WO2022233209A1

WO2022233209A1 - Alanyl-glutamine injection and production process therefor

Info

Publication number: WO2022233209A1
Application number: PCT/CN2022/084966
Authority: WO
Inventors: 刘思川; 刘文军; 谭鸿波; 葛均友; 王亮; 袁南南; 施顺东
Original assignee: 四川科伦药业股份有限公司
Priority date: 2021-05-07
Filing date: 2022-04-02
Publication date: 2022-11-10
Also published as: CN113171340A; CN113171340B

Abstract

Disclosed are an alanyl-glutamine injection and a preparation method therefor. The method comprises the following steps: S1. pre-treatment of water for injection: controlling dissolved oxygen in the water for injection so that the oxygen content of same is controlled to be 5 mg/L or less; S2, preparation: dissolving alanyl-glutamine in the pre-treated water for injection to obtain an alanyl-glutamine injection, and filling gas to safeguard against residual oxygen in the preparation process, so as to maintain the oxygen content at 5 mg/L or less; S3, filling: filling the alanyl-glutamine injection obtained in step S2 into a plastic bag according to the dosage, and filling with gas to safeguard against residual oxygen in the filling process, to maintain the oxygen content at 5 mg/L or less; and S4, sterilization: performing sterilization at the following sterilization parameters: 110°C-124° C and an F0 value of 6-25.

Description

Alanylglutamine injection and production process thereof

technical field

The invention relates to the technical field of injection medicine production, in particular to an alanylglutamine injection and a production process thereof.

Background technique

Alanyl Glutamine Injection is indicated for parenteral nutrition in patients requiring glutamine supplementation, including those in catabolic and hypermetabolic conditions.

The existing alanyl glutamine injection is packaged in a glass infusion bottle, which is self-heavy, easy to be broken during transportation, and has problems such as rubber stopper falling off during use, and it is difficult to carry out automatic transformation in production, requiring a lot of labor and labor intensity. larger.

Alanylglutamine injection is a large infusion that is sensitive to high temperature and oxygen. Simply replacing the soft plastic packaging material will result in abnormal product content and impurities, and the quality of this variety cannot be guaranteed.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a kind of production technology of alanyl glutamine injection, by improving process parameters, realize that alanyl glutamine injection adopts soft plastic packaging material packaging, and does not affect product quality, its product Content and impurities are normal.

The present invention is achieved through the following technical solutions:

A production technique of alanylglutamine injection, comprising the following steps:

S1. Pretreatment of water for injection: Control the dissolved oxygen in the water for injection so that the oxygen content is controlled below 5mg/L;

S2. Preparation: Dissolve alanyl glutamine in pretreated water for injection to obtain alanyl glutamine injection, inflate gas during the preparation process to ensure residual oxygen, and maintain the oxygen content at 5mg/L the following;

S3, filling: filling the alanylglutamine injection obtained in step S2 in a plastic bag according to the dose, and filling gas during the filling process to ensure residual oxygen, so that the oxygen content is maintained below 5mg/L;

S4. Sterilization: Sterilization parameters are: 110℃～124℃, F0 value 6～25 sterilization.

The idea of the present invention is:

Provided is a plastic bag packaging process suitable for alanylglutamine injection.

Due to its sensitivity to high temperature and oxygen, the existing alanyl glutamine injection is packaged in plastic bags, which easily leads to the inability of product quality to be guaranteed. Therefore, it is basically packaged in glass bottles, which has a large weight of its own. , high cost, and fragile defects.

The present invention improves the production process, and the main improvement points are:

Dissolved oxygen is controlled in water for injection before preparation, and gas is filled to ensure residual oxygen during preparation and filling. According to the characteristics of alanyl glutamine injection, new sterilization parameters are adopted to realize alanyl glutamine injection. Amide injection is packaged with soft plastic packaging material, which does not affect product quality, and its product content and impurities are normal.

Further, in step S1, the water for injection is pressurized, evacuated, and then filled with gas to control the oxygen content in the product.

Further, the gas used for controlling the oxygen content includes at least one of nitrogen and carbon dioxide.

Further, when a mixed gas of nitrogen and carbon dioxide is used, the volume ratio of nitrogen and carbon dioxide is 1:10-10:1.

Further, in step S2 and step S3, the gas used includes at least one of nitrogen and carbon dioxide.

Further, in step S3, the plastic bag used for filling is a vertical polypropylene infusion bag.

Further, add antioxidants and barrier bags to the vertical polypropylene infusion bag after filling, or add antioxidants and double-layer barrier bags to the vertical polypropylene infusion bag after filling, and then carry out sterilization treatment ; Or add antioxidants and barrier bags after sterilization of vertical polypropylene infusion bags; or add antioxidants and double barrier bags after sterilization of vertical polypropylene infusion bags.

The alanylglutamine injection prepared by the above-mentioned production process.

Compared with the prior art, the present invention has the following advantages and beneficial effects:

1. The present invention controls the dissolved oxygen in the water for injection before preparation, and fills the gas in the preparation and filling process to ensure residual oxygen, and adopts new sterilization parameters according to the characteristics of alanyl glutamine injection to achieve Alanyl glutamine injection is packaged in soft plastic packaging, which does not affect product quality, and its product content and impurities are normal.

2. The present invention provides a new technical idea for the packaging of alanylglutamine injection, which is beneficial to saving costs and improving transportation safety.

3. The process of the present invention is simple to operate, does not use expensive equipment, and is suitable for large-scale promotion.

Detailed ways

In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below in conjunction with the examples. limit.

Example 1:

The control method of oxygen content is as follows:

The water for injection adopts the pressure and then vacuumizes and then fills the gas to realize the control of the oxygen content in the product. The filling gas is nitrogen, or it can be carbon dioxide or a mixture of nitrogen and carbon dioxide (the volume ratio of nitrogen and carbon dioxide is 1:10- 10:1);

The filling gas is nitrogen, or carbon dioxide or a mixture of nitrogen and carbon dioxide (the volume ratio of nitrogen and carbon dioxide is 1:10-10:1);

S3. Filling: Fill the alanyl glutamine injection obtained in step S2 into a vertical polypropylene infusion bag according to the dose, and inflate gas during the filling process to ensure residual oxygen, so that the oxygen content is maintained at 5mg/ L or less;

The filling gas is nitrogen, or carbon dioxide or a mixture of nitrogen and carbon dioxide (the volume ratio of nitrogen and carbon dioxide is 1:10-10:1)

S4. Sterilization: Add antioxidants and barrier bags to the vertical polypropylene infusion bag after filling, remove the air in the packaging gap by vacuuming, and then use the sterilization parameters: 120 ° C, F0 value 6 sterilization.

Example 2:

This embodiment is based on Embodiment 1, and the difference from Embodiment 1 is:

The sterilization parameters are: 124 ° C, F0 value 20 sterilization, add antioxidants and double-layer barrier bags to the vertical polypropylene infusion bag after filling.

Comparative Example 1:

This comparative example adopts the existing glass bottle packaging process, specifically:

S1, preparation: alanyl glutamine is dissolved in water for injection to obtain alanyl glutamine injection;

S2, filling: filling the alanylglutamine injection obtained in step S1 in a glass infusion bottle according to the dosage;

S3. Sterilization: The sterilization parameters are: 120℃, F0 value 6 sterilization.

Comparative Example 2:

This comparative example is based on Example 1, and the difference from Example 1 is:

Water for injection was not pretreated, and the oxygen content of water for injection was 20 mg/ml.

Comparative Example 3:

Residual oxygen control was not carried out during the preparation and filling process, and the oxygen content of alanylglutamine injection was 5 mg/L.

Comparative Example 4:

Antioxidants and barrier bags are not used.

Comparative Example 5:

Sterilization parameters are different:

Use existing sterilization parameters: 110°C, 30min.

To embodiment 1-embodiment 2, comparative example 1-comparative example 5 prepares alanyl glutamine injection and carries out performance detection, and detection method is as follows:

The measurement methods of the relevant substances are as follows:

Precisely measure this product respectively, dilute it with mobile phase to make a solution containing about 4 mg of alanylglutamine per 1ml, as the test solution; accurately weigh an appropriate amount of the impurity reference substance, and add the flow rate according to the concentration in the table below. Phase dissolved and diluted to make a reference solution. According to the chromatographic conditions under the content determination item, inject 20 μl of the reference solution into the liquid chromatograph, record the chromatogram, and the resolution between the impurity peaks should meet the requirements. Precisely measure 20 μl of the test solution and the reference solution, respectively, inject them into a liquid chromatograph, and record the chromatogram. If there is any impurity peak in the chromatogram of the test solution, calculate the peak area according to the external standard method. Compared with the labeled amount of the main component, the content of cyclo-(L-alanyl-L-glutamine) shall not exceed 5.0%, the content of cyclo-(L-alanyl-L-glutamic acid) shall not exceed 0.05%, L-pyroglutamic acid-L-alanine should not exceed 0.65%, L-pyroglutamic acid should not exceed 0.25%, D-alanyl-L-glutamine should not exceed 0.25%, L-propyl Aminoacyl-L-glutamic acid should not exceed 1.0%; other single unknown impurities should not exceed 0.5%, calculated by the external standard method based on the peak area of alanine glutamine, and the total of other unknown impurities should not exceed 1.0%.

The test results are shown in Table 1:

Table 1

Ammonia value

The test should be carried out at 20-25°C. Precisely weigh 5ml of this product, put it in a 50ml measuring bottle, dilute it with water to the mark, shake well, and use it as the test solution; accurately weigh 29.7mg of ammonium chloride, put it in a 500ml measuring bottle, add an appropriate amount of water to dissolve and dilute to the mark , shake well to get (equivalent to 20μg of NH ₄ ⁺ in each 1ml), as the reference solution. Precisely measure reductase I solution (NADH) (take an appropriate amount of reduced coenzyme I, and use 2-oxoglutaric acid buffer to make a solution containing 0.2 mg per 1 ml. The solution can be stored at 4 °C for 3 days) 1.0 ml , Set in the absorption tank, add 0.1ml of the test solution and 1.9ml of water, mix well, and react for 5 minutes. According to UV-Vis spectrophotometry (General Rule 0401), with water as the reference, measure the absorbance A1 at the wavelength of 340nm, then add glutamate dehydrogenase solution (GLDH) (take an appropriate amount of glutamate dehydrogenase, add water Dilute to make 0.02ml of a solution containing 1000 units per 1ml, mix well, and measure the absorbance A2 after 20 minutes. Determine the absorbance of water and reference solution by the same method, and they are B1, B2 and C1, C2 respectively. Calculate by the following formula. Ammonia content should not exceed 340mg/L.

In the formula, Cst is the ammonia concentration of the reference solution, μg/ml;

10 is the dilution factor of the test solution.

content

According to high performance liquid chromatography (general rule 0512) determination.

Chromatographic conditions and system suitability test use amino-bonded silica gel as filler; use 0.05mol/L potassium dihydrogen phosphate buffer (adjust pH to 4.0 with phosphoric acid)-acetonitrile (35:65) as mobile phase; detection wavelength 215nm; The flow rate was 0.7 ml per minute; the column temperature was 30°C. Take appropriate amount of D-alanyl-L-glutamine and alanyl-glutamine reference substance, add mobile phase to dissolve and dilute to make 10μg of D-alanyl-L-glutamine and alanine per 1ml Take 20 μl of the mixed solution of 50 μg of acylglutamine and inject it into the liquid chromatograph, and record the chromatogram. The number of theoretical plates is not less than 3000 calculated by the alanyl glutamine peak, and the separation degree of the D-alanyl-L-glutamine peak and the alanyl glutamine peak should meet the requirements.

Determination method: Precisely measure an appropriate amount of this product, dissolve it with mobile phase and quantitatively dilute it to make a solution containing about 0.05 mg of alanyl glutamine per 1 ml, as the test solution, precisely measure 20 μl, and inject it into liquid chromatography. instrument, record the chromatogram; another appropriate amount of alanylglutamine reference substance was taken, and the same method was used for determination. Calculate the peak area according to the external standard method, that is:

Embodiment 1-embodiment 2, comparative example 1-comparative example 5 prepares the detection result of related substance of alanyl glutamine injection and ammonia content as shown in table 2:

Table 2

It can be seen from the data in Table 2 that:

1), the impurity content of the alanyl glutamine injection prepared by the process of the present invention is equivalent to the existing glass bottle packaging technology, and it is proved that the performance of the alanyl glutamine injection prepared by the process of the present invention is stable.

2), the control of oxygen content in the production process and the control of sterilization parameters can all affect the impurity content of the prepared alanylglutamine injection.

The specific embodiments described above further describe the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above descriptions are only specific embodiments of the present invention, and are not intended to limit the scope of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

A production technique of alanylglutamine injection, characterized in that, comprising the following steps:

S1. Pretreatment of water for injection: Control the dissolved oxygen in the water for injection so that the oxygen content is controlled below 5mg/L;

S2. Preparation: Dissolve alanyl glutamine in pretreated water for injection to obtain alanyl glutamine injection, inflate gas during the preparation process to ensure residual oxygen, and maintain the oxygen content at 5mg/L the following;

S3, filling: filling the alanylglutamine injection obtained in step S2 in a plastic bag according to the dose, and filling gas during the filling process to ensure residual oxygen, so that the oxygen content is maintained below 5mg/L;

S4. Sterilization: Sterilization parameters are: 110℃～124℃, F0 value 6～25 sterilization.
The production technique of a kind of alanylglutamine injection according to claim 1, is characterized in that, in step S1, the water for injection adopts the pressure after vacuuming and then fills with gas to realize the control of oxygen content in the product.
The production technique of a kind of alanylglutamine injection according to claim 2, is characterized in that, the gas that controls oxygen content adopts comprises at least a kind of in nitrogen and carbon dioxide.
The production technique of a kind of alanylglutamine injection according to claim 3, is characterized in that, when adopting the mixed gas of nitrogen and carbon dioxide, the volume ratio of nitrogen and carbon dioxide is 1:10-10:1.
The production technique of a kind of alanylglutamine injection according to claim 1, is characterized in that, in step S2 and step S3, the gas that adopts comprises at least a kind of in nitrogen gas and carbon dioxide.
The production technique of a kind of alanylglutamine injection according to claim 5, is characterized in that, when adopting the mixed gas of nitrogen and carbon dioxide, the volume ratio of nitrogen and carbon dioxide is 1:10-10:1.
The production process of a kind of alanylglutamine injection according to claim 1, is characterized in that, in step S3, the plastic bag used for filling is vertical polypropylene infusion bag.
The production process of a kind of alanylglutamine injection according to claim 7, it is characterized in that, after filling, add antioxidant and barrier bag outside the vertical polypropylene infusion bag after filling, or after filling The vertical polypropylene infusion bag is sterilized after adding antioxidants and double-layer barrier bags; or the vertical polypropylene infusion bag is sterilized and then packed with antioxidants and barrier bags; Antioxidants are added after bacteria and packed in double barrier bags.
The alanylglutamine injection prepared by the described production process of claim 1-8.