Cefpodoxime proxetil pharmaceutical composition, dry suspension and preparation method

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a cefpodoxime proxetil pharmaceutical composition, a dry suspension and a preparation method. According to the invention, SWELSTARTM PD-1 is taken as a disintegrating agent, the mass ratio of anhydrous citric acid to sodium glutamate is controlled in a specific proportion range, and a dry method-coating combined process is adopted, so that the stability of the prepared head poxime ester dry suspension is remarkably improved, and the application prospect is wide. The content of impurities A, C + B-II, H-I + H-II and total impurities is obviously slower than that of commercially available products and contrast under the condition of high-temperature storage, and meanwhile, the dissolution level of the prepared head poxime ester dry suspension in media with the pH value of 4.0, water and pH value of 6.8 is also improved, so that the clinical effect of the product is more favorably exerted, and the application prospect of the head poxime ester dry suspension is broad. Therefore, original products can be replaced, and the method has high popularization and application value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a cefpodoxime axetil pharmaceutical composition, a dry suspension and a preparation method thereof. Background Art

[0002] Cefpodoxime Proxetil, English name Cefpodoxime Proxetil, chemical name (6R,7R)-3-methoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-(RS)-1-(isopropoxycarbonyloxy)ethyl ester, molecular formula C 21 H 27 N5O9S2, molecular weight 557.60.

[0003] Cefpodoxime proxetil is a third-generation semi-synthetic cephalosporin antibiotic that is highly sensitive to a variety of Gram-positive and Gram-negative bacteria and has the characteristics of broad spectrum, high efficiency, and long half-life. Cefpodoxime proxetil is a prodrug that is metabolized into the active ingredient cefpodoxime by the action of digestive system enzymes after oral administration, and then absorbed into the blood circulation system to exert systemic antibacterial effects. It is widely used in the treatment of respiratory tract, urinary tract, obstetrics and gynecology infectious diseases and suppurative otitis media.

[0004] Cefpodoxime preparations include granules, coated tablets, dispersible tablets, capsules, dry suspensions and other dosage forms. Dry suspensions have the advantages of solid preparations, such as easy to carry, convenient transportation, good stability, etc., and have the advantages of liquid preparations, such as convenient to take, suitable for patients with difficulty swallowing, such as children, the elderly, etc., and have been widely used in clinical practice. The original manufacturer uses cefpodoxime, fillers, adhesives, flavoring agents, colorants, defoamers, pH regulators and sweeteners to granulate in a fluidized bed, and then mixes the whole granules with flavor lubricants to prepare cefpodoxime dry suspensions. The focus is on how to cover up the bitterness of cefpodoxime, but the stability of cefpodoxime raw materials is poor, and the storage stability of cefpodoxime dry suspensions prepared by this method is poor. Therefore, it is necessary to provide a preparation process that can effectively improve the storage stability of cefpodoxime dry suspensions to improve the drug safety and bioavailability of cefpodoxime. Summary of the invention

[0005] Aiming at the problem that the existing cefpodoxime proxetil dry suspension has poor storage stability, the present invention provides a cefpodoxime proxetil pharmaceutical composition, a dry suspension and a preparation method.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] A cefpodoxime proxetil pharmaceutical composition, comprising a co-crushed cefpodoxime proxetil, a disintegrant, a lubricant, a filler and a coating material;

[0008] The cefpodoxime proxetil co-crushed product comprises cefpodoxime proxetil, anhydrous citric acid and sodium glutamate; the mass ratio of anhydrous citric acid to sodium glutamate in the cefpodoxime proxetil co-crushed product is (0.8-1.2):1; the disintegrant is SWELSTAR TM PD-1.

[0009] The stability of cefpodoxime proxetil API is poor. It gradually undergoes double bond transformation and partial hydrolysis of the side chain under the influence of temperature and humidity. Cefpodoxime proxetil has poor solubility and is a BCS IV class drug with poor solubility and permeability. It easily forms gel or gel-like substances when it comes into contact with water, which reduces its disintegration rate and dissolution rate, and reduces its absorption in the gastrointestinal tract, resulting in low bioavailability. Therefore, how to improve the stability and dissolution rate of cefpodoxime proxetil to improve its bioavailability has become a difficult problem that needs to be solved in the current cefpodoxime proxetil preparations.

[0010] Compared with the prior art, the cefpodoxime proxetil pharmaceutical composition provided by the present invention uses the co-crushed product of cefpodoxime proxetil, anhydrous citric acid and sodium glutamate as raw materials, increases the contact specific surface area of ​​cefpodoxime proxetil and water-soluble excipients, and can improve the dissolution rate of cefpodoxime proxetil in water, acidic medium and alkaline medium; at the same time, by selecting SWELSTAR TM As a disintegrant, PD-1 can effectively increase the disintegration rate of the preparation, thereby increasing the dissolution rate of cefpodoxime proxetil, which is beneficial to improve the bioavailability of cefpodoxime proxetil in the gastrointestinal tract. TM PD-1, as a disintegrant, is also beneficial to improving the stability of cefpodoxime proxetil; and, by controlling the ratio of anhydrous citric acid to sodium glutamate in the co-crushed material to (0.8-1.2):1, the stability of cefpodoxime proxetil is significantly improved.

[0011] It should be noted that the dosage of cefpodoxime proxetil in the present invention is calculated based on the potency of cefpodoxime proxetil.

[0012] Furthermore, the D90 of the cefpodoxime axetil co-crushed product is ≤10 μm.

[0013] The preferred particle size of the cefpodoxime proxetil co-crushed product can increase the dissolution rate of cefpodoxime proxetil in the medium.

[0014] Furthermore, the cefpodoxime proxetil pharmaceutical composition also includes a suspending agent, a flavoring agent, a sweetener, a colorant and a flavor.

[0015] Furthermore, the lubricant is one or more of talc, magnesium stearate or micro-powder silica gel.

[0016] Preferably, the lubricant is talc.

[0017] Furthermore, the suspending agent is one or more of colloidal silicon dioxide, sodium carboxymethyl cellulose or xanthan gum.

[0018] Preferably, the suspending agent is colloidal silicon dioxide.

[0019] Furthermore, the filler is one or more of sucrose, pregelatinized starch, mannitol, lactose, starch, dextrin or glucose.

[0020] Preferably, the filler is sucrose.

[0021] Furthermore, the flavoring agent includes a first flavoring agent and a second flavoring agent, wherein the first flavoring agent includes one or more of lactose, sucralose, sucrose, aspartame, maltose, fructose, sodium glutamate, sodium citrate or amino acids, and the second flavoring agent is sodium chloride.

[0022] Preferably, the first flavoring agent is lactose and sodium chloride.

[0023] Specifically, the mass ratio of lactose to sodium chloride is (10-20):(4-6).

[0024] Furthermore, the sweetener is aspartame.

[0025] Furthermore, the colorant is red iron oxide.

[0026] Furthermore, the flavor is strawberry powder flavor.

[0027] The sweeteners, colorants and flavors described in the present invention may also be other sweeteners, colorants and flavors commonly used in the pharmaceutical field, such as acesulfame potassium, yellow pigment, orange flavor, etc., and the present invention does not make any special limitation.

[0028] Furthermore, the coating material includes sucrose, hydroxypropyl cellulose and water.

[0029] Furthermore, each gram of cefpodoxime proxetil pharmaceutical composition includes the following components by mass: 50 mg of cefpodoxime proxetil, 4 mg to 6 mg of anhydrous citric acid, 4 mg to 6 mg of sodium glutamate, 25 mg to 35 mg of disintegrant, 1 mg to 2 mg of lubricant, 10 mg to 15 mg of suspending agent, 680 mg to 720 mg of filler, 14 mg to 26 mg of flavoring agent, 0.2 mg to 1 mg of colorant, 1 mg to 2 mg of flavor, and 315 mg to 415 mg of coating material.

[0030] Specifically, the coating material includes 120 mg to 130 mg of sucrose, 6 mg to 10 mg of hydroxypropyl cellulose and 225 mg to 275 mg of water.

[0031] In a second aspect, the present invention provides a cefpodoxime proxetil dry suspension prepared from any of the above-mentioned cefpodoxime proxetil pharmaceutical compositions.

[0032] Furthermore, each gram of cefpodoxime proxetil dry suspension includes the following components by weight: cefpodoxime proxetil 50 mg, anhydrous citric acid 4 mg to 6 mg, sodium glutamate 4 mg to 6 mg, SWELSTAR TM PD-125mg~35mg, sucrose 680mg~720mg, lactose 10mg~20mg, aspartame 15mg~25mg, sodium chloride 4mg~6mg, colloidal silicon dioxide 10mg~15mg, red iron oxide 0.2mg~1mg, talc 1mg~2mg, strawberry flavor 1mg~2mg, coating material 315mg~415mg.

[0033] Specifically, the coating material includes 120 mg to 130 mg of sucrose, 6 mg to 10 mg of hydroxypropyl cellulose and 225 mg to 275 mg of water.

[0034] Preferably, cefpodoxime proxetil 50 mg, anhydrous citric acid 5 mg, sodium glutamate 5 mg, SWELSTAR TM PD-1 30mg, sucrose 700mg, lactose 15mg, aspartame 20mg, sodium chloride 5mg, colloidal silicon dioxide 10mg, red iron oxide 0.2mg, talc 1mg, strawberry flavor 1mg, coating material 324mg.

[0035] Specifically, the coating material includes 128 mg of sucrose, 8 mg of hydroxypropyl cellulose and 250 mg of water.

[0036] In a third aspect, the present invention also provides a method for preparing a cefpodoxime axetil dry suspension, comprising the following steps:

[0037] S1, mixing cefpodoxime proxetil, anhydrous citric acid and sodium glutamate uniformly, and crushing to obtain a co-crushed product of cefpodoxime proxetil;

[0038] Grind sucrose and sodium chloride separately to obtain sucrose powder and sodium chloride powder;

[0039] S2, the cefpodoxime axetil co-grinded product, SWELSTAR TM PD-1, sucrose powder, sodium chloride powder, lactose, aspartame, colloidal silicon dioxide and red iron oxide are uniformly mixed, dry granulated, sieved to obtain granules;

[0040] S3, coating the particles with a coating material, and sieving to obtain coated particles;

[0041] S4, mixing the coated granules, essence and talcum powder evenly to obtain cefpodoxime proxetil dry suspension.

[0042] The preparation method of the cefpodoxime proxetil dry suspension provided by the invention comprises the following steps: cefpodoxime proxetil, anhydrous citric acid and sodium glutamate are co-crushed, and then auxiliary materials other than essence and talcum powder are added for dry granulation, so that the influence of the preparation process on the stability of cefpodoxime proxetil is effectively reduced; at the same time, cefpodoxime proxetil, anhydrous citric acid and sodium glutamate in a specific ratio are co-crushed, so that the contact specific surface area between the active component and the water-soluble auxiliary materials is increased, so that the prepared cefpodoxime proxetil dry suspension can be quickly dissolved in an acidic medium, water and an alkaline medium, and the dissolution amount in water and an alkaline medium is better than that of a reference preparation, thereby improving the bioavailability of cefpodoxime proxetil in the gastrointestinal tract. Furthermore, by adding coating materials to coat the granules after dry granulation, the hydrophilicity of the granules can be effectively improved to prevent the granules from floating on the water surface and affecting dissolution. The coating layer covers the co-crushed granules and isolates them from the outside air. While reducing the oxidative degradation of cefpodoxime proxetil, it also reduces the bitterness of cefpodoxime proxetil and improves palatability, which is beneficial to improving clinical medication compliance and can achieve a good replacement for the original product.

[0043] Furthermore, in S1, sucrose and sodium chloride are crushed separately and passed through an 80-mesh sieve to obtain sucrose powder and sodium chloride powder.

[0044] Furthermore, in S2, the process parameters of the dry granulation are: roller pressure is 0.08mPa~0.12mPa, feeding speed is 100rpm~200rpm, roller speed is 2rpm~4rpm, primary granulation speed is 140rpm~160rpm, and secondary granulation speed is 140rpm~160rpm.

[0045] Furthermore, in S2, after dry granulation, the process further comprises: passing the granulated material through a sieve with an aperture of 0.4 mm to 0.6 mm for dry granulation, sieving the granulated material to obtain particles between 40 mesh and 100 mesh, and performing secondary granulation on the fine powder below 100 mesh.

[0046] Furthermore, in S3, a fluidized bed is used for coating, and the fluidized bed adopts a bottom spraying process, the inlet air temperature is 65℃~75℃, and the air volume is 60m 3 / h~70m 3 / h, the atomization pressure is 0.25bar~0.35bar, and the peristaltic pump speed is 4rpm~5rpm.

[0047] It should be noted that after coating, the particles are sieved with a 40-mesh sieve, and particles smaller than 40 mesh are taken. Essence and talcum powder are added, mixed, and sampled for testing to obtain a cefpodoxime proxetil dry suspension.

[0048] The invention prepares a cefpodoxime proxetil dry suspension by dry granulation, and the prepared cefpodoxime proxetil dry suspension has a faster disintegration speed and dissolution rate, and compared with a reference preparation, the solubility in water and in pH 4.0 and pH 6.8 media is improved to a certain extent, which is helpful to improve the absorption and utilization of the product, and at the same time, the quality of the cefpodoxime proxetil dry suspension is significantly improved, the storage stability is significantly improved, and a good replacement for the original research product can be achieved, and the preparation process is simple, the repeatability is good, and large-scale industrial production is easy to achieve. DETAILED DESCRIPTION

[0049] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0050] In order to better illustrate the present invention, further examples are given below.

[0051] Example 1

[0052] This embodiment provides a cefpodoxime proxetil dry suspension, and the prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0053]

[0054]

[0055] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is as follows:

[0056] Step 1: Grind sucrose (filler) and sodium chloride separately, and pass through an 80-mesh sieve to obtain sucrose powder and sodium chloride powder;

[0057] Putting cefpodoxime proxetil, anhydrous citric acid and sodium glutamate into a high-speed grinder and grinding them for 50 seconds to obtain a cefpodoxime proxetil co-grinded product with a D90 of ≤10 μm;

[0058] Step 2: The cefpodoxime axetil co-grinded product and SWELSTAR TMPD-1, sucrose powder (filler), sodium chloride powder, lactose, aspartame, colloidal silicon dioxide and red iron oxide were placed in a three-dimensional mixer and mixed for 30 minutes, and then placed in a dry granulator, and the process parameters were set as follows: roller pressure was 0.10 mPa, feeding speed was 150 rpm, roller speed was 3 rpm, primary granulation speed was 150 rpm, and secondary granulation speed was 150 rpm; the obtained granules were granulated through a sieve with an aperture of 0.5 mm, and granules between 40 mesh and 100 mesh were sieved, and fine powder below 100 mesh was subjected to secondary granulation;

[0059] Step 3, adding sucrose (coating) and hypromellose to water, mixing evenly to obtain a coating solution;

[0060] Step 4: Add the 40-100 mesh particles and coating liquid into the fluidized bed for coating. The fluidized bed adopts the bottom spraying process, the inlet air temperature is 70℃, and the air volume is 65m 3 / h, atomization pressure is 0.30bar, and the peristaltic pump speed is 4.5rpm;

[0061] Step 5: The coated particles are sieved with a 40-mesh screen, particles smaller than 40 mesh are taken, strawberry essence and talcum powder are added, and the particles are mixed in a three-dimensional mixer for 15 minutes. Samples are taken for testing, and the particles are packaged to obtain a cefpodoxime proxetil dry suspension, with 1 g of sample in each bag.

[0062] Example 2

[0063] This embodiment provides a cefpodoxime proxetil dry suspension, and the prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0064]

[0065]

[0066] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is as follows:

[0067] Step 1: Grind sucrose (filler) and sodium chloride separately, and pass through an 80-mesh sieve to obtain sucrose powder and sodium chloride powder;

[0068] Putting cefpodoxime proxetil, anhydrous citric acid and sodium glutamate into a high-speed grinder and grinding them for 50 seconds to obtain a cefpodoxime proxetil co-grinded product with a D90 of ≤10 μm;

[0069] Step 2: The cefpodoxime axetil co-grinded product and SWELSTAR TMPD-1, sucrose powder (filler), sodium chloride powder, lactose, aspartame, colloidal silicon dioxide and red iron oxide were placed in a three-dimensional mixer and mixed for 30 minutes, and then placed in a dry granulator, and the process parameters were set as follows: roller pressure was 0.10 mPa, feeding speed was 150 rpm, roller speed was 3 rpm, primary granulation speed was 150 rpm, and secondary granulation speed was 150 rpm; the obtained granules were granulated through a sieve with an aperture of 0.5 mm, and granules between 40 mesh and 100 mesh were sieved, and fine powder below 100 mesh was subjected to secondary granulation;

[0070] Step 3, adding sucrose (coating) and hypromellose to water, mixing evenly to obtain a coating solution;

[0071] Step 4: Add the 40-100 mesh particles and coating liquid into the fluidized bed for coating. The fluidized bed adopts the bottom spraying process, the inlet air temperature is 70℃, and the air volume is 65m 3 / h, atomization pressure is 0.30bar, and the peristaltic pump speed is 4.5rpm;

[0072] Step 5: The coated particles are sieved with a 40-mesh screen, particles smaller than 40 mesh are taken, strawberry essence and talcum powder are added, and the particles are mixed in a three-dimensional mixer for 15 minutes. Samples are taken for testing, and the particles are packaged to obtain a cefpodoxime proxetil dry suspension, with 1 g of sample in each bag.

[0073] Example 3

[0074] This embodiment provides a cefpodoxime proxetil dry suspension, and the prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0075]

[0076]

[0077] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is as follows:

[0078] Step 1: Grind sucrose (filler) and sodium chloride separately, and pass through an 80-mesh sieve to obtain sucrose powder and sodium chloride powder;

[0079] Putting cefpodoxime proxetil, anhydrous citric acid and sodium glutamate into a high-speed grinder and grinding them for 50 seconds to obtain a cefpodoxime proxetil co-grinded product with a D90 of ≤10 μm;

[0080] Step 2: The cefpodoxime axetil co-grinded product and SWELSTAR TMPD-1, sucrose powder (filler), sodium chloride powder, lactose, aspartame, colloidal silicon dioxide and red iron oxide were placed in a three-dimensional mixer and mixed for 30 minutes, and then placed in a dry granulator, and the process parameters were set as follows: roller pressure was 0.10 mPa, feeding speed was 150 rpm, roller speed was 3 rpm, primary granulation speed was 150 rpm, and secondary granulation speed was 150 rpm; the obtained granules were granulated through a sieve with an aperture of 0.5 mm, and granules between 40 mesh and 100 mesh were sieved, and fine powder below 100 mesh was subjected to secondary granulation;

[0081] Step 3, adding sucrose (coating) and hypromellose to water, mixing evenly to obtain a coating solution;

[0082] Step 4: Add the 40-100 mesh particles and coating liquid into the fluidized bed for coating. The fluidized bed adopts the bottom spraying process, the inlet air temperature is 70℃, and the air volume is 65m 3 / h, atomization pressure is 0.30bar, and the peristaltic pump speed is 4.5rpm;

[0083] Step 5: The coated particles are sieved with a 40-mesh screen, particles smaller than 40 mesh are taken, strawberry essence and talcum powder are added, and the particles are mixed in a three-dimensional mixer for 15 minutes. Samples are taken for testing, and the particles are packaged to obtain a cefpodoxime proxetil dry suspension, with 1 g of sample in each bag.

[0084] Comparative Example 1

[0085] This comparative example provides a cefpodoxime proxetil dry suspension, the prescription (500 bags of dosage, 500g) is as follows:

[0086] Components Mass / g Cefpodoxime Proxetil(Potency) 25 Citric Acid 1 Sodium Citrate 0.2 Croscarmellose Sodium 21 Sucrose (bulking agent) 163.9 Aspartame 8 Colloidal Silica 1.5 Hydroxypropylcellulose 19 Magnesium Stearate 1.5 essence 0.5

[0087] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is as follows:

[0088] (1) Pretreatment of raw materials and auxiliary materials:

[0089] Sucrose is crushed and passed through a 60-mesh sieve, cross-linked sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, aspartame, magnesium stearate, flavor, citric acid, and sodium citrate are mixed and passed through a 60-mesh sieve, and silicon dioxide is passed through a 120-mesh sieve for later use; cefpodoxime axetil raw material and 2 times the amount of crushed sucrose are mixed, passed through a 60-mesh sieve, and set aside;

[0090] (2) Mixing:

[0091] Add the mixture of cefpodoxime proxetil and sucrose obtained in step (1), together with the remaining sucrose, croscarmellose sodium, hydroxypropyl methylcellulose, citric acid, sodium citrate, aspartame, magnesium stearate, silicon dioxide and flavor to a wet granulator for mixing;

[0092] (3) Granulation:

[0093] Add the uniformly mixed cefpodoxime proxetil and excipients into a dry granulator, with a pressure of 80 bar, a roller speed of 10 rpm, a feeding speed of 40 rpm, and granulate through a 1.5 mm sieve, control the granulation speed at 100 rpm, sieve out particles between 12 and 60 meshes, and granulate the fine powder below 60 meshes for the second time according to the above method;

[0094] (4) Total mixing:

[0095] Add the 12-mesh to 60-mesh granules after the second granulation in step (3) into a three-dimensional motion mixer and mix for 5 minutes to check the moisture, solubility, content, and particle size, calculate the filling amount, and then package the granules, with 1g of sample in each bag.

[0096] Comparative Example 2

[0097] This comparative example provides a cefpodoxime proxetil dry suspension, the prescription (500 bags of dosage, 500g) is as follows:

[0098]

[0099]

[0100] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is as follows:

[0101] 1) Take sucrose, citric acid and sodium glutamate, grind them, pass them through a 60-mesh sieve and set aside; weigh other auxiliary materials and set aside;

[0102] 2) Prepare a 75% ethanol solution with a hydroxypropyl cellulose concentration of 1.5%, stir until dissolved, and use for coating;

[0103] 3) Sucrose coating: Add the prescribed amount of sucrose into the fluidized bed and coat it with hydroxypropylcellulose ethanol solution; set the inlet air temperature to 40°C and the inlet air volume to 30m 3 / h, atomization pressure 2.0MPa, liquid supply speed 5r / min, sucrose coating. After coating, fluidized bed drying until the moisture content is below 3.0%, take out for use.

[0104] 4) Wet granulation: Cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate, and yellow ferric oxide were added to a wet granulator, and the stirring was set at 180 rpm and the shearing was set at 120 rpm for wet granulation; the wet granules were dried to <3.0%.

[0105] 5) Total mixing: Add silicon dioxide, talcum powder and banana essence to the dry granules for total mixing to obtain cefpodoxime proxetil granules, with 1 g sample in each bag.

[0106] Comparative Example 3

[0107] This comparative example provides a cefpodoxime proxetil dry suspension, which is different from the embodiment only in that the mass ratio of anhydrous citric acid to sodium glutamate is 1:2, and the rest is exactly the same. The specific prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0108]

[0109]

[0110] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is exactly the same as that in Example 1, and will not be repeated here.

[0111] Comparative Example 4

[0112] This comparative example provides a cefpodoxime proxetil dry suspension, which is different from Example 1 only in that the mass ratio of anhydrous citric acid to sodium glutamate is 2:1, and the rest is exactly the same. The specific prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0113]

[0114]

[0115] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is exactly the same as that in Example 1, and will not be repeated here.

[0116] Comparative Example 5

[0117] This comparative example provides a cefpodoxime proxetil dry suspension, which is different from Example 1 only in that the disintegrant is cross-linked carboxymethyl cellulose sodium, and the rest is exactly the same. The specific prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0118]

[0119]

[0120] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is exactly the same as that in Example 1, and will not be repeated here.

[0121] Comparative Example 6

[0122] This comparative example provides a cefpodoxime proxetil dry suspension, which is different from Example 1 only in that the disintegrant is carboxymethylcellulose calcium, and the rest is exactly the same. The prescription dosage (500 bags of dosage, 500g) is shown in the following table:

[0123]

[0124]

[0125] The preparation method of the above-mentioned cefpodoxime proxetil dry suspension is exactly the same as that in Example 1, and will not be repeated here.

[0126] Quality Research

[0127] 1. Related characteristics detection

[0128] Examples 1 to 3, Comparative Examples 1 to 2, and commercially available products were quality tested with reference to the quality standards of the Chinese Pharmacopoeia 2020 edition, Part II, Cefpodoxime Proxetil Dry Suspension, and the results are shown in Table 1.

[0129] Table 1

[0130]

[0131]

[0132] Note: The solubility in the table refers to the solubility at pH 3.0 and 45 min, which is the second method of Pharmacopoeia General Chapter 0931.

[0133] The manufacturer of Commercial Product 1 is Daiichi Sankyo, and its trade name is BANAN; the manufacturer of Commercial Product 2 is Hainan Sanye Meihao, and its trade name is Chun Di. The subsequent Commercial Product 1 and Commercial Product 2 refer to these two products.

[0134] The results show that the cefpodoxime proxetil dry suspension prepared in the embodiment of the present invention has lower impurity content, better content uniformity, and slightly higher solubility than the commercially available product and Comparative Examples 1 to 2.

[0135] 2. Dissolution curve

[0136] According to the guidance method of the 2020 edition of the Chinese Pharmacopoeia, the solubility of Examples 1 to 3, Comparative Examples 1 to 2, and commercially available products in pH 1.2 hydrochloric acid solution, pH 4.0 acetate buffer, water, and pH 6.8 phosphate buffer was tested. The medium volume was 900 mL and the rotation speed was 75 rpm. The dissolution curve test results are shown in Tables 2 to 5.

[0137] Table 2 Dissolution curve in hydrochloric acid medium at pH 1.2

[0138]

[0139]

[0140] Table 3 Dissolution curve in pH 4.0 acetate medium

[0141]

[0142] Table 4 Dissolution curve in water

[0143]

[0144] Table 5 Dissolution curve in pH 6.8 phosphate buffer

[0145]

[0146]

[0147] As a result, the cefpodoxime axetil dry suspension prepared in the embodiment of the present invention can be rapidly dissolved in different dissolution media compared with the commercially available products and the comparative examples, which is beneficial to improve the bioavailability of the preparation and ensure the efficacy. The dissolution of commercial product 1 in aqueous medium is relatively low, and the dissolution of commercial product 2 in pH 1.2 hydrochloric acid medium is relatively low. Comparative Examples 1 and 2 have relatively low dissolution in the other three media except for the higher dissolution in pH 1.2 hydrochloric acid medium.

[0148] 3. Stability test

[0149] Examples 1 to 3, Comparative Examples 1 to 2 and commercially available products were exposed at a high temperature of 60° C. for 10 days and 30 days, and samples were taken to detect the impurities in the cefpodoxime proxetil dry suspension. The results are shown in Table 6.

[0150] Table 6

[0151]

[0152]

[0153] As a result, the cefpodoxime proxetil dry suspension prepared in the embodiment of the present invention has better stability than the commercial product and comparative examples 1 to 2. When placed at 60°C for 30 days, the related substances are significantly lower than the commercial product and comparative examples 1 to 2. Compared with commercial product 1 and commercial product 2 comparative examples 1 to 2 at a high temperature of 60 degrees Celsius, the cefpodoxime proxetil dry suspension prepared in the embodiment of the present invention shows a lower trend in the growth of single impurities and total impurities, proving that the cefpodoxime proxetil dry suspension prepared in the embodiment of the present invention has a greater stability advantage under high temperature environment.

[0154] The cefpodoxime proxetil dry suspension prepared in Example 1 and Comparative Examples 3 to 6 was exposed at a high temperature of 60° C. for 10 days and 30 days, and samples were taken to detect the content and impurities in the cefpodoxime proxetil dry suspension. The results are shown in Table 7.

[0155] Table 7

[0156]

[0157] The results showed that when the mass ratio of citric acid to sodium glutamate was 1:1, the stability of the prepared cefpodoxime axetil dry suspension was optimal. TMPD-1 as a disintegrant has lower hygroscopicity and water retention than cross-linked sodium carboxymethyl cellulose or calcium carboxymethyl cellulose, making the storage stability of cefpodoxime proxetil dry suspension higher.

[0158] 4. Medication compliance

[0159] In order to investigate the clinical medication compliance of the cefpodoxime proxetil dry suspension prepared in the examples of the present invention, we gave Examples 1 to 3, commercially available products and Comparative Examples 1 to 2 to 10 healthy volunteers respectively, and recorded the taste of the subjects after taking them, and scored according to the following standards:

[0160] Criteria for evaluating bitterness:

[0161] 0: no bitterness;

[0162] 1: Almost no bitterness, you need to feel it carefully to find the bitterness;

[0163] 2: Very light bitterness;

[0164] 3: Bitter, but not very bitter;

[0165] 4: Very bitter.

[0166] The evaluation results are shown in Table 8.

[0167] Table 8 Bitterness evaluation results

[0168] index Commercially available product 1 Commercially available product 2 Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 bitterness 1 2 1 1 1 2 2

[0169] In summary, the present invention is based on SWELSTAR TM PD-1 is used as a disintegrant, and the mass ratio of anhydrous citric acid to sodium glutamate is controlled within a specific ratio range. A dry method-coating combined process is adopted, so that the stability of the prepared head poxime ester dry suspension is significantly improved, which is manifested in that the growth of impurities A, impurity C+impurity B-II, impurity H-I+impurity H-II and total impurities under high-temperature storage conditions is significantly slower than that of commercially available products and comparative examples. At the same time, the dissolution level of the prepared head poxime ester dry suspension in pH 4.0, water and pH 6.8 media is also improved, which is more conducive to the clinical effect of the product, thereby being able to replace the original research product; in addition, the head poxime ester dry suspension prepared by the present invention has good medication compliance, and the preparation production process is simple, easy to realize large-scale industrial production, and has high promotion and application value.

[0170] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A cefpodoxime proxetil pharmaceutical composition, characterized in that: It includes cefpodoxime proxetil co-crushed material, disintegrant, lubricant, filler and coating material; The cefpodoxime proxetil co-crushed product comprises cefpodoxime proxetil, anhydrous citric acid and sodium glutamate; the mass ratio of anhydrous citric acid to sodium glutamate in the cefpodoxime proxetil co-crushed product is (0.8-1.2):1; the disintegrant is SWELSTAR TM PD-1.

2. The cefpodoxime proxetil pharmaceutical composition according to claim 1, characterized in that: The cefpodoxime proxetil pharmaceutical composition further comprises a suspending agent, a flavoring agent, a sweetener, a colorant and an essence.

3. The cefpodoxime proxetil pharmaceutical composition according to claim 1, characterized in that: The lubricant is one or more of talc, magnesium stearate or micro-powder silica gel; and / or The filler is one or more of sucrose, pregelatinized starch, mannitol, lactose, starch, dextrin or glucose; and / or The coating material includes sucrose, hydroxypropylcellulose and water.

4. The cefpodoxime proxetil pharmaceutical composition according to claim 2, characterized in that: The suspending agent is one or more of colloidal silicon dioxide, sodium carboxymethyl cellulose or xanthan gum.

5. The cefpodoxime proxetil pharmaceutical composition according to claim 2, characterized in that: The flavoring agent includes a first flavoring agent and a second flavoring agent, wherein the first flavoring agent includes one or more of lactose, sucralose, sucrose, aspartame, maltose, fructose, sodium glutamate, sodium citrate or amino acids, and the second flavoring agent is sodium chloride; and / or The sweetener is aspartame; and / or The colorant is red iron oxide; and / or The flavor is strawberry powder flavor.

6. The cefpodoxime proxetil pharmaceutical composition according to any one of claims 1 to 5, characterized in that: Each gram of cefpodoxime proxetil pharmaceutical composition includes the following components by mass: 50 mg of cefpodoxime proxetil, 4 mg to 6 mg of anhydrous citric acid, 4 mg to 6 mg of sodium glutamate, 25 mg to 35 mg of disintegrant, 1 mg to 2 mg of lubricant, 10 mg to 15 mg of suspending agent, 680 mg to 720 mg of filler, 14 mg to 26 mg of flavoring agent, 0.2 mg to 1 mg of colorant, 1 mg to 2 mg of flavor, and 315 mg to 415 mg of coating material.

7. A cefpodoxime proxetil dry suspension, characterized in that: The composition is prepared from the cefpodoxime proxetil pharmaceutical composition according to any one of claims 1 to 6.

8. The cefpodoxime proxetil dry suspension according to claim 7, characterized in that Each gram of cefpodoxime proxetil dry suspension contains the following components: cefpodoxime proxetil 50 mg, anhydrous citric acid 4 mg to 6 mg, sodium glutamate 4 mg to 6 mg, SWELSTAR TM PD-1 25mg~35mg, sucrose 680mg~720mg, lactose 10mg~20mg, aspartame 15mg~25mg, sodium chloride 4mg~6mg, colloidal silicon dioxide 10mg~15mg, red iron oxide 0.2mg~1mg, talc 1mg~2mg, strawberry flavor 1mg~2mg, coating material 315mg~415mg.

9. The cefpodoxime proxetil dry suspension according to claim 8, characterized in that Cefpodoxime Proxetil 50mg, Anhydrous Citric Acid 5mg, Sodium Glutamate 5mg, SWELSTAR TM PD-1 30mg, sucrose 700mg, lactose 15mg, aspartame 20mg, sodium chloride 5mg, colloidal silicon dioxide 10mg, red iron oxide 0.2mg, talc 1mg, strawberry flavor 1mg, coating material 324mg.

10. A method for preparing the cefpodoxime proxetil dry suspension according to claim 8 or 9, characterized in that: The steps include: S1, mixing cefpodoxime proxetil, anhydrous citric acid and sodium glutamate uniformly, and crushing to obtain a co-crushed product of cefpodoxime proxetil; Grind sucrose and sodium chloride separately to obtain sucrose powder and sodium chloride powder; S2, the cefpodoxime axetil co-grinded product, SWELSTAR TM PD-1, sucrose powder, sodium chloride powder, lactose, aspartame, colloidal silicon dioxide and red iron oxide are uniformly mixed, dry granulated, and sieved to obtain granules; S3, coating the particles with a coating material, and sieving to obtain coated particles; S4, mixing the coated granules, essence and talcum powder evenly to obtain cefpodoxime proxetil dry suspension.

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