Pharmaceutical composition containing faropenem sodium and preparation method of preparation of pharmaceutical composition

Abstract

The invention relates to the technical field of biological medicine, in particular to a pharmaceutical composition containing faropenem sodium and a preparation method of a preparation thereof, and the pharmaceutical composition comprises 61.75 parts by weight of faropenem sodium, 430 parts by weight of filler, 0.5 part by weight of chelating agent and 7.5 parts by weight of adhesive. More specifically, the pharmaceutical composition contains 61.75 parts by weight of faropenem sodium, 283.5 parts by weight of lactose as a filler, 146.5 parts by weight of mannitol as a filler, 0.5 part by weight of sodium calcium edetate as a chelating agent and 7.5 parts by weight of hydroxypropyl cellulose-SL as an adhesive. Researches show that the pharmaceutical preparation prepared from the pharmaceutical composition has better stability.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically to a pharmaceutical composition containing faropenem sodium and a preparation method thereof. Technical Background

[0002] Faropenem sodium is a β-lactam antibiotic. It has a bactericidal effect by inhibiting the synthesis of bacterial cell walls. The drug has strong antibacterial activity, especially against Gram-positive bacteria such as Staphylococcus aureus, penicillin-resistant pneumococci, Streptococcus faecalis, and anaerobic bacteria such as Bacteroides fragilis. Its antibacterial activity is significantly better than that of existing cephalosporins, such as ceftriaxone, cefditoren, cefixime, and cefaclor. Its anti-Gram-negative bacteria activity is similar to that of oral cephalosporins, and its anti-Pseudomonas aeruginosa effect is weaker. This product is stable to β-lactamase and also has good antibacterial effect on cephalosporin-resistant Citrobacter freundii and Enterobacter cloacae.

[0003] Faropenem sodium can be prepared into an oral preparation, but the stability of the preparation is poor. Therefore, how to prepare a preparation with better stability is of great significance. Summary of the invention

[0004] Based on the above reasons, the applicant has obtained a new pharmaceutical composition containing faropenem sodium after several creative efforts. The pharmaceutical composition contains 61.75 parts by weight of faropenem sodium, 430 parts by weight of filler, 0.5 parts by weight of chelating agent, and 7.5 parts by weight of binder; more specifically, the pharmaceutical composition contains 61.75 parts by weight of faropenem sodium, 283.5 parts by weight of filler lactose, 146.5 parts by weight of filler mannitol, 0.5 parts by weight of chelating agent calcium sodium edetate, and 7.5 parts by weight of binder hydroxypropylcellulose-SL. Studies have shown that the pharmaceutical preparation prepared from the pharmaceutical composition of the present invention has better stability.

[0005] The present invention is achieved through the following technical solutions.

[0006] A faropenem sodium pharmaceutical composition comprises faropenem sodium, a filler, a chelating agent and a binder.

[0007] The faropenem sodium pharmaceutical composition comprises 61.75 parts by weight of faropenem sodium, 430 parts by weight of a filler, 0.5 parts by weight of a chelating agent, and 7.5 parts by weight of a binder.

[0008] The faropenem sodium pharmaceutical composition comprises 61.75 parts by weight of faropenem sodium, 430 parts by weight of fillers lactose and mannitol, 0.5 parts by weight of chelating agent calcium sodium edetate, and 7.5 parts by weight of adhesive hydroxypropylcellulose-SL.

[0009] The faropenem sodium pharmaceutical composition comprises 61.75 parts by weight of faropenem sodium, 283.5 parts by weight of filler lactose, 146.5 parts by weight of filler mannitol, 0.5 parts by weight of chelating agent calcium sodium edetate, and 7.5 parts by weight of binder hydroxypropylcellulose-SL.

[0010] The faropenem sodium pharmaceutical composition is prepared as a solid preparation, preferably a granule.

[0011] The faropenem sodium pharmaceutical composition, wherein the preparation method of the granules is:

[0012] (1) Pass faropenem sodium, lactose, and mannitol through a No. 2 sieve, add them into a wet granulator, and mix them evenly;

[0013] (2) Granulation: Hydroxypropylcellulose-SL is added to water and stirred to dissolve to obtain solution I, calcium sodium edetate is added to solution I, and the mixture is mixed to obtain solution II, and the solution is added to wet granulator II to prepare a soft material; the soft material is poured into a swing granulator and granules are prepared using a 24-mesh nylon screen;

[0014] (3) Drying: Add the wet granules into the boiling granulation dryer, set the air inlet valve to open 25%, and the air volume to 1000m 3 / h, vacuum the swirled particles into the boiling drying granulator; set the air inlet temperature to 40℃ and the fan air volume to 500-1500m 3 / h starts drying, and stops drying when the material temperature reaches 40℃;

[0015] (4) Granulation, mixing and packaging. DETAILED DESCRIPTION

[0016] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention.

[0017] Test 1 Bulking agent (sucrose or lactose) selection

[0018] Sucrose and lactose were used to replace the refined white sugar in the reference preparation as fillers to prepare samples, and the growth of related substances was investigated by comparison. The stability of the sample using lactose was better than that of the sample using sucrose, so lactose was selected to replace the refined white sugar in the reference preparation.

[0019] Table 1 Sample preparation method

[0020]

[0021] Table 2 Sample stability test results

[0022]

[0023]

[0024] Analysis of results: Under high temperature (50°C) conditions, the growth rate of related substances in the sample prepared with lactose (230321-1) was slower than that in the sample prepared with sucrose (230322-1); but compared with the reference preparation, the growth of total impurities was similar, but two impurities with relative retention times of 0.51 and 0.98 were produced and grew significantly; and the growth of two impurities with relative retention times of 0.70 and 0.77 was faster than that of the reference preparation.

[0025] Test 2: Screening of the dosage of hydroxypropyl cellulose (HPC-SL)

[0026] Hydroxypropyl cellulose (HPC-SL) is used as a binder in the formulation, which will affect the size of the particles and the content of the powder. The amount of hydroxypropyl cellulose is selected based on the powder content of the particles.

[0027] Table 3 Hydroxypropyl cellulose (HPC-SL) dosage screening

[0028]

[0029] The results show that as the amount of HPC-SL increases, the powder content of the sample will decrease. When the small trial batch is 600 bags / batch, the initial screening HPC-SL dosage is 1.3%; when it is initially expanded to 750 bags, the powder content rises to 13.6%, close to the upper limit. After the HPC-SL dosage is adjusted to 1.5%, the powder content is significantly reduced when the batch is expanded again.

[0030] Trial 3 Aspartame Selection

[0031] Aspartame can be used as a flavoring agent. By comparing the high temperature stability of samples containing aspartame and samples without aspartame, it was found that aspartame would cause unknown impurities to increase when the samples were kept at high temperature. In the end, aspartame was not added to the prescription. See the table below for details.

[0032] Table 4 Stability of samples with and without aspartame - related substances test results

[0033]

[0034]

[0035] The sample (230406-1) prepared by removing aspartame from the prescription showed a significantly lower growth rate of total impurities and individual impurities than the sample (230321-1) containing aspartame and the reference preparation (0X001) under high temperature (50°C) conditions.

[0036] Test 4: Selection of drying conditions

[0037] After granulation, the wet granules were dried in a fluidized bed dryer to investigate the effects of different inlet air temperatures and drying endpoints on sample stability. The inlet air temperature was selected to be 40°C and the material temperature was dried to 40°C. See the table below for details.

[0038] Table 5 Drying conditions selection

[0039] Sample batch number 230321-1 230321-2 230321-3 Sample batch 600 bags 600 bags 600 bags Inlet air temperature 30℃ 35℃ 40℃ Fan frequency 15％ 15％ 15％ Drying end point 30.4℃ 35.3℃ 40.0℃ Particle moisture 2.18％ 2.22％ 2.05％

[0040] Table 6 Stability of samples prepared under different drying conditions

[0041]

[0042]

[0043] The results show that the inlet air temperature and the material temperature at the end of drying have little effect on the relevant substances of the product when the temperature is between 30℃ and 40℃. However, the high temperature 50℃ stability sample shows that a higher drying temperature (40℃) is conducive to the stability of the product. The inlet air temperature is selected to be 40℃, and the drying is stopped when the material temperature reaches 40℃.

[0044] Detection and analysis methods

[0045] Related substances Ⅰ were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). New preparation for clinical use.

[0046] Test solution Take the product, add water to dissolve and dilute to make a solution containing about 0.5 mg of faropenem per 1 ml.

[0047] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the mark with water, and shake well.

[0048] For the excipient solution, take appropriate amounts of each excipient component according to the prescription composition, add water to dissolve it and prepare a solution containing the same concentration of excipients as the test sample solution.

[0049] System suitability solution Take 10 ml of the test solution and irradiate it under 254 nm UV light for 3 hours.

[0050] Sensitivity solution: Accurately measure an appropriate amount of the control solution and quantitatively dilute it with water to prepare a solution containing approximately 0.25 μg of faropenem per 1 ml.

[0051] The chromatographic conditions were as follows: octadecylsilane bonded silica gel was used as filler (4.6 mm × 250 mm, 5 μm or chromatographic column of equivalent performance); a ghost-busting column (Welch, Ghost-Buster Column, 4.6 mm × 50 mm) was installed before the injector and after the mixer; mobile phase A was phosphate buffer (6.12 g of potassium dihydrogen phosphate, 1.79 g of sodium dihydrogen phosphate and 1.61 g of tetrabutylammonium bromide were dissolved in water and diluted to make 1000 ml)-acetonitrile (95:5); mobile phase B was phosphate buffer-acetonitrile (55:45); the flow rate was 1.0 ml per minute, and linear gradient elution was performed according to the table below; the column temperature was 40°C; the detection wavelength was 240 nm; the injection volume was 20 μl.

[0052] Table 7

[0053]

[0054] System suitability requirements In the system suitability solution chromatogram, the peak with a relative retention time of about 0.8 is impurity I. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0055] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0056] If there are impurity peaks in the chromatogram of the limit test solution, after deducting the solvent peak and the excipient peak, the peak area of ​​impurity I (multiplied by the correction factor 0.37) shall not be greater than 1.0 times (1.0%) the main peak area of ​​the control solution, the area of ​​other individual impurity peaks shall not be greater than 0.2 times (0.2%) the main peak area of ​​the control solution, and the sum of the areas of all impurity peaks shall not be greater than 2.0 times (2.0%) the main peak area of ​​the control solution. Peaks smaller than the main peak area of ​​the sensitivity solution (0.05%) are negligible.

[0057] The S isomer was determined by high performance liquid chromatography (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0058] Test solution Take the product, add mobile phase to dissolve and dilute to make a solution containing about 0.5 mg of faropenem per 1 ml.

[0059] For the control solution, accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute it to the mark with the mobile phase, shake well, then accurately measure 3 ml, place it in a 10 ml volumetric flask, dilute it to the mark with the mobile phase, shake well.

[0060] System suitability solution: Accurately weigh an appropriate amount of faropenem reference substance and faropenem S isomer reference substance, add mobile phase to dissolve and dilute to make a mixed solution containing approximately 0.25 mg of each in each 1 ml.

[0061] Sensitivity solution: Accurately measure an appropriate amount of system suitability solution and dilute with mobile phase to make a mixed solution containing approximately 0.25 μg of each per 1 ml.

[0062] The chromatographic conditions are as follows: octadecylsilane bonded silica gel is used as a filler (4.6 mm × 250 mm, 5 μm or a chromatographic column of equivalent performance); phosphate buffer (4.8 g of potassium dihydrogen phosphate, 5.4 g of sodium dihydrogen phosphate and 1.0 g of tetrabutylammonium bromide are dissolved in water and diluted to make 1000 ml) - methanol - acetonitrile (76:16:8) is used as the mobile phase; the flow rate is 1.0 ml per minute; the column temperature is 30°C; the detection wave is 305 nm long; and the injection volume is 20 μl.

[0063] System suitability requirements In the system suitability solution chromatogram, the separation between the faropenem peak and the S isomer peak should meet the requirements. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0064] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0065] If there is a chromatographic peak in the chromatogram of the limit test solution with the same retention time as the S isomer, its peak area shall not be greater than the main peak area of ​​the control solution (0.3%).

[0066] [Content Determination] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition, Part IV, General Rules 0512).

[0067] Take an appropriate amount of the test sample solution, weigh it accurately, add the mobile phase to dissolve it and quantitatively dilute it to make a solution containing about 0.25 mg of faropenem per 1 ml.

[0068] Reference solution: Take an appropriate amount of faropenem reference substance, weigh it accurately, add mobile phase to dissolve it and quantitatively dilute it to make a solution containing about 0.25 mg of faropenem per 1 ml.

[0069] System suitability solution: Accurately weigh an appropriate amount of faropenem reference substance and faropenem S isomer reference substance, add mobile phase to dissolve and dilute to make a mixed solution containing approximately 0.25 mg of each in each 1 ml.

[0070] Chromatographic conditions see under Isomers.

[0071] System suitability requirements In the system suitability solution chromatogram, the separation between the faropenem peak and the S-isomer peak should meet the requirements.

[0072] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the content of faropenem in the test sample by the peak area according to the external standard method.

[0073] Preparation Example

[0074] Preparation Example 1

[0075] Faropenem sodium 61.75g, fillers lactose and mannitol 430g in total, chelating agent calcium sodium edetate 0.5g, binder hydroxypropylcellulose-SL 7.5g.

[0076] (1) Pass faropenem sodium, lactose, and mannitol through a No. 2 sieve, add them into a wet granulator, and mix them evenly;

[0077] (2) Granulation: Hydroxypropylcellulose-SL is added to water and stirred to dissolve to obtain solution I, calcium sodium edetate is added to solution I, and the mixture is mixed to obtain solution II, and the solution is added to wet granulator II to prepare a soft material; the soft material is poured into a swing granulator and granules are prepared using a 24-mesh nylon screen;

[0078] (3) Drying: Add the wet granules into the boiling granulation dryer, set the air inlet valve to open 25%, and the air volume to 1000m 3 / h, vacuum the swirled particles into the boiling drying granulator; set the air inlet temperature to 40℃ and the fan air volume to 500-1500m 3 / h starts drying, and stops drying when the material temperature reaches 40℃;

[0079] (4) Granulating, mixing and packaging to obtain 1000 bags of granules.

[0080] Preparation Example 2

[0081] Faropenem sodium 6.175kg, fillers lactose and mannitol 430kg in total, chelating agent calcium sodium edetate 0.05kg, binder hydroxypropylcellulose-SL 0.75kg.

[0082] (1) Pass faropenem sodium, lactose, and mannitol through a No. 2 sieve, add them into a wet granulator, and mix them evenly;

[0083] (2) Granulation: Hydroxypropylcellulose-SL is added to water and stirred to dissolve to obtain solution I, calcium sodium edetate is added to solution I, and the mixture is mixed to obtain solution II, and the solution is added to wet granulator II to prepare a soft material; the soft material is poured into a swing granulator and granules are prepared using a 24-mesh nylon screen;

[0084] (3) Drying: Add the wet granules into the boiling granulation dryer, set the air inlet valve to open 25%, and the air volume to 1000m 3 / h, vacuum the swirled particles into the boiling drying granulator; set the air inlet temperature to 40℃ and the fan air volume to 500-1500m 3 / h starts drying, and stops drying when the material temperature reaches 40℃;

[0085] (4) Granulating, mixing and packaging to obtain 100,000 bags of granules.

[0086] The preparation of Example 2 was tested and analyzed, and the results were as follows:

[0087] Table 8 pH 1.2 hydrochloric acid solution:

[0088]

[0089] Table 9 pH 4.0 acetate buffer

[0090]

[0091]

[0092] Table 10 pH 6.8 phosphate buffer

[0093]

[0094] Table 11 Water

[0095]

[0096] Conclusion: The cumulative dissolution rate of the preparation in Example 2 in pH 4.0, pH 6.8 and water media was greater than 85% at 15 min, which was similar to the reference preparation. In pH 1.0 hydrochloric acid medium, the dissolution platform was reached at 5 min. Due to the degradation of both the reference preparation and the pilot sample, the subsequent cumulative dissolution rate continued to decrease.

[0097] Table 12 Results of investigation on factors affecting formulation of Example 2

[0098]

[0099]

[0100] Test conclusion: The above impact tests show that the preparation of the present invention has good stability.

[0101] The above embodiments are only used to illustrate the present invention, but not to limit the present invention. Although the present invention is described in detail with reference to the embodiments, it should be understood by those skilled in the art that various combinations, modifications or equivalent substitutions of the technical solutions of the present invention do not depart from the spirit and scope of the technical solutions of the present invention, and should be included in the scope of the claims of the present invention.

Claims

1. A faropenem sodium pharmaceutical composition, characterized in that The pharmaceutical composition contains faropenem sodium, a filler, a chelating agent and a binder.

2. A faropenem sodium pharmaceutical composition according to claim 1, wherein there are 61.75 parts by weight of faropenem sodium, 430 parts by weight of filler, 0.5 parts by weight of chelating agent, and 7.5 parts by weight of binder.

3. A pharmaceutical composition of faropenem sodium according to claim 1, wherein the composition comprises 61.75 parts by weight of faropenem sodium, 430 parts by weight of fillers lactose and mannitol in total, 0.5 parts by weight of chelating agent calcium sodium edetate, and 7.5 parts by weight of binder hydroxypropylcellulose-SL.

4. A pharmaceutical composition of faropenem sodium according to claim 1, wherein the composition comprises 61.75 parts by weight of faropenem sodium, 283.5 parts by weight of filler lactose, 146.5 parts by weight of filler mannitol, 0.5 parts by weight of chelating agent calcium sodium edetate, and 7.5 parts by weight of binder hydroxypropylcellulose-SL.

5. A faropenem sodium pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is prepared as a solid preparation, preferably a granule.

6. A faropenem sodium pharmaceutical composition according to claim 5, wherein the preparation method of the granules is: (1) Pass faropenem sodium, lactose, and mannitol through a No. 2 sieve, add them into a wet granulator, and mix them evenly; (2) Granulation: Hydroxypropylcellulose-SL is added to water and stirred to dissolve to obtain solution I, calcium sodium edetate is added to solution I, and the mixture is mixed to obtain solution II, and the solution is added to wet granulator II to prepare a soft material; the soft material is poured into a swing granulator and granules are prepared using a 24-mesh nylon screen; (3) Drying: Add the wet granules into the boiling granulation dryer, set the air inlet valve to open 25%, and the air volume to 1000m 3 / h, vacuum the swirled particles into the boiling drying granulator; set the air inlet temperature to 40℃ and the fan air volume to 500-1500m 3 / h starts drying, and stops drying when the material temperature reaches 40℃; (4) Granulation, mixing and packaging.

Images