze-dried powder is obtained; the freeze drying process comprises the following specific steps:
Figure DEST_PATH_IMAGE002
putting the filled and half-plugged semi-finished product into a freeze-drying box;
Figure DEST_PATH_IMAGE004
pre-freezing: setting the temperature of a freeze-drying box to be reduced to minus 30 +/-1 ℃ from 10 ℃ at a constant speed for 1 hour, and then keeping the temperature at minus 30 +/-1 ℃ for 1 to 2 hours;
Figure DEST_PATH_IMAGE006
primary drying: uniformly raising the temperature from minus 30 +/-1 ℃ to minus 15 ℃ for 0.5 to 1 hour, and keeping the temperature at minus 15 ℃ for 3 to 5 hours; uniformly raising the temperature from-15 ℃ to-5 ℃ for 1 hour, and keeping the temperature at-5 ℃ for 1-2 hours;
secondary drying: uniformly heating the mixture from-5 ℃ to 25 ℃, keeping the temperature for 1.5-2 hours, and drying the mixture at 25 ℃ for 2-3 hours to obtain the esomeprazole sodium freeze-dried powder.
2. The esomeprazole sodium lyophilized powder of claim 1, wherein the concentration of the sodium hydroxide solution is 0.1 mol/L.
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