Cefuroxime axetil direct compression granules and preparation process thereof

Abstract

The application discloses a kind of cefuroxime axetil direct compression granules and its preparation process, the preparation process includes the following steps: step (1) preparation of konjac glucomannan-microcrystalline cellulose complex;Step (2) preparation of intermediate;Step (3) preparation of direct compression granules and the like steps.The cefuroxime axetil direct compression granules prepared in the application can effectively mask the bitter taste of cefuroxime axetil, while improving the dissolution and controlling the dissolution rate of cefuroxime axetil drug, thereby improving the bioavailability of cefuroxime axetil drug, etc., and the corresponding preparation process is simple, can save coating step, etc., suitable for large-scale production in industry.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to cefuroxime axetil direct compression granules and a preparation process thereof. Background Art

[0002] Cefuroxime axetil is a second-generation oral cephalosporin. As a prodrug of cefuroxime, it is absorbed by the gastrointestinal tract after oral administration and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood, releasing cefuroxime into the systemic circulation. Cefuroxime axetil exists in both crystalline and amorphous forms and readily forms a gel-like substance upon contact with water. This not only reduces its solubility but also impairs drug absorption, resulting in low bioavailability.

[0003] Furthermore, cefuroxime axetil has an extremely bitter, persistent taste that is difficult to mask with conventional sweeteners or flavorings. While patents have reported using hot-melt coating technology to mask the bitterness and address the problem of hydrogelation, this method suffers from the cumbersome and time-consuming coating process, the inability to completely prevent gelation and bitterness, and the increased impurity content during the coating process. Therefore, the existing technology in this area still needs further improvement and development. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a cefuroxime axetil direct compression granule and a preparation process thereof. The preparation process is simple and can omit the coating step, etc.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] In one aspect, the present application provides a preparation process of cefuroxime axetil direct compression granules, the preparation process comprising the following steps:

[0007] Step (1) Preparation of Konjac Glucomannan-Microcrystalline Cellulose Complex: Konjac Glucomannan is added to water, and after complete dissolution, microcrystalline cellulose is added, stirred until uniform, and then dried to obtain Konjac Glucomannan-Microcrystalline Cellulose Complex;

[0008] Step (2) Preparation of an intermediate: cefuroxime axetil and the konjac glucomannan-microcrystalline cellulose complex are mixed and uniformly stirred, followed by drying to obtain an intermediate;

[0009] Step (3) Preparation of direct compression granules: After uniformly mixing the intermediate, disintegrant, lubricant, solubilizer and glidant, granulation is performed to obtain cefuroxime axetil direct compression granules.

[0010] Furthermore, in step (1), the microcrystalline cellulose includes one or more of microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH301, microcrystalline cellulose PH302, microcrystalline cellulose UF702, microcrystalline cellulose UF711, microcrystalline cellulose KG801, microcrystalline cellulose KG802, and microcrystalline cellulose KG1000;

[0011] Furthermore, the mass ratio of the konjac glucomannan to the microcrystalline cellulose is 1:0.5-5;

[0012] Specifically, the mass ratio of the konjac glucomannan to the microcrystalline cellulose can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, or 1:5;

[0013] Furthermore, the mass ratio of the konjac glucomannan to the water is 1:10-20;

[0014] Specifically, the mass ratio of the konjac glucomannan to the water can be 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20;

[0015] Furthermore, in the step (1), the water content of the konjac glucomannan-microcrystalline cellulose composite is between 5-20 wt%;

[0016] Specifically, the water content of the konjac glucomannan-microcrystalline cellulose composite can be 5wt%, 8wt%, 10wt%, 12wt%, 14wt%, 15wt%, 16wt%, 18wt%, or 20wt%;

[0017] Furthermore, the drying method is to use a freeze dryer for drying, and after drying, the dried product is sieved through a 30-80 mesh screen;

[0018] Specifically, it is processed through a 50-70 mesh sieve;

[0019] Furthermore, in the step (2), the cefuroxime axetil is an ultrafine amorphous cefuroxime axetil powder, the average particle size of which is less than or equal to 20 μm;

[0020] Specifically, the average particle size of the ultrafine amorphous cefuroxime axetil powder of cefuroxime axetil can be 2 μm, 4 μm, 6 μm, 8 μm, 10 μm, 12 μm, 14 μm, 16 μm, 18 μm, or 20 μm;

[0021] Furthermore, the mass ratio of the cefuroxime axetil to the konjac glucomannan-microcrystalline cellulose complex is 1:1-5;

[0022] Specifically, the mass ratio of the cefuroxime axetil to the konjac glucomannan-microcrystalline cellulose complex can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5;

[0023] Further, in the step (2), the drying specifically comprises the following steps: placing the mixture after stirring uniformly in a vacuum drying machine at 30-45°C, and drying until the water content is less than 0.5wt%;

[0024] Further, in the step (3), the disintegrant comprises one or more of microcrystalline cellulose, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl starch;

[0025] Further, the lubricant comprises one or more of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, and talc;

[0026] Further, the solubilizer comprises one or more of sodium dodecyl sulfate, polysorbate 80, polysorbate, polyoxyethylene stearate, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, Tween 80, polyethylene glycol, and poloxamer;

[0027] Further, the flow agent comprises one or more of colloidal silicon dioxide, micro-powder silica gel, talc, fumed silica, and magnesium stearate;

[0028] Further, the mass ratio of the intermediate, the disintegrant, the lubricant, the solubilizer, and the flow agent is 100:40-60:5-15:3-7:3-7; preferably 100:45-55:8-12:4-6:4-6;

[0029] Specifically, the mass ratio of the intermediate, the disintegrant, the lubricant, the solubilizer, and the flow agent can also be 20:10:2:1:1;

[0030] In another aspect, the present application also provides a cefuroxime axetil direct compression granule, characterized in that the cefuroxime axetil direct compression granule is prepared by the preparation process of any one of claims 1-7;

[0031] Alternatively, the raw materials of the cefuroxime axetil direct compression granule comprise cefuroxime axetil, konjac glucomannan-microcrystalline cellulose complex, disintegrant, lubricant, solubilizer, and flow agent;

[0032] Further, the preparation method of the konjac glucomannan-microcrystalline cellulose complex comprises the following steps: taking konjac glucomannan and adding it to water, completely dissolving, adding microcrystalline cellulose, stirring until uniform, and drying to obtain the konjac glucomannan-microcrystalline cellulose complex;

[0033] Furthermore, the mass ratio of the cefuroxime axetil, konjac glucomannan-microcrystalline cellulose complex, disintegrant, lubricant, solubilizer and glidant is 20-40:40-60:40-60:5-15:3-7:3-7.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The present invention realizes efficient coating and functional regulation of cefuroxime axetil by constructing a konjac glucomannan-microcrystalline cellulose porous composite and combining it with a specific water content control strategy, which is specifically manifested as follows: (1) a dense pore structure is formed inside the konjac glucomannan-microcrystalline cellulose composite, which significantly improves the adsorption capacity of cefuroxime axetil powder and reduces drug exposure by physical coating; (2) the water content of the composite after freeze drying is limited to 5-20wt%, which, on the one hand, avoids excessive water from causing drug hydrolysis or by-product generation, thereby ensuring drug purity; on the other hand, within this water content range, Within the range, the composite shrinks due to the moisture gradient during the subsequent dehydration and drying process, forming a dense binding interface with cefuroxime axetil, effectively preventing the coating layer from falling off when mixed with other excipients; (3) By blocking the contact between the drug and the taste receptors through coating, the bitter taste of cefuroxime axetil can be effectively masked, and the pore structure of the composite and the coating layer can regulate the drug dissolution kinetics, delay the release rate and improve bioavailability; (4) The traditional coating process can be abandoned, and the drug coating can be completed directly through the integrated step of composite adsorption-drying, which greatly simplifies the process and reduces production costs, etc., and is suitable for large-scale production. DETAILED DESCRIPTION

[0036] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application. In the description herein, all terms will be understood in their broadest reasonable sense, such as "and / or" should be understood to mean "and / or" and "one or more" should be understood to mean "one or more" unless otherwise indicated. In this application, expressions of the form "at least one of X and Y" when preceding the enumeration of items X and Y, means X and / or Y, i.e. X alone, Y alone, or both X and Y. When following the enumeration of items X and Y, "at least one of X and Y" means at least one X or at least one Y. When preceding the enumeration of items X, Y, and Z, "at least one of X, Y, and Z" means X and / or Y and / or Z, i.e. X alone, Y alone, Z alone, two of X, Y, and Z, all three of X, Y, and Z, etc. When following the enumeration of items X, Y, and Z, "at least one of X, Y, and Z" means at least one X, at least one Y, or at least one Z. When preceding the enumeration of items X, Y, Z, and W, "at least one of X, Y, Z, and W" means X and / or Y and / or Z and / or W, i.e. X alone, Y alone, Z alone, W alone, two of X, Y, Z, and W, three of X, Y, Z, and W, all four of X, Y, Z, and W, etc. When following the enumeration of items X, Y, Z, and W, "at least one of X, Y, Z, and W" means at least one X, at least one Y, at least one Z, or at least one W. It will be further understood that the terms "comprises" and / or "comprising" when used in this application are taken to specify the presence of stated features, integers, steps and / or components but do not preclude the presence or addition of one or more other features, integers, steps, components and / or groups thereof.

[0038] The application will be further described in the following specific examples, which are only part of the application and cannot be used as a limitation of the application.

[0039] Example 1

[0040] The present example provides a cefuroxime axetil direct compression granule and a preparation process thereof, which comprises the following steps:

[0041] (1) Preparation of konjac glucomannan-microcrystalline cellulose complex: 100 g of konjac glucomannan was added to 1.5 L of deionized water, stirred until completely dissolved, then 100 g of microcrystalline cellulose PH102 was added, stirred until uniform, then sent to a freeze dryer for drying, then passed through a 60 mesh sieve to obtain konjac glucomannan-microcrystalline cellulose complex powder with a water content of about 15 wt%;

[0042] (2) Preparation of intermediate: 100 g of ultra-fine amorphous cefuroxime axetil powder (average particle size of 10 μm and uniform particle size distribution) and 200 g of konjac glucomannan-microcrystalline cellulose complex powder were placed in a mixer and stirred at a speed of 30 r / min for 30 min, then the mixture was placed in a 40°C vacuum dryer to dry to a water content of less than 0.5 wt% to obtain an intermediate, i.e. konjac glucomannan-microcrystalline cellulose coated cefuroxime axetil;

[0043] (3) Direct compression granules preparation: 100 g of the intermediate, 50 g of microcrystalline cellulose PH102, 10 g of glyceryl behenate, 5 g of sodium dodecyl sulfate and 5 g of colloidal silicon dioxide are sieved through a 40 mesh sieve, then placed in a mixer and stirred at a speed of 30 r / min for 30 min. After passing the inspection, direct compression granulation is carried out to obtain cefuroxime axetil direct compression granules.

[0044] Example 2

[0045] The present example provides a kind of cefuroxime axetil direct compression granules and its preparation process, the preparation process includes the following steps:

[0046] (1) Preparation of konjac glucomannan-microcrystalline cellulose composite: 100 g of konjac glucomannan is added to 1.5 L of deionized water, stirred until completely dissolved, then 100 g of microcrystalline cellulose PH102 is added, stirred until uniform, then sent into the freeze dryer for drying, then sieved through a 60 mesh sieve, to obtain a konjac glucomannan-microcrystalline cellulose composite powder with a water content of about 15 wt%;

[0047] (2) Preparation of intermediate: 100 g of ultra-fine amorphous cefuroxime axetil powder (average particle size of 10 μm, and uniform particle size distribution) and 100 g of konjac glucomannan-microcrystalline cellulose composite powder are placed in a mixer and stirred at a speed of 30 r / min for 30 min, then the mixture is placed in a vacuum dryer at 40°C to dry to a water content of less than 0.5 wt%, to obtain an intermediate, i.e. konjac glucomannan-microcrystalline cellulose coated cefuroxime axetil;

[0048] (3) Direct compression granules preparation: 100 g of the intermediate, 50 g of microcrystalline cellulose PH102, 10 g of glyceryl behenate, 5 g of sodium dodecyl sulfate and 5 g of colloidal silicon dioxide are sieved through a 40 mesh sieve, then placed in a mixer and stirred at a speed of 30 r / min for 30 min. After passing the inspection, direct compression granulation is carried out to obtain cefuroxime axetil direct compression granules.

[0049] Example 3

[0050] The present example provides a kind of cefuroxime axetil direct compression granules and its preparation process, the preparation process includes the following steps:

[0051] (1) Preparation of konjac glucomannan-microcrystalline cellulose composite: 100 g of konjac glucomannan is added to 1.5 L of deionized water, stirred until completely dissolved, then 100 g of microcrystalline cellulose PH102 is added, stirred until uniform, then sent into the freeze dryer for drying, then sieved through a 60 mesh sieve, to obtain a konjac glucomannan-microcrystalline cellulose composite powder with a water content of about 15 wt%;

[0052] (2) Preparation of intermediate: 100 g of ultrafine amorphous cefuroxime axetil powder (average particle size of 10 μm and uniform particle size distribution) and 150 g of konjac glucomannan-microcrystalline cellulose composite powder were placed in a mixer and stirred at 30 r / min for 30 min. The resulting mixture was then dried in a vacuum dryer at 40° C. until the water content was less than 0.5 wt % to obtain an intermediate, i.e., konjac glucomannan-microcrystalline cellulose-coated cefuroxime axetil;

[0053] (3) Preparation of direct compression granules: 100 g of the intermediate, 50 g of microcrystalline cellulose PH102, 10 g of glyceryl behenate, 5 g of sodium lauryl sulfate and 5 g of colloidal silicon dioxide were passed through a 40-mesh sieve and then placed in a mixer. The mixture was stirred and mixed at a speed of 30 r / min for 30 min. After passing the inspection, the mixture was directly granulated to obtain cefuroxime axetil direct compression granules.

[0054] Comparative Example 1

[0055] Compared with Example 1, the only difference is that: steps (1)-(2) are not performed, but 100 g of konjac glucomannan and 100 g of microcrystalline cellulose PH102 are directly placed in a mixer, stirred and mixed at a speed of 30 r / min for 30 min, and then 100 g of ultrafine amorphous cefuroxime axetil powder (average particle size of 10 μm and uniform particle size distribution) is added, and stirring and mixing is continued at a speed of 30 r / min for 30 min, and then the obtained mixture is placed in a vacuum dryer at 40° C. and dried to a water content of less than 0.5 wt % to obtain an intermediate, and then the intermediate is subjected to step (3).

[0056] Comparative Example 2

[0057] Compared with Example 1, the only difference is that the konjac glucomannan in step (1) is replaced by microcrystalline cellulose PH102 of equal mass.

[0058] Comparative Example 3

[0059] Compared with Example 1, the only difference is that the microcrystalline cellulose PH102 in step (1) is replaced by konjac glucomannan of equal mass.

[0060] Analysis and Testing

[0061] (1) Bitterness test

[0062] The cefuroxime axetil dry suspensions prepared in Examples 1-3 and Comparative Examples 1-3 were respectively administered to 100 healthy volunteers. After taking the suspensions, the taste of the volunteers was recorded. The results are shown in Table 1.

[0063] Table 1 Evaluation results of cefuroxime axetil dry suspension

[0064]

[0065] (2) Dissolution study

[0066] Take 10 tablets of each of Examples 1-3 and Comparative Examples 1-3, and respectively follow the dissolution method (Appendix XC Method 2 of Part II of the 2010 edition of the Chinese Pharmacopoeia) with 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, and operate at a speed of 50 r / min in accordance with the law. Take 5 ml of the solution at 15 and 45 min, respectively (and supplement an equal amount of dissolution medium at the same time), filter, and accurately measure an appropriate amount of the filtrate, quantitatively dilute with the dissolution medium to prepare a solution containing about 15 μg per milliliter, and measure and calculate the dissolution amount of each tablet at different times, i.e., the mass fraction ratio. The results are shown in Table 2.

[0067] Table 2 Dissolution test results

[0068] Time / min Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 15 70.2％ 76.8％ 74.1％ 84.8％ 89.7％ 61.3％ 45 99.2％ 99.9％ 99.4％ 99.9％ 99.9％ 82.6％

[0069] This article uses specific examples to illustrate the principles and implementation methods of this application. The description of the above embodiments is only used to help understand the method of this application and its core ideas. At the same time, for those skilled in the art, according to the ideas of this application, there will be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting this application, and the scope of protection of the present invention should be based on the scope defined by the claims. For those skilled in the art in this field, without departing from the spirit and scope of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the scope of protection of the present invention. Those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A process for preparing cefuroxime axetil direct compression granules, characterized in that: The preparation process comprises the following steps: Step (1) Preparation of Konjac Glucomannan-Microcrystalline Cellulose Complex: Konjac Glucomannan is added to water, and after complete dissolution, microcrystalline cellulose is added, stirred until uniform, and then dried to obtain Konjac Glucomannan-Microcrystalline Cellulose Complex; wherein the mass ratio of the Konjac Glucomannan to the microcrystalline cellulose is 1:0.5-5, and the water content of the Konjac Glucomannan-Microcrystalline Cellulose Complex is between 5wt% and 20wt%; Step (2) Preparation of an intermediate: cefuroxime axetil and the konjac glucomannan-microcrystalline cellulose complex are mixed, stirred evenly, and then dried to obtain an intermediate; wherein the cefuroxime axetil is an ultrafine amorphous cefuroxime axetil powder having an average particle size of less than or equal to 20 μm, and the mass ratio of the cefuroxime axetil to the konjac glucomannan-microcrystalline cellulose complex is 1:1-5; Step (3) Preparation of direct compression granules: The intermediate, disintegrant, lubricant, solubilizer and glidant are uniformly mixed and then granulated to obtain cefuroxime axetil direct compression granules.

2. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In the step (1), the microcrystalline cellulose includes one or more of microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH301, microcrystalline cellulose PH302, microcrystalline cellulose UF702, microcrystalline cellulose UF711, microcrystalline cellulose KG801, microcrystalline cellulose KG802, and microcrystalline cellulose KG1000; And / or, the mass ratio of the konjac glucomannan to the microcrystalline cellulose is 1:0.5-2; And / or, the mass ratio of the konjac glucomannan to the water is 1:10-20.

3. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In the step (1), the water content of the konjac glucomannan-microcrystalline cellulose composite is between 10-20 wt%; And / or, the drying method is to use a freeze dryer for drying, and after drying, the dried product is screened with a 30-80 mesh sieve.

4. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In the step (2), the mass ratio of the cefuroxime axetil to the konjac glucomannan-microcrystalline cellulose complex is 1:1-2.

5. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In step (2), the specific steps of drying are: placing the mixture obtained after uniform stirring in a vacuum dryer at 30-45°C and drying until the water content is less than 0.5wt%.

6. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In step (3), the disintegrant includes one or more of microcrystalline cellulose, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and sodium carboxymethyl starch; And / or, the lubricant includes one or more of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, and talc; And / or, the solubilizer includes one or more of sodium lauryl sulfate, polyoxyethylene stearate, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, Tween 80, polyethylene glycol, and poloxamer; And / or, the glidant includes one or more of colloidal silicon dioxide, talc, fumed silicon dioxide, and magnesium stearate.

7. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In the step (3), the mass ratio of the intermediate, disintegrant, lubricant, solubilizer and glidant is 100:40-60:5-15:3-7:3-7.

8. The preparation process of cefuroxime axetil direct compression granules according to claim 1, characterized in that: In the step (3), the mass ratio of the intermediate, disintegrant, lubricant, solubilizer and glidant is 100:45-55:8-12:4-6:4-6.

9. A cefuroxime axetil direct compression granule, characterized in that: The cefuroxime axetil direct compression granules are prepared by the preparation process according to any one of claims 1 to 8.

10. The cefuroxime axetil direct compression granules according to claim 9, characterized in that The mass ratio of the cefuroxime axetil, konjac glucomannan-microcrystalline cellulose complex, disintegrant, lubricant, solubilizer and glidant is 40-60:40-60:40-60:5-15:3-7:3-7.

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