A preparation method of cefprozil dry suspension and cefprozil dry suspension

Abstract

The invention belongs to the technical field of drug preparation, and discloses a preparation method of a cefprozil dry suspension and a cefprozil dry suspension. The cefprozil dry suspension comprises cefprozil and excipients, and the preparation method comprises the following steps: (1) excipient mixing: mixing at least part of the excipients to obtain a premixed powder for standby use; (2) dry suspension preparation: uniformly mixing the premixed powder, the remaining excipients, and cefprozil with a particle size D90 of 40 to 200 μm; wherein, if all the excipients are mixed to form a premixed powder in step (1), the remaining excipients are not included in step (2). In the present invention, the raw material drug cefprozil is not crushed or sieved, but is directly mixed with the premixed powder obtained by mixing various excipients to prepare a dry suspension, the process steps are simple, and the content of related substances in the obtained dry suspension can be effectively controlled, thereby ensuring the quality of the drug.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and in particular relates to a preparation method of a cefprozil dry suspension and the cefprozil dry suspension. Background Art

[0002] Cefprozil belongs to the β-lactam antibiotics. Its mechanism of action is similar to that of other cephalosporins. It exerts its antibacterial effect mainly by hindering the biosynthesis of bacterial cell walls. Its anti-Gram-negative bacillus activity and stability against Gram-negative bacillus β-lactamase are stronger than those of first-generation cephalosporins, and it has good application prospects.

[0003] Cefprozil is prepared into a dry suspension, which is convenient to carry, has good stability, and is easy to take. However, the existing processes for preparing cefprozil dry suspensions mostly mix raw materials and auxiliary materials to make soft materials, then make the soft materials into wet granules, and further dry them to process them into dry suspensions, and the preparation process is cumbersome. In addition, the study of related substances is one of the key projects in drug quality research. The content of related substances is a direct indicator of drug purity. How to ensure that the content of related substances meets the standard during the preparation process is one of the key factors to be considered in drug preparation.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art. On the one hand, a method for preparing a cefprozil dry suspension is provided, which has simple process steps and can effectively control the content of related substances therein.

[0006] Another aspect of the present invention provides a cefprozil dry suspension prepared by the method for preparing the cefprozil dry suspension.

[0007] In order to solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a method for preparing a cefprozil dry suspension, wherein the cefprozil dry suspension comprises cefprozil and an auxiliary material, and the preparation method comprises the following steps:

[0009] (1) Mixing auxiliary materials: mixing at least part of the auxiliary materials to obtain a premixed powder for later use;

[0010] (2) Preparation of dry suspension: uniformly mix the premixed powder, the remaining excipients, and cefprozil with a particle size D90 of 40 to 200 μm to obtain a dry suspension;

[0011] If all the auxiliary materials are mixed to form a premixed powder in step (1), then step (2) does not include any remaining auxiliary materials.

[0012] In a preferred embodiment, the particle size D90 of the cefprozil is 40-160 μm, more preferably 50-160 μm.

[0013] In the present invention, the raw material cefprozil and the premixed powder obtained by mixing the auxiliary materials are directly mixed to prepare the dry suspension, the process steps are simple, and the cumbersome preparation process is avoided. The raw material of cefprozil with a particle size D90 of 40 to 200 μm is selected, and the raw material is directly mixed with the premixed powder without pulverization or screening. After detection, the content of related substances in the obtained dry suspension can be significantly reduced, thereby ensuring the quality of the medicine.

[0014] In a further embodiment, the auxiliary material includes sucrose. In step (1), the sucrose is crushed, sieved, and dried. The moisture content of the sucrose powder after drying is not higher than 1.0wt%;

[0015] The dried sucrose powder is then mixed with other auxiliary materials to obtain a premixed powder; or, part of the dried sucrose powder is mixed with other auxiliary materials to obtain a premixed powder, and the remaining dried sucrose powder is then added in step (2).

[0016] As a specific implementation method, in step (1), all the dried sucrose powder is mixed with other auxiliary materials to prepare a premixed powder; in step (2), the premixed powder is evenly mixed with cefuroxime.

[0017] As another specific implementation, in step (1), the dried sucrose powder having the same mass as other auxiliary materials is weighed and mixed with the other auxiliary materials to prepare a premixed powder; in step (2), the premixed powder, the remaining dried sucrose powder, and cefprozil are uniformly mixed to obtain a cefprozil dry suspension.

[0018] In the above scheme, the crushed sucrose powder is dried and then mixed with the raw materials and other auxiliary materials, which avoids the problem of sucrose powder absorbing water and agglomerating, thereby improving the phenomenon of agglomeration during the mixing process of raw materials and auxiliary materials.

[0019] In a further scheme, the air inlet temperature for sucrose drying is 45-70°C and the drying time is 30-60 min;

[0020] Preferably, the inlet air temperature is 50-65°C.

[0021] Specifically, the drying equipment used for drying sucrose is a fluidized bed dryer or a boiling dryer.

[0022] As a specific implementation method, the sieved sucrose powder is transferred to a fluidized bed dryer for drying, the inlet air temperature is set at 45-70° C., the drying time is controlled at 30-60 min, and when the moisture content is measured to be no more than 1.0 wt %, the material is discharged for use.

[0023] In a further embodiment, one or more of the other auxiliary materials are sieved and then mixed with the dried sucrose powder;

[0024] Preferably, the sieve aperture of sucrose powder is 20-100 mesh, and the sieve aperture of other auxiliary materials is 30-100 mesh;

[0025] More preferably, the sieve aperture of sucrose powder is 60 mesh, and the sieve aperture of other auxiliary materials is 40 mesh.

[0026] In the present invention, one or several of the other auxiliary materials are initially in the form of particles, which are screened and then mixed, so as to reduce the direct participation of large particles of auxiliary materials in the mixing, which is beneficial to improving the uniformity of material mixing and preventing the agglomeration of the raw materials when the auxiliary materials are mixed to form a dry suspension.

[0027] In addition, for sucrose powder, the smaller the particle size, the larger the specific surface area, and the easier it is to absorb water and agglomerate. Therefore, the sieving aperture of sucrose powder should be controlled within a certain range, on the one hand to avoid excessively large particles affecting the uniformity of subsequent material mixing, and on the other hand to avoid sucrose powder being too fine and resulting in water absorption and agglomeration, which can further avoid the phenomenon of material agglomeration during the mixing process of raw and auxiliary materials.

[0028] As a specific embodiment, the auxiliary materials further include glycine, sodium chloride and sodium benzoate. In step (1), the glycine, sodium chloride and sodium benzoate are respectively sieved through a 40-mesh sieve, and then the sieved materials are mixed with the dried sucrose powder.

[0029] In a further embodiment, in step (1), the premixed powder is sieved and set aside;

[0030] Preferably, the sieve aperture of the premixed powder is 60-100 mesh;

[0031] More preferably, the sieve aperture of the premixed powder is 80 mesh.

[0032] As a specific implementation, various auxiliary materials are added to a mixing device in a certain order, and after mixing, they are sieved through an 80-mesh sieve to obtain a sieved premixed powder for standby use. The mixing time is preferably 5 to 20 minutes.

[0033] In a specific embodiment, the following auxiliary materials are added to a mixing device in sequence: sucrose powder, colloidal silicon dioxide, aspartame, microcrystalline cellulose-sodium carboxymethyl cellulose, flavor, glycine, sodium chloride, sodium benzoate, and pigment, and after mixing, the mixture is sieved through an 80-mesh sieve for later use.

[0034] As a specific implementation, the mixing device is a three-dimensional motion mixer, preferably a three-eccentric mixer, and the premixed powder obtained by mixing is transferred to a swing granulator for sieving.

[0035] In the above scheme, the auxiliary materials are pre-mixed and then sieved, and then mixed with the raw material drug cefprozil, which has a significant effect on improving the agglomeration phenomenon of materials in the mixing process of raw and auxiliary materials.

[0036] In a further solution, in step (2), part of the premixed powder is first added for mixing, and after the mixing is uniform, the remaining premixed powder is added and the mixing is continued.

[0037] As a specific implementation method, 1 / 3 to 2 / 3 of the sieved premixed powder is added to a mixing device, then cefprozil is added, and finally the remaining sieved premixed powder is added, and after being fully mixed in the mixing device, the material is discharged to obtain the cefprozil dry suspension.

[0038] In the above scheme, the auxiliary materials are mixed with cefuroxime in batches, which is more conducive to the mixing uniformity of the raw and auxiliary materials.

[0039] In a further embodiment, the mass proportion of cefprozil in the cefprozil dry suspension is 7.5% to 10.0%.

[0040] In a further embodiment, the auxiliary material includes sucrose accounting for 70% to 85% by weight of the cefprozil dry suspension.

[0041] In a further embodiment, the auxiliary materials include the following components based on the mass percentage in the cefprozil dry suspension:

[0042] Flavor corrector 0.01%~2.0%;

[0043] Suspending agent 2.0%~15.0%;

[0044] Fragrance 0.01%~2.0%;

[0045] Colorant 0.01%~2.0%;

[0046] Flow aid 0.5%~5.0%;

[0047] Antioxidant 0.01%~2.0%;

[0048] Preservatives 0.01%~5.0%;

[0049] Flocculant 0~2.0%.

[0050] In a preferred embodiment, the mass proportion of the suspending agent is 4.0% to 13.0%, more preferably 13.0%.

[0051] In a preferred embodiment, the antioxidant accounts for 0.075% to 0.15% by mass.

[0052] In a preferred embodiment, the mass proportion of the flocculant is 0.01% to 1.5%.

[0053] As a specific embodiment, the flavor corrective includes aspartame and / or neotame.

[0054] As a specific embodiment, the suspending agent includes microcrystalline cellulose-sodium carboxymethyl cellulose and / or colloidal microcrystalline cellulose.

[0055] As a specific implementation, the fragrance includes one or more of orange flavor, mixed fruit flavor and peach powder flavor.

[0056] As a specific embodiment, the colorant includes erythrosine aluminum lake and / or allura red aluminum lake.

[0057] As a specific embodiment, the glidant includes colloidal silicon dioxide.

[0058] As a specific embodiment, the antioxidant includes glycine.

[0059] As a specific embodiment, the preservative includes sodium benzoate.

[0060] As a specific implementation, the flocculant includes sodium chloride.

[0061] In a specific embodiment of the present invention, the preparation method of the cefprozil dry suspension specifically comprises the following steps:

[0062] A. Pretreatment of auxiliary materials: After sucrose is crushed, it is passed through a 60-mesh sieve and set aside; glycine, sodium chloride, and sodium benzoate are passed through a 40-mesh sieve respectively and set aside;

[0063] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 45-70°C, the drying time is 30-60 minutes, and when the moisture content is not more than 1.0wt%, the material is discharged for use;

[0064] C. Premixing and sieving auxiliary materials: Weigh various auxiliary materials according to the prescription amount, add dried sucrose powder, colloidal silicon dioxide, aspartame (or neotame), microcrystalline cellulose-sodium carboxymethyl cellulose (or colloidal microcrystalline cellulose), flavor, glycine, sodium chloride, sodium benzoate, and pigment to the mixing equipment in sequence, mix for a certain period of time, and pass through an 80-mesh sieve to obtain a sieved premixed powder;

[0065] D. Total mixing of raw materials and auxiliary materials: fully mix cefprozil and the sieved premixed powder obtained in step C according to the prescribed amount, and discharge the mixture to obtain a cefprozil dry suspension.

[0066] In another specific embodiment of the present invention, the preparation method of the cefprozil dry suspension specifically comprises the following steps:

[0067] A. Pretreatment of auxiliary materials: After sucrose is crushed, it is passed through a 60-mesh sieve and set aside; glycine, sodium chloride, and sodium benzoate are passed through a 40-mesh sieve respectively and set aside;

[0068] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 45-70°C, the drying time is 30-60 minutes, and when the moisture content is not more than 1.0wt%, the material is discharged for use;

[0069] C. Premixing and sieving of auxiliary materials: colloidal silicon dioxide, aspartame (or neotame), microcrystalline cellulose-sodium carboxymethyl cellulose (or colloidal microcrystalline cellulose), flavor, glycine, sodium chloride, sodium benzoate, and pigment are weighed according to the prescription amount and added to a mixing device. Dry sucrose powder having the same weight as the total weight of the above auxiliary materials is weighed and added to the mixing device together. After mixing for a certain period of time, the mixture is sieved through an 80-mesh sieve to obtain a sieved premixed powder;

[0070] D. Total mixing of raw and auxiliary materials: fully mix the remaining dry sucrose powder, cefprozil and the sieved premixed powder obtained in step C according to the prescribed amount, and discharge the mixture to obtain the cefprozil dry suspension.

[0071] In a further embodiment, the auxiliary material further comprises anhydrous citric acid accounting for 0.01% to 2.0% by weight in the cefprozil dry suspension.

[0072] Specifically, for the solution in which the auxiliary material includes anhydrous citric acid, in step (1), glycine, sodium chloride, anhydrous citric acid and sodium benzoate are respectively sieved through a 40-mesh sieve, and then the sieved materials are mixed with dried sucrose powder and other auxiliary materials to obtain a premixed powder.

[0073] As a specific embodiment, the preparation method of the cefprozil dry suspension specifically comprises the following steps:

[0074] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0075] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 45-70°C, the drying time is 30-60 minutes, and when the moisture content is not more than 1.0wt%, the material is discharged for use;

[0076] C. Premixing and sieving of auxiliary materials: Weigh various auxiliary materials according to the prescription amount, add dried sucrose powder, colloidal silicon dioxide, aspartame (or neotame), microcrystalline cellulose-sodium carboxymethyl cellulose (or colloidal microcrystalline cellulose), flavor, glycine, sodium chloride, anhydrous citric acid, sodium benzoate, and pigment to the mixing equipment in sequence, mix for a certain period of time, and pass through an 80-mesh sieve to obtain a sieved premixed powder;

[0077] D. Total mixing of raw materials and auxiliary materials: fully mix cefprozil and the sieved premixed powder obtained in step C according to the prescribed amount, and discharge the mixture to obtain a cefprozil dry suspension.

[0078] As another specific embodiment, the preparation method of the cefprozil dry suspension specifically comprises the following steps:

[0079] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0080] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 45-70°C, the drying time is 30-60 minutes, and when the moisture content is not more than 1.0wt%, the material is discharged for use;

[0081] C. Premixing and sieving of auxiliary materials: colloidal silicon dioxide, aspartame (or neotame), microcrystalline cellulose-sodium carboxymethyl cellulose (or colloidal microcrystalline cellulose), flavor, glycine, sodium chloride, anhydrous citric acid, sodium benzoate, and pigment are weighed according to the prescription amount and added to a mixing device, and dry sucrose powder of the same weight as the total weight of the above auxiliary materials is weighed and added to the mixing device together, mixed for a certain period of time, and then sieved through an 80-mesh sieve to obtain a sieved premixed powder;

[0082] D. Total mixing of raw and auxiliary materials: fully mix the remaining dry sucrose powder, cefprozil and the sieved premixed powder obtained in step C according to the prescribed amount, and discharge the mixture to obtain the cefprozil dry suspension.

[0083] The second aspect of the present invention provides a cefprozil dry suspension, which is prepared by the above-mentioned method for preparing the cefprozil dry suspension.

[0084] In the present invention, the cefprozil dry suspension prepared by the above preparation method is subjected to an accelerated test, and the sample has the same trend as the reference preparation, and there is basically no decrease in content. There is no agglomeration phenomenon in the dry suspension, and the content of related substances in the sample is controlled at a very low level, meeting the drug quality requirements.

[0085] After adopting the above technical scheme, the present invention has the following beneficial effects compared with the prior art.

[0086] 1. In the preparation method of the present invention, cefprozil is directly mixed with the premixed powder obtained by mixing with the auxiliary materials without additional crushing or screening, which can effectively control the content of related substances in the prepared dry suspension, ensure the quality of the drug, and improve the stability of the dry suspension.

[0087] 2. In the preparation method of the present invention, cefprozil and auxiliary materials are directly mixed in solid form, the process steps are simple, easy to operate, and conducive to improving production efficiency.

[0088] 3. In the preparation method of the present invention, sucrose is dried, pre-mixed with auxiliary materials, and then sieved, and then further mixed with cefprozil, which can avoid the phenomenon of material agglomeration during the mixing process of raw and auxiliary materials.

[0089] The specific embodiments of the present invention are described in further detail below. DETAILED DESCRIPTION

[0090] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The following embodiments are used to illustrate the present invention but are not used to limit the scope of the present invention.

[0091] Example 1

[0092] In this example, cefprozil dry suspension was prepared according to the prescription shown in Table 1 below.

[0093] Table 1

[0094]

[0095] Specifically, the preparation method of this embodiment includes the following steps:

[0096] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0097] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the water content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0098] C. Premixing and sieving of auxiliary materials: according to the prescription, weigh dry sucrose powder, aspartame, colloidal microcrystalline cellulose, fruit essence, allure red aluminum lake, colloidal silicon dioxide, anhydrous citric acid, glycine, sodium benzoate, and sodium chloride, mix them in a three-dimensional motion mixer for 20 minutes, and then pass through an 80-mesh sieve to obtain the sieved premixed powder for later use;

[0099] D. Total mixing of raw and auxiliary materials: Cefprozil and the premixed powder sieved in step C are added into a three-dimensional motion mixer according to the prescribed amount, and mixed evenly to obtain a cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0100] Comparative Example 1

[0101] This comparative example adopts the same prescription as in Example 1 above, and prepares cefprozil dry suspension according to the following preparation method:

[0102] A. Raw material crushing: Cefprozil raw material (particle size D90 before treatment is 160 μm) is put into a crusher, and the crusher is operated 10 times to crush the cefprozil; the particle size D90 of the crushed cefprozil is 45 μm;

[0103] B. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0104] C. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the moisture content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0105] D. Premixing and sieving of auxiliary materials: according to the prescription, weigh dry sucrose powder, aspartame, colloidal microcrystalline cellulose, fruit flavor, allure red aluminum lake, colloidal silicon dioxide, anhydrous citric acid, glycine, sodium benzoate, and sodium chloride, mix them in a three-dimensional motion mixer for 20 minutes, and then pass through an 80-mesh sieve to obtain the sieved premixed powder for later use;

[0106] E. Total mixing of raw and auxiliary materials: Add the cefprozil crushed in step A and the premixed powder sieved in step C into a three-dimensional motion mixer according to the prescribed amount, mix them evenly, and prepare a cefprozil dry suspension.

[0107] Test Example 1

[0108] This test example conducted a stability test on the cefprozil dry suspension prepared in Example 1 and Comparative Example 1, and the specific test process is as follows:

[0109] The reference preparation, as well as the dry suspension prepared in Example 1 and Comparative Example 1 were respectively packaged with composite membranes and placed under accelerated conditions of 40°C ± 2°C, 75% ± 5% RH for 6 months. Samples were taken for testing in March and June, respectively, and the key stability items were tested and compared with the results of day 0.

[0110] The test results are shown in Table 2 below, where the manufacturer of the reference preparation is Lupin Limited.

[0111] Table 2 Stability test results

[0112]

[0113] From the above test results, it can be seen that the content of related substances in the cefprozil dry suspension prepared in Example 1 is consistent with the change trend of the reference preparation, and is always lower than the reference preparation. In Comparative Example 1, cefprozil was crushed, and the crushed cefprozil was mixed with excipients to prepare a dry suspension. The data at 0 month was basically consistent with that in Example 1, indicating that the crushing process did not directly introduce impurities, but after being placed for a period of time, the content of related substances increased significantly and was higher than the reference preparation. It can be seen that the stability of the dry suspension prepared after cefprozil was crushed was deteriorated.

[0114] The cefprozil dry suspension prepared in Example 1 did not change significantly after an accelerated test for 6 months. However, in Comparative Example 1, cefprozil was crushed and then mixed with auxiliary materials to prepare a dry suspension. After an accelerated test for 6 months, the content of the active ingredient decreased significantly.

[0115] The above test results show that the solution of the present invention does not crush or sieve the cefprozil raw material, which is conducive to the obtained dry suspension having good stability.

[0116] Example 2

[0117] In this example, cefprozil dry suspension was prepared according to the prescription shown in Table 3 below.

[0118] Table 3

[0119]

[0120] Specifically, the preparation method of this embodiment includes the following steps:

[0121] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0122] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the water content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0123] C. Premixing and sieving auxiliary materials: according to the prescription, weigh aspartame, colloidal silicon dioxide, sodium benzoate, allura red aluminum lake, orange flavor, microcrystalline cellulose-sodium carboxymethyl cellulose, glycine, sodium chloride, anhydrous citric acid, and weigh dry sucrose powder equal to the total weight of the above auxiliary materials, mix them together for 20 minutes, and then pass through an 80-mesh sieve to obtain a sieved premixed powder for later use;

[0124] D. Total mixing of raw materials and auxiliary materials: adding the remaining dry sucrose powder, cefprozil, and the premixed powder sieved in step C according to the prescribed amount, mixing evenly, and preparing a cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0125] In step D of the above preparation process, no agglomeration of the materials was observed, and the particle size of the particles in the obtained dry suspension was uniform.

[0126] Comparative Example 2

[0127] This comparative example adopts the same prescription as in Example 2 above, and prepares cefprozil dry suspension according to the following preparation method:

[0128] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass it through a 60-mesh sieve to obtain sucrose powder for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate are respectively passed through a 40-mesh sieve for later use;

[0129] B. Premixing and sieving auxiliary materials: according to the prescription, weigh aspartame, colloidal silicon dioxide, sodium benzoate, allura red aluminum lake, orange flavor, microcrystalline cellulose-sodium carboxymethyl cellulose, glycine, sodium chloride, anhydrous citric acid, and weigh sucrose powder of the same weight as the total weight of the above auxiliary materials, mix them together for 20 minutes, and then pass through an 80-mesh sieve to obtain a sieved premixed powder for later use;

[0130] C. Total mixing of raw and auxiliary materials: adding the remaining sucrose powder, cefprozil, and the premixed powder sieved in step C according to the prescribed amount, mixing evenly, to prepare a cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0131] In the above comparative example, sucrose was not dried, but was crushed and sieved before mixing with other raw materials. During the total mixing of raw materials in step C, the materials showed obvious agglomeration.

[0132] Example 3

[0133] In this example, cefprozil dry suspension was prepared according to the prescription shown in Table 4 below.

[0134] Table 4

[0135]

[0136] Specifically, the preparation method of this embodiment includes the following steps:

[0137] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0138] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the water content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0139] C. Premixing and sieving auxiliary materials: Weigh according to the prescription, add dry sucrose powder, colloidal silicon dioxide, aspartame, microcrystalline cellulose-sodium carboxymethyl cellulose, orange flavor, glycine, sodium chloride, anhydrous citric acid, sodium benzoate, and allure red aluminum lake into a three-dimensional motion mixer in order, mix for 20 minutes, and pass through an 80-mesh sieve to obtain the sieved premixed powder for later use;

[0140] D. Total mixing of raw and auxiliary materials: Cefprozil and the premixed powder sieved in step C are added into a three-dimensional motion mixer according to the prescribed amount, and mixed evenly to obtain a cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0141] In step D of the above preparation process, no agglomeration of the materials was observed, and the particle size of the particles in the obtained dry suspension was uniform.

[0142] Comparative Example 3

[0143] This comparative example adopts the same prescription as in Example 3 above, and prepares cefprozil dry suspension according to the following preparation method:

[0144] A. Pretreatment of auxiliary materials: After pulverizing sucrose, pass through a 60-mesh sieve for later use; glycine, sodium chloride, anhydrous citric acid, and sodium benzoate pass through a 40-mesh sieve for later use;

[0145] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the water content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0146] C. Total mixing of raw and auxiliary materials: Weigh according to the prescription, add cefprozil, dry sucrose powder, colloidal silicon dioxide, aspartame, microcrystalline cellulose-sodium carboxymethyl cellulose, orange flavor, glycine, sodium chloride, anhydrous citric acid, sodium benzoate, and allura red aluminum lake into a three-dimensional motion mixer in order, mix well, and prepare cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0147] In the above comparative example, the auxiliary materials were not pre-mixed and screened, but directly mixed with the raw material drug cefprozil, and a certain amount of agglomerated powders of different shapes existed in the mixed materials.

[0148] Test Example 2

[0149] This test example investigates the influence of the mass proportion of the suspending agent in the cefprozil dry suspension. Specifically, based on the scheme provided in Example 3, only the mass proportion of microcrystalline cellulose-sodium carboxymethyl cellulose was changed, and the missing or excess mass was adapted by adjusting the mass proportion of sucrose to obtain 5 groups of samples shown in the following Table 5.

[0150] Table 5

[0151]

[0152] This test example tests the sedimentation volume ratios of the above 5 groups of samples. The test results are shown in Table 6 below.

[0153] Table 6 Test results of the effect of the mass ratio of suspending agent on dry suspension

[0154]

[0155] According to the above test results, it can be seen that when the amount of microcrystalline cellulose-sodium carboxymethyl cellulose is less than 2.0%, such as only 1.0%, the sedimentation volume ratio of the prepared dry suspension is very low, which does not meet the qualified standard, indicating that its stability after dispersion is poor. Therefore, the scheme of the present invention controls the mass proportion of the suspending agent in the cefprozil dry suspension to 2.0%~15.0%, preferably controlled to 4.0%~13.0%, which is conducive to ensuring that the dry suspension is stably dispersed in the solution. In a more preferred scheme, the mass proportion of the suspending agent is controlled to 13.0%, which can reach a sedimentation ratio of 0.98, and the stability after dispersion is very good.

[0156] Example 4

[0157] Compared with the above-mentioned Example 3, this Example does not add anhydrous citric acid to the auxiliary materials, and the missing mass is supplemented by sucrose. Specifically, this Example prepares cefprozil dry suspension according to the prescription shown in Table 7 below.

[0158] Table 7

[0159]

[0160] Specifically, the preparation method of this embodiment includes the following steps:

[0161] A. Pretreatment of auxiliary materials: After sucrose is crushed, it is passed through a 60-mesh sieve and set aside; glycine, sodium chloride, and sodium benzoate are passed through a 40-mesh sieve respectively and set aside;

[0162] B. Sucrose drying treatment: the sieved sucrose powder is placed in a fluidized bed dryer, the air inlet temperature is set at 60°C, the drying time is 30-60 minutes, and when the water content is not more than 1.0wt%, the material is discharged to obtain dry sucrose powder for standby use;

[0163] C. Premixing and sieving auxiliary materials: Weigh according to the prescription, add dry sucrose powder, colloidal silicon dioxide, aspartame, microcrystalline cellulose-sodium carboxymethyl cellulose, orange flavor, glycine, sodium chloride, sodium benzoate, and allura red aluminum lake into a three-dimensional motion mixer in order, mix for 20 minutes, and then sieve through an 80-mesh sieve to obtain the sieved premixed powder for later use;

[0164] D. Total mixing of raw and auxiliary materials: Cefprozil and the premixed powder sieved in step C are added into a three-dimensional motion mixer according to the prescribed amount, and mixed evenly to obtain a cefprozil dry suspension; wherein the particle size D90 of cefprozil is 160 μm.

[0165] Test Example 3

[0166] This test example investigates the pH stability of the cefprozil dry suspension prepared in Examples 3 and 4 above. The specific method is as follows: According to the acidity item of the cefprozil dry suspension of Part II of the Pharmacopoeia 2020: take an appropriate amount of the content of this product, add water to make a solution containing about cefprozil (according to C 18 H 19 N3O5S) 35mg suspension, determine according to the method, store the solution in the refrigerator, and measure once every 2 days.

[0167] The pH value measurement results of each group of samples at different storage days are shown in the following Table 8.

[0168] Table 8 pH stability test results of cefprozil dry suspension

[0169]

[0170] According to the above test results, it can be seen that adding anhydrous citric acid to the excipients can reduce the acidity of the dry suspension, and the acidity of the dry suspension is stable whether the anhydrous citric acid is present in the prescription or not.

[0171] Test Example 4

[0172] This test example investigates the influence of the mass proportion of flocculant in cefprozil dry suspension. Specifically, based on the scheme provided in Example 4, only the mass proportion of sodium chloride was changed, and the missing or excess mass was adapted by adjusting the mass proportion of sucrose to obtain 8 groups of samples shown in the following Table 9.

[0173] Table 9

[0174]

[0175] This test example tests the sedimentation volume ratios of the above 8 groups of samples. The test results are shown in Table 10 below.

[0176] Table 10 Test results of the effect of flocculant mass ratio on dry suspension

[0177]

[0178] According to the above test results, it can be seen that when the dosage of sodium chloride is high, for example, 2.5%, the sedimentation volume of the prepared dry suspension is relatively low, which does not meet the qualified level, indicating that its stability after dispersion is poor. The scheme of the present invention controls the mass proportion of flocculant in the cefprozil dry suspension to 0%~2.0%, which can achieve a sedimentation volume ratio of not less than 0.90, which is conducive to ensuring the stability of the dry suspension in the solution. In the preferred embodiment of the present invention, the mass proportion of flocculant is controlled at 0%~0.15%, which can achieve a sedimentation volume ratio of not less than 0.99.

[0179] The addition of flocculant sodium chloride can make the dry suspension in a flocculated state after being dissolved in water, thereby increasing stability. Therefore, in a better solution, a small amount of flocculant needs to be added without affecting the dispersibility, and the better quality proportion of the flocculant is controlled at 0.075%~0.15%.

[0180] Test Example 5

[0181] This test example investigates the influence of the mass proportion of antioxidants in the cefprozil dry suspension. Specifically, based on the scheme provided in Example 4, only the mass proportion of glycine was changed, and the missing or excess mass was adapted by adjusting the mass proportion of sucrose to obtain 6 groups of samples shown in the following Table 11.

[0182] Table 11

[0183]

[0184] This test example tests the sedimentation volume ratios of the above 6 groups of samples. The test results are shown in Table 12 below.

[0185] Table 12 Test results of the effect of antioxidant mass ratio on dry suspension

[0186]

[0187] According to the above test results, it can be seen that when the dosage of glycine is high, for example, 2.5%, the sedimentation volume of the prepared dry suspension is relatively low, which does not meet the qualified level, indicating that its stability after dispersion is poor. The scheme of the present invention controls the mass proportion of the antioxidant in the cefprozil dry suspension to 0.01% to 2.0%, which can achieve a sedimentation volume ratio higher than 0.90, which is conducive to ensuring the stability of the dry suspension in the solution.

[0188] The addition of antioxidant glycine can introduce charges, reduce the repulsive force between the charges of the particles, form loose flocculent aggregates, and improve the stability of the preparation. It is necessary to add a small amount of antioxidant without affecting the dispersibility. In the preferred embodiment of the present invention, the mass proportion of the antioxidant is controlled at 0.01% to 1.5%, and a sedimentation volume ratio of not less than 0.96 can be achieved.

[0189] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with the present application can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. A method for preparing a cefprozil dry suspension, characterized in that: The cefprozil dry suspension comprises cefprozil and excipients, and the mass proportion of the cefprozil in the cefprozil dry suspension is 7.5% to 10.0%; Calculated by weight percentage in the cefprozil dry suspension, the excipients include the following components: Sucrose 70%~90%; Suspending agent 2.0%~15.0%; Flocculant 0~2.0%; Antioxidant 0.01%~2.0%; Flavor corrector 0.01%~2.0%; Fragrance 0.01%~2.0%; Colorant 0.01%~2.0%; Flow aid 0.5%~5.0%; Preservatives 0.01%~5.0%; The suspending agent includes microcrystalline cellulose-sodium carboxymethyl cellulose and / or colloidal microcrystalline cellulose; the flocculant includes sodium chloride; the antioxidant includes glycine; The preparation method comprises the following steps: (1) Mixing auxiliary materials: crushing sucrose, sieving, and drying, wherein the moisture content of the sucrose powder after drying is not higher than 1.0 wt %; mixing the dried sucrose powder with other auxiliary materials to obtain a premixed powder, sieving, and setting aside; (2) Preparation of dry suspension: the premixed powder and cefprozil with a particle size D90 of 50 to 160 μm are uniformly mixed to obtain a dry suspension; Alternatively, the preparation method comprises the following steps: (1) Mixing auxiliary materials: crushing sucrose, sieving, and drying. The moisture content of the sucrose powder after drying is not higher than 1.0wt%; mixing part of the dried sucrose powder with other auxiliary materials to obtain a premixed powder, sieving, and setting aside; (2) Preparation of dry suspension: The premixed powder, the remaining dried sucrose powder, and cefprozil with a particle size D90 of 50 to 160 μm are uniformly mixed to obtain a dry suspension.

2. The method for preparing the cefprozil dry suspension according to claim 1, wherein The inlet air temperature for sucrose drying is 45~70℃ and the drying time is 30~60min.

3. The method for preparing the cefprozil dry suspension according to claim 1, characterized in that: One or more of the other auxiliary materials are sieved and then mixed with the dried sucrose powder.

4. The method for preparing the cefprozil dry suspension according to any one of claims 1 to 3, characterized in that: In step (2), a portion of the premixed powder is first added for mixing, and after the mixture is evenly mixed, the remaining premixed powder is added and the mixture is continued to mix.

5. A cefprozil dry suspension, characterized in that: The cefprozil dry suspension is prepared by the preparation method of the cefprozil dry suspension as described in any one of claims 1 to 4.

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