WO2013177927A1 - Injection-use esomeprazole sodium lyophilized powder composition and preparation method therefor - Google Patents

Abstract

An injection-use esomeprazole sodium lyophilized powder composition and a preparation method therefor, related to the medical field. The active ingredients of the composition are esomeprazole sodium and arginine. The specific steps for preparing the injection-use lyophilized powder are: adding into water for injection esomeprazole sodium of a mass percent between 0.1% and 99.9%, arginine of a mass percent between 99.9% and 0.1%, and mannitol that is 5 to 10 times the amount of the active ingredients; dissolving by stirring, then adding an NaOH solution to adjust the pH value to 11.0; adding 0.1% of activated carbon and stirring for 30 minutes; filtering out the activated carbon, then filtering the medicament solution via 0.45μ and 0.22μ microporous membranes; canning the filtered medicament solution, and feeding into a lyophilizer, cooling to -40°C, thermally-insulating for two hours, then gradually warming to a temperature between -5°C and 0°C for lyophilization, and after warming to 35°C, thermally-insulating for three hours; ending the lyophilization, and removing from a container to acquire the injection-use esomeprazole sodium and arginine lyophilized powder injection. The advantages of the present invention are: convenient liquid processing, simplified aseptic operation process, increased preparation stability, obviation of the need for heat treatment for removal of water in the product, and increased rehydration (solubility) property of the preparation.

Description

 Esomeprazole sodium freeze-dried powder composition for injection and preparation method thereof

TECHNICAL FIELD The present invention relates to the field of medicine, and in particular to an esomeprazole sodium lyophilized powder composition for injection and a preparation method thereof. Background technique:

 Gastric ulcer is one of the common and frequently-occurring diseases in the Chinese population. Its occurrence is mainly related to the imbalance between the damage factors of the gastric duodenal mucosa and the mucosal self-defense repair factors. H. pylori infection, non-anti-inflammatory drugs (NSAIDs such as aspirin), and abnormal gastric acid secretion are common causes of ulceration. Typical ulcer pain is characterized by long-term, periodic, and rhythmic.

 In the stomach cavity, gastric acid and pepsin are important digestive substances in gastric juice. Gastric acid is a strong acid substance and is highly aggressive; pepsin has the function of hydrolyzing proteins, which can destroy proteins on the stomach wall. However, in the presence of these erosion factors, the gastrointestinal tract can still resist and maintain mucosal integrity. And its own function, mainly because the stomach, duodenal mucosa also has a series of defense and repair mechanisms. We call the harmful erosion of gastric acid and pepsin the damage mechanism, and the defense and repair mechanism of the gastrointestinal tract itself is called the protection mechanism. It is currently believed that the protective mechanism of the gastric duodenal mucosa of normal people is sufficient to resist the erosion of gastric acid and pepsin. However, when certain factors impair a certain part of the protective mechanism, gastric acid and protease may erode the mucosa and cause ulcer formation. Excessive gastric acid secretion far exceeds the defense and repair of the mucosa and may also cause ulceration. Recent studies have shown that Helicobacter pylori and non-anti-inflammatory drugs are the most common causes of ulcer damage caused by gastrointestinal protective mechanisms, and gastric acid plays a key role in ulcer formation. In addition, drugs, stress, and hormones can also cause ulcers. Various psychological factors and poor eating habits can induce ulcers. Summary of the invention:

The object of the present invention is to provide an esomeprazole sodium lyophilized powder composition for injection and preparation thereof The method is clinically capable of treating gastric ulcer, repairing ulcer wounds, and treating digestive ulcers efficiently and rapidly.

 The specific technical solution of the present invention is:

 An esomeprazole sodium lyophilized powder composition for injection, characterized in that the main drug of the composition is: mass percentage of 0.1% to 99.9% of esomeprazole sodium and 99.9%~0.1% of fine Amino acid.

 A method for preparing a lyophilized powder for injection using the main drug of the above composition, characterized in that the specific operation steps are:

 (1) The mass percentage is 0.1% to 99. 9% of esomeprazole sodium, 99.9%~0. 1% arginine, and 5 to 10 times the main drug mannitol is added to the injection In water

 (2) stirring and dissolving, adding NaOH solution to adjust the pH value 11. 0;

 (3) adding 0.1% activated carbon for 30 minutes;

 (4) The activated carbon is filtered off, and the liquid is filtered through a 0. 45 μ πι and 0. 22 μ πι microporous membrane;

 (5) The filtered liquid can be canned, sent to a freeze dryer, cooled to -40 ° C, after 2 hours of heat preservation, slowly warmed to _5 ° C ~ 0 ° C sublimation drying, and then warmed to 35 ° After C, keep warm for 3 hours;

 (6) After lyophilization is completed, the lyophilized powder needle of esomeprazole sodium and arginine for injection is obtained.

 Arginine (Arg) is an amino acid drug involved in the ornithine cycle. Under the activity of liver arginase, it promotes the conversion of ammonia into non-toxic urea, which is excreted in the urine to reduce blood ammonia. It is mainly used for patients with hepatic coma caused by elevated blood ammonia and various types of hepatic coma. New pharmacological studies have found that Arg is a physiological prerequisite for nitrogen NO, which is produced by NO synthase (N0S). NO has a variety of physiological activities in the body: diastolic blood vessels, anti-platelet aggregation, anti-thrombosis and anti-vascular smooth muscle hyperplasia. Therefore, as a substrate for the synthesis of NO, exogenous Arg is provided, and the concentration of NO in the body is promoted through the Arg-NO pathway, and Arg can protect against myocardial ischemia-reperfusion injury in the clinic.

Esomeprazole is a new member of proton pump inhibitors. Proton pump inhibitor (PPI) covalently binds to gastric wall cells H and K-ATPase, inhibits the activity of the enzyme, and secretes gastric acid. It is effective in the treatment of acid-related diseases such as gastroesophageal reflux disease and peptic ulcer. The existing PPIs include omeprazole, lansoprazole and pantoprazole. Esomeprazole is a levorotatory isomer of omeprazole, which has a fast onset and a better acid suppression effect. It mainly occurs in the form of sodium salts and magnesium salts. A single esomeprazole sodium preparation can only be used as a therapeutic effect and can only be repaired by the body itself. A single arginine does not serve the purpose of treatment. Therefore, combining the two not only treats the gastric ulcer, but also repairs the ulcer area, thereby improving the treatment effect.

 The lyophilized powder needle for producing injection esomeprazole sodium and arginine by the freeze-drying process has the following advantages: 1) convenient liquid processing, simplifies the aseptic operation process; 2) improves the stability of the preparation; 3) Remove moisture from the product without heat treatment; 4) Enhance rehydration (dissolution) of the formulation. detailed description:

 In order to make the technical means, the creative features, the achievement of the object and the effect of the present invention easy to understand, the present invention will be further described below in conjunction with the specific embodiments.

 Example 1. Preparation of freeze-dried powder for esomeprazole sodium composition for injection, based on 1000

Prescription

 Esomeprazole sodium (based on esomeprazole) 40g

 Arginine 40g

 Mannitol 250g

 Water for injection 2000ml

 2. Preparation process

 The solution of the activated carbon is added to the water for injection, and the solution is stirred and dissolved, and then the NaOH solution is added to adjust the pH value of 11.0, and 0.1% of the activated carbon is stirred for 30 minutes, and filtered. Activated carbon, the liquid is filtered through 0. 45 μ πι and 0. 22 μ πι microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 After sublimation at °C~0°C, heat up to 35°C, heat for 3 hours, freeze-drying, and out of the box.

 Example 2, Preparation of freeze-dried powder for esomeprazole sodium composition for injection, based on 1000

Prescription

 Esomeprazole sodium (based on esomeprazole) 40g

 Arginine 60g

 Mannitol 250g

 Water for injection 2000ml

2. Preparation process The solution of the activated carbon is added to the water for injection, and the solution is stirred and dissolved, and then the NaOH solution is added to adjust the pH value of 11.0, and 0.1% of the activated carbon is stirred for 30 minutes, and filtered. Activated carbon, the liquid is filtered through 0. 45 μ πι and 0. 22 μ πι microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 After sublimation at °C~0°C, heat up to 35°C, heat for 3 hours, freeze-drying, and out of the box.

 Example 3, Preparation of freeze-dried powder for esomeprazole sodium composition for injection, based on 1000

Prescription

 Esomeprazole sodium (based on esomeprazole) 40g

 Honeydew 250g

 Water for injection 2000ml

 2. Preparation process

 The solution of the activated carbon is added to the water for injection, and the solution is stirred and dissolved, and then the NaOH solution is added to adjust the pH value of 11.0, and 0.1% of the activated carbon is stirred for 30 minutes, and filtered. Activated carbon, the liquid is filtered through 0. 45 μ πι and 0. 22 μ πι microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 After sublimation at °C~0°C, heat up to 35°C, heat for 3 hours, freeze-drying, and out of the box.

 Experimental data

50 SD rats. Fasted for 24 hours before the test. The abdominal cavity was opened under ether anesthesia, and a glass tube with an inner diameter of 5 mm and a length of 30 mm was placed vertically on the serosal surface of the stomach. 0.2 ml of glacial acetic acid was added to the lumen. After 5 minutes, the glacial acetic acid was removed with a cotton swab and sutured. Surgical incision. On the second day after normal diet, the animals were randomly divided into 5 groups: control group 1 (distilled water), control group 2 (sodium esomeprazole for injection), treatment group 1 (example 1), treatment group 2 ( Example 2), Treatment Group 3 (Example 3); continuous administration for 15 days. The stomach was dissected and fixed with formaldehyde. The stomach was dissected along the large curvature of the stomach and flattened on a glass plate. The vertical and vertical diameters d1 and d2 of the ulcer were measured. The ulcer area S (mm ² ) was calculated as the ulcer index using the formula S = X (dl/2) X (d2/2), and the ulcer healing rate and the ulcer inhibition rate were calculated. See the table below

Control group 1 0 0 18.3±8· 7

Control group 2 1.3 (esomeprazole) 9 90 3.7±3· 5 81.3

1.3 (esomeprazole)

 Treatment group 1 9 90 2.1±2· 5 86.2

 1.3 arginine)

1.3 (esomeprazole)

 Treatment group 2 10 100 1.8±2· 2 88.8

 1.5 (arginine)

1.3 (esomeprazole)

 Treatment group 3 100 100 1.9±2· 4 88.3

 2.0 (arginine) According to experimental data, the first, second and third examples have a good therapeutic effect on ulcers. The cure rate of treatment groups 1, 2, 3 is better than that of esomeprazole sodium alone (control group 2 High, has a good therapeutic effect on gastric ulcers, and can repair ulcer area.

 The basic principles, main features, and advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited by the foregoing embodiments, and that the present invention is only described in the foregoing embodiments and the description of the present invention, without departing from the spirit and scope of the invention. Various changes and modifications are intended to fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and their equivalents.

Claims

Claim

 An esomeprazole sodium lyophilized powder composition for injection, characterized in that the main drug of the composition is: a mass percentage of 0.1% to 99.9% of esomeprazole sodium and 99.9% to 0.1% Arginine.

 A method of preparing a lyophilized powder for injection using the main drug of the composition of claim 1, wherein the specific operation steps are:

 (1) adding 0.1% to 99.9% by mass of esomeprazole sodium, 99.9% to 0.1% arginine, and 5 to 10 times the main drug to mannitol to water for injection;

 (2) After stirring and dissolving, adding NaOH solution to adjust the pH value 11.0;

 (3) Add 0.1% activated carbon and stir for 30 minutes;

 (4) The activated carbon is filtered off, and the liquid is filtered through a 0.45 μm and 0.22 μπι microporous membrane;

 (5) The filtered liquid can be canned, sent to a freeze dryer, cooled to -40 ° C, after 2 hours of heat preservation, slowly warmed to _5 ° C ~ 0 ° C sublimation drying, and then warmed to 35 ° After C, keep warm for 3 hours;

 (6) After lyophilization is completed, the lyophilized powder needle of esomeprazole sodium and arginine for injection is obtained.