CN109134469B - Ertapenem sodium pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The invention relates to an ertapenem sodium solid pharmaceutical composition and a preparation method thereof, wherein the pharmaceutical composition contains ertapenem sodium shown in formula 1, a compound shown in formula 2 or a sodium salt, a hydrate or a solvate thereof, and pharmaceutically acceptable auxiliary materials. The ertapenem sodium solid pharmaceutical composition provided by the invention has the advantages that the proportion of the compound in the formula 2 or pharmaceutically acceptable salts, hydrates or solvates thereof is up to more than 80%, and the stability of the final preparation of the ertapenem sodium is greatly improved.

Description

Ertapenem sodium pharmaceutical composition and preparation method thereof

The application is a divisional application of an invention patent application with application date of 31.12.2013, application number of 201310750967.7 and invention name of ertapenem sodium pharmaceutical composition and a preparation method thereof.

Technical Field

The invention belongs to the field of medicines, and particularly relates to an ertapenem sodium pharmaceutical composition and a preparation method thereof.

Background

Ertapenem sodium (Ertapenem sodium, structural formula is shown in formula 1), chemical name is: the (1R,5S,6S,8R,2S, 4S) -2- [2- [ 3-carboxy-phenylcarbamoyl ] -pyrrolidinyl-4-thio ] -6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid monosodium salt is a novel broad spectrum carbapenem antibiotic developed by Merck and Aslicon of America and has good antibacterial activity against gram-positive bacteria, gram-negative aerobic bacteria and gram-negative anaerobic bacteria.

The commercial product of ertapenem sodium is named as Yiwang, and is sterile freeze-dried powder. The product per unit of ertapenem sodium formulation also contained 175mg of sodium bicarbonate, adjusted to pH 7.5 with sodium hydroxide.

CN1198162A first discloses a stable form of ertapenem as shown in formula 2,

the compound of formula 2 disclosed in this patent is prepared by mixing the compound of formula 1 with a carbon dioxide source (e.g., sodium carbonate or sodium bicarbonate) and dissolving the mixture, and the compound of formula 2 is usually prepared. However, the compositions disclosed therein are in liquid form and the compounds of formula 2 cannot be present in the compositions in a fixed ratio.

CN1481385A discloses a method for preparing a final formulation product of a compound of formula 2 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the final formulation is a lyophilized powder. In this patent specification it is mentioned that the process provides a high conversion of the alkali metal salt (e.g. the monosodium salt) of carbapenem to the compound of formula 2, but there is no mention in the patent of what such a high conversion is.

No structure confirmation data and detection method for the compound of formula 2 is disclosed in any of the above 2 documents.

In summary, the proportion of the compound of formula 2 or a pharmaceutically acceptable salt, hydrate or solvate thereof in the final ertapenem sodium formulation disclosed in the prior art is not specifically disclosed. Since the compound of formula 2 is a stable form of ertapenem, and the proportion of the compound in the final preparation determines the stability of the final preparation, the preparation process of the ertapenem sodium final preparation is yet to be studied to improve the proportion of the compound of formula 2 or pharmaceutically acceptable salts, hydrates or solvates thereof in the final preparation, thereby improving the stability of the ertapenem sodium final preparation.

Disclosure of Invention

The inventor conducts a great deal of research on the formula process of the ertapenem sodium preparation, and finally finds a method capable of improving the conversion rate of the compound in the formula 2 in the final preparation, the proportion of the compound in the formula 2 in the final preparation or pharmaceutically acceptable salts, hydrates or solvates thereof is up to more than 80%, and the stability of the ertapenem sodium final preparation is greatly improved.

Accordingly, in one aspect, the present invention provides a solid pharmaceutical composition characterized by: which contains ertapenem sodium shown in formula 1, a compound shown in formula 2 or a sodium salt, a hydrate or a solvate thereof, and pharmaceutically acceptable auxiliary materials,

wherein:

the compound shown in the formula 2 or the pharmaceutically acceptable salt, hydrate or solvate thereof accounts for not less than 80 percent, preferably not less than 85 percent and more preferably not less than 90 percent of the total amount of the compound and ertapenem sodium shown in the formula 1.

The sodium salt of the compound represented by the formula 2 is selected from the group consisting of:

the sodium salts of the compounds represented by the above formulas 2-a to 2-g are simply referred to as carbamates.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition, which comprises the following steps:

(1) preparing a sodium bicarbonate ethanol water solution: dissolving a prescribed amount of sodium bicarbonate into a 5-10% ethanol water solution to prepare a sodium bicarbonate ethanol water solution with the sodium bicarbonate concentration of 2-12%, preferably 3-7% (w/w), and cooling to-5-0 ℃ for later use;

(2) slowly adding the ertapenem sodium raw material with the prescription amount into the sodium bicarbonate ethanol aqueous solution in the step (1) accounting for 40-70% of the total dosage at the temperature of-5-0 ℃, stirring, then slowly adding the rest (30-60%) of the sodium bicarbonate ethanol aqueous solution, and optionally dropwise adding a proper amount of sodium hydroxide solution to maintain the pH value of the reaction system between 7.0-8.0;

(3) optionally, treating the solution obtained in the step (2) with activated carbon, filtering, and performing sterile filtration to obtain a sterile solution;

(4) freeze-drying the solution obtained in the step (2) to obtain the solid pharmaceutical composition of the invention; or freeze-drying the sterile solution obtained in the step (3) to obtain the sterile solid pharmaceutical composition of the invention.

Wherein:

the molar ratio of the total amount of sodium bicarbonate to the raw material ertapenem sodium in the step (2) is 3-1.5: 1, and preferably 2.5-2: 1.

The initial dosage of the sodium bicarbonate ethanol aqueous solution in the step (2) is preferably 45-60% of the total dosage; the concentration (w/w) of the sodium hydroxide solution is 1-10%, preferably 2-5%; the pH of the reaction system is preferably maintained at 7.3 to 7.7, more preferably 7.4 to 7.6.

The dosage of the active carbon in the step (3) is 0.05-0.2% (w/w), and the content of the liquid medicine adsorbed for 60min has no obvious influence in the range. The sterile filtration is preferably a 0.22um microfiltration membrane selected from one or both of a polyvinylidene fluoride and polyethersulfone microfiltration membrane.

Step (4) is preferably: quantitatively subpackaging the solution obtained in the step (2) into injection bottles, and then carrying out freeze drying to obtain the solid pharmaceutical composition; or quantitatively subpackaging the sterile solution obtained in the step (3) into injection bottles, and then carrying out freeze drying to obtain the sterile solid pharmaceutical composition of the invention. The injection bottle is preferably a freeze-dried penicillin bottle made of neutral borosilicate glass.

The freeze drying, generally speaking, requires soaking the vials at about-45 to-40 ℃ for about 3 to 5 hours, then maintaining the temperature, and maintaining the pressure in the chamber of the lyophilizer at 20 to 30 Pa for about 2 to 4 hours; heating the freeze dryer plate layer to about-30 to-25 ℃, and maintaining the pressure of the chamber of the low-pressure freeze dryer at about 20 to 30 Pa for about 26 to 40 hours; heating the freeze dryer sheet to about 0 ℃ and maintaining at about 20 to 30 Pa for about 4 to 8 hours; then heating to 20 ℃, and maintaining for about 10-15 hours at about 10 Pa; then heating to 40 ℃, and maintaining for about 8-12 hours at about 10 Pa; the lyophilizer plate was then cooled to room temperature. The vials are fully sealed under a partial vacuum at a pressure of about 20-30 Pa or less prior to removal from the lyophilizer. And (3) under the partial vacuum condition that the pressure is less than or equal to 10 Pa, pressing and plugging the injection bottle, and taking out the injection bottle from the freeze dryer.

Or carrying out batch freeze-drying on the solution obtained in the step (2), and then subpackaging the obtained powder to obtain the solid pharmaceutical composition; or (3) carrying out batch freeze-drying on the sterile solution obtained in the step (3), and then carrying out sterile subpackaging on the obtained powder to obtain the sterile solid pharmaceutical composition of the invention.

In another aspect, the present invention relates to the use of the solid pharmaceutical composition according to the present invention for the preparation of an anti-infective medicament.

The compound 2 or pharmaceutically acceptable salt, hydrate or solvate thereof in the ertapenem sodium solid pharmaceutical composition provided by the invention accounts for more than 80%, and through long-term test for 24 months, the related substances are rarely increased, and the sample stability is good; compared with the product on the market, Yiwangzhi, has relatively less impurity increase, more stable property, more favorable storage and safer clinical medication.

Detailed Description

The following examples are intended only to illustrate the invention in more detail, but not to limit the invention.

The detection method of the carbamate content comprises the following steps:

the instrument comprises the following steps: bruker Advance 600 type nuclear magnetic resonance spectrometer

Solvent: d₂O

The detection method comprises the following steps: to the detection sample¹H-¹³C heteronuclear multiple bond correlation two-dimensional spectroscopy (HMBC) experiments.

Example 1: preparation of ertapenem sodium solid pharmaceutical composition

Table 1: ertapenem sodium solid pharmaceutical composition prescription (1000 bottles, specification: 1g)

Name of raw and auxiliary materials	Dosage (g)
		Ertapenem sodium	1046g
Sodium bicarbonate	353g
		Ethanol	350g
Sodium hydroxide	Proper amount of
		Water for injection	To 11000g
	Subpackaging according to 11g per bottle to make 1000 bottles

The preparation process comprises the following steps:

(1) preparing a 5% ethanol aqueous solution: adding 350g ethanol into 6650g water for injection, mixing, and standing; and dissolving the sodium bicarbonate with the prescription amount in the ethanol water solution, and cooling to-5-0 ℃ to prepare the sodium bicarbonate ethanol water solution for later use.

(2) Weighing 50% of sodium bicarbonate ethanol aqueous solution, slowly adding the ertapenem sodium raw material (with the HPLC purity of 99.1%) in a prescription amount into the solution at the temperature of-5-0 ℃, stirring, immediately dropwise adding the rest (namely 50% of the total amount) of sodium bicarbonate ethanol aqueous solution, adjusting and maintaining the pH value of the solution to 7.5 by using 2% (w/w) of sodium hydroxide solution, uniformly stirring, adding water for injection to 11000g, and uniformly stirring; the time used was 1 hour.

The following steps are carried out in a hundred-grade clean environment:

(3) sterilizing and filtering the liquid medicine by two-stage microporous filter membranes (filter cores) with the diameter of 0.22 mu m; the time used was 0.5 hour.

(4) The method comprises the following steps of (1) carrying out split charging of liquid medicine in 20ml of clean sterile tube freeze-dried penicillin bottles, wherein the theoretical charging amount is 11 g/bottle, carrying out half-tamponade, and immediately transferring a sample subjected to half-tamponade to a freeze-drying machine with a precooled drying oven to-5 ℃ for 2 hours; the lyophilization program was started and the lyophilization curve was as follows:

table 2 example 1 lyophilization profile

(5) And (3) pressing, rolling an aluminum-plastic cover, inspecting and labeling to obtain the solid pharmaceutical composition.

Taking final product samples D₂Dissolving O to prepare a solution of 200mg/mL, and detecting the content of carbamate, wherein the ratio of the carbamate to ertapenem sodium is 95: 5.

Example 2 to 9 preparation of ertapenem sodium solid pharmaceutical composition (pH examination of reaction System)

Referring to the recipe process of example 1, except for changing the pH of the solution prepared in step (2), the results are shown in the following table:

TABLE 3 Experimental results for examples 2 to 9

Examples	pH value of the liquid medicine	Ratio of the final product carbamate to ertapenem sodium
			2	7.0	80:20
3	7.2	83:17
			4	7.3	86:14
5	7.4	91:9
			6	7.6	90:10
7	7.7	85:15
			8	7.8	82:18
9	8.0	80:20

The experimental result shows that the pH value is controlled between 7.0 and 8.0 when the liquid medicine is prepared, and the carbamate content in the final freeze-dried product is more than 80 percent; when the pH value of the liquid medicine is 7.3-7.7, the carbamate content is more than 85%; when the pH value of the liquid medicine is 7.4-7.6, the carbamate content is more than 90%; at a pH of 7.5, the carbamate content was 95% (see example 1).

Examples 10 to 14 preparation of solid ertapenem sodium pharmaceutical compositions (investigation of the amount of sodium bicarbonate)

Referring to the formulation process of example 1, except for changing the amount of sodium bicarbonate used in step (1), the results are shown in the following table:

TABLE 4 Experimental results for examples 10 to 14

The experiment result shows that the molar ratio of the sodium bicarbonate to the ertapenem sodium is 1.5-3, and the carbamate content in the final freeze-dried product is more than 80%; when the molar ratio is 1.8-2.5, the content of carbamate is more than 85%; when the molar ratio is between 2.2 and 2.0, the carbamate content is more than 90 percent (see examples 1 and 12).

Example 15: preparation of ertapenem sodium solid pharmaceutical compositions (examination of initial amount of aqueous sodium bicarbonate ethanol solution)

Referring to the recipe of example 1, except for changing the initial amount of the aqueous ethanol sodium bicarbonate solution used in step (2), the results are shown in the following table:

TABLE 5 results of examples 15 to 21

The experimental result shows that the initial dosage of the sodium bicarbonate ethanol aqueous solution in the step (2) is 40-70% of the total dosage, and the carbamate content in the final freeze-dried product is more than 80%; when the using amount is 45-60% of the total using amount, the content of the carbamate is more than 85%; the carbamate content is above 90% when the amount is between 50 and 55% of the total amount (see examples 1 and 18).

Example 22: long term stability test

The samples of the examples 1, 2, 6 and 7 of the invention are taken, the packages on the market are simulated, the samples are placed in the dark under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 60% +/-10%, the samples are sampled at the end of 0, 3, 6, 9, 12, 18 and 24 months for detection, the detection is carried out according to the key stability investigation items and the measurement method, samples of Yiwang imitated products are taken under the conditions, the samples are sampled at the same time point, the change conditions of related substances are investigated, and the results are shown in Table 6.

TABLE 6 Long-term stability test results for ertapenem sodium solid pharmaceutical compositions

TABLE 6-1

TABLE 6-2

Tables 6 to 3

The test result shows that: through long-term test for 24 months, the ertapenem sodium solid pharmaceutical composition has little increase of related substances and good stability of samples; compared with the product on the market, Yiwangzhi, has relatively less impurity increase, more stable property, more favorable storage and safer clinical medication.

Claims (12)

1. A solid pharmaceutical composition characterized by: which contains ertapenem sodium shown in formula 1, sodium salt of a compound shown in formula 2 and pharmaceutically acceptable auxiliary materials,

the weight percentage of the sodium salt of the compound shown in the formula 2 to the total amount of ertapenem sodium shown in the formula 1 is not less than 80 percent;

the sodium salt of the compound represented by formula 2 is selected from the group consisting of compounds represented by the following formulae 2-a to 2-g:

2. the pharmaceutical composition of claim 1, wherein: the weight percentage of the sodium salt of the compound shown in the formula 2 to the total amount of ertapenem sodium shown in the formula 1 is not less than 85%.

3. The pharmaceutical composition of claim 2, wherein: the weight percentage of the sodium salt of the compound shown in the formula 2 to the total amount of ertapenem sodium shown in the formula 1 is not less than 90%.

4. A process for preparing a pharmaceutical composition according to any one of claims 1 to 3, wherein: the method comprises the following steps:

(1) preparing a sodium bicarbonate ethanol water solution: dissolving a prescribed amount of sodium bicarbonate into a 5-10% ethanol water solution to prepare a sodium bicarbonate ethanol water solution with the sodium bicarbonate concentration of 2-12% (w/w), and cooling to-5-0 ℃ for later use;

(2) slowly adding the ertapenem sodium raw material with the prescription amount into the sodium bicarbonate ethanol aqueous solution in the step (1) with the initial amount, which is 40-70 (w/w)% of the total amount, at the temperature of-5-0 ℃, stirring, then slowly adding the rest amount of the sodium bicarbonate ethanol aqueous solution, and optionally dropwise adding a proper amount of sodium hydroxide solution to maintain the pH value of the reaction system between 7.0-8.0;

(3) optionally, treating the solution obtained in the step (2) with activated carbon, filtering, and performing sterile filtration to obtain a sterile solution;

(4) freeze-drying the solution obtained in the step (2) to obtain a solid pharmaceutical composition; or (4) freeze-drying the sterile solution obtained in the step (3) to obtain the sterile solid pharmaceutical composition.

5. A process for preparing a pharmaceutical composition according to claim 4, wherein: the concentration of the sodium bicarbonate in the step (1) is 3-7%.

6. A process for preparing a pharmaceutical composition according to claim 4, wherein: the molar ratio of the total amount of sodium bicarbonate to the raw material ertapenem sodium in the step (2) is 1.5-3: 1.

7. A process for preparing a pharmaceutical composition according to claim 4, wherein: the molar ratio of the total amount of sodium bicarbonate to the raw material ertapenem sodium in the step (2) is 2.5-2: 1.

8. A process for preparing a pharmaceutical composition according to claim 4, wherein: the initial dosage of the sodium bicarbonate ethanol aqueous solution in the step (2) is 45-60 (w/w)% of the total dosage.

9. A process for preparing a pharmaceutical composition according to claim 4, wherein: in the step (2), the pH value of the reaction system is maintained at 7.3-7.7.

10. A process for preparing a pharmaceutical composition according to claim 4, wherein: in the step (2), the pH value of the reaction system is maintained at 7.4-7.6.

11. A process for preparing a pharmaceutical composition according to claim 4, wherein: step (4) quantitatively subpackaging the solution obtained in step (2) or the sterile solution obtained in step (3) into injection bottles, and then carrying out freeze drying;

the freeze drying process comprises the following steps: soaking the injection bottle at-45 to-40 ℃ for 3 to 5 hours, then maintaining the temperature, and maintaining the pressure of a cavity of a low-pressure freeze dryer for 2 to 4 hours under 20 to 30 Pa; heating the freeze dryer plate layer to-30 to-25 ℃, and maintaining the pressure of the cavity of the low-pressure freeze dryer for 26 to 40 hours under 20 to 30 Pa; heating the freeze dryer plate layer to 0 ℃, and maintaining the temperature for 4-8 hours at 20-30 Pa; then heating to 20 ℃, and maintaining for 10-15 hours at 10 Pa; then heating to 40 ℃, and maintaining for 8-12 hours at 10 Pa; then cooling the freeze dryer plate layer to room temperature; and (3) under the partial vacuum condition that the pressure is less than or equal to 10 Pa, pressing and plugging the injection bottle, and taking out the injection bottle from the freeze dryer.

12. Use of a pharmaceutical composition according to any one of claims 1 to 3 or a solid pharmaceutical composition obtained by a process according to any one of claims 4 to 11 for the manufacture of an anti-infective medicament.