Combined auxiliary material applied to cefdinir preparation as well as preparation method and application of combined auxiliary material

Abstract

The invention relates to the field of medicines, and particularly discloses a combined auxiliary material applied to a cefdinir preparation as well as a preparation method and application of the combined auxiliary material. The combined auxiliary material applied to the cefdinir preparation is prepared from the following raw materials in parts by weight: 1 to 3 parts of polyoxyl 40 stearate, 50 to 150 parts of microcrystalline cellulose, 0.03 to 0.05 part of colloidal silicon dioxide, 1 to 3 parts of 2-hydroxyethyl methacrylate, 3 to 5 parts of lactose and 0.5 to 0.8 part of medicinal adhesive. According to the invention, excessive microcrystalline cellulose is compounded with a small amount of polyoxyl 40 stearate, lactose and colloidal silicon dioxide, so that the dispersibility of polyoxyl 40 stearate in the combined auxiliary material is enhanced, the phenomenon of sticking caused by too high concentration of polyoxyl 40 stearate in a pharmaceutical preparation is reduced, and the dissolution rate of the medicine is improved.

Description

Technical Field

[0001] The present application relates to the field of medicine, and in particular to a combination of excipients used in cefdinir preparations, a preparation method thereof, and an application thereof. Background Art

[0002] Cefdinir can be used to treat tonsillitis, sinusitis, otitis media, acute bronchitis, pneumonia, abdominal cavity, urogenital tract infection, etc. Since its launch, it has been widely used in the clinic for infections caused by sensitive bacteria in internal medicine, surgery, dermatology, obstetrics and gynecology, urology, etc. Clinical studies have shown that the efficacy of cefdinir can reach 82%, and the incidence of side effects is 3%. It is an efficient, safe and convenient cephalosporin oral antibacterial drug. The raw material of cefdinir is a slightly yellow powder with poor water solubility, easy to generate static electricity, poor fluidity, and unstable under wet, light and heat conditions, which affects the safety and effectiveness of the drug.

[0003] The excipients and processes of traditional oral solid preparations cannot solve the problem of low solubility of poorly soluble raw materials, and the process is complicated, time-consuming, energy-consuming and labor-intensive when preparing in large quantities. Currently, polyoxyl 40 stearate is used in original preparations on the market to improve solubility and bioavailability, but the commonly used pharmaceutical excipients are used in small amounts, but the proportion of polyoxyl 40 stearate is too high, and polyoxyl 40 stearate is a waxy solid with a melting point of 46-51°C. On the one hand, it is easy to block the screen when passing through a 60-mesh sieve, and on the other hand, it is easy to stick to the prescription due to its high content, making it difficult to industrialize. Summary of the invention

[0004] In order to improve the dissolution rate of a cefdinir preparation, the present application provides a combination of excipients used in a cefdinir preparation, a preparation method thereof, and an application thereof.

[0005] In the first aspect, the present application provides a combination of excipients used in cefdinir preparations, using the following technical solution: A combined auxiliary material used in a cefdinir preparation comprises the following raw materials in parts by weight: 1-3 parts of polyoxyl 40 stearate, 50-150 parts of microcrystalline cellulose, 0.03-0.05 parts of colloidal silicon dioxide, 1-3 parts of 2-hydroxyethyl methacrylate, 3-5 parts of lactose, and 0.5-0.8 parts of a pharmaceutical adhesive.

[0006] By adopting the above technical scheme, an excess of microcrystalline cellulose is compounded with a small amount of polyoxyl 40 stearate, the proportion of polyoxyl 40 stearate is reduced, and the good adsorption and dispersibility of microcrystalline cellulose is utilized. Polyoxyl 40 stearate can be adsorbed through the porous structure and high specific surface area of ​​microcrystalline cellulose, the aggregation of polyoxyl 40 stearate is reduced, the dispersibility of polyoxyl 40 stearate in the combined excipients is enhanced, and the sticking phenomenon of polyoxyl 40 stearate in the drug preparation due to excessive concentration is reduced. Polyoxyl 40 stearate can reduce the surface tension of drug particles and improve the solubility of drugs. Microcrystalline cellulose can enhance the fluidity of drugs, promote the dispersion of drug particles, and accelerate the dissolution process of drugs.

[0007] 2-Hydroxyethyl methacrylate increases the hydrophilicity of the drug, improves the solubility and dispersibility of the drug in an aqueous environment, and thus improves the dissolution rate of cefdinir preparations. Colloidal silicon dioxide has good adsorption and dispersibility, and is compounded with lactose and microcrystalline cellulose to disperse polyoxyl 40 stearate, reduce the excessive concentration of polyoxyl 40 stearate in drug preparations, and reduce the sticking phenomenon of polyoxyl 40 stearate.

[0008] Preferably, the pharmaceutical binder is at least one of sucrose stearate, povidone, and hydroxypropyl cellulose.

[0009] By adopting the above technical solution, sucrose stearate, povidone and hydroxypropyl cellulose as adhesives can promote the formation of drug particles, improve the stability of drug particles, and enable the rapid release and absorption of drugs.

[0010] Preferably, the length of the microcrystalline cellulose is 100-200 nm, and the width of the microcrystalline cellulose is 1-30 nm.

[0011] Preferably, the microcrystalline cellulose is carboxylated and the preparation method of carboxylated microcrystalline cellulose comprises the following specific steps: mixing microcrystalline cellulose with ammonium persulfate, heating to 60-80°C, ultrasonically stirring, adding water to obtain a suspension, and centrifuging and washing the suspension to obtain carboxylated microcrystalline cellulose.

[0012] By adopting the above technical solution, the carboxylated microcrystalline cellulose has a higher surface charge density, which can form an electrostatic repulsion layer on the surface of polyoxyl 40 stearate, thereby reducing the aggregation of polyoxyl 40 stearate and improving the dispersibility of polyoxyl 40 stearate in the pharmaceutical preparation. The carboxylated microcrystalline cellulose can promote the rapid dispersion of drug particles and accelerate the dissolution process of cefdinir preparation.

[0013] Preferably, the mass ratio of the microcrystalline cellulose to ammonium cellulose is 1:(0.8-1.2).

[0014] In the second aspect, the present application provides a method for preparing a combination of excipients used in a cefdinir preparation, using the following technical solution: A preparation method of a combination of auxiliary materials used in a cefdinir preparation comprises the following specific steps: heating purified water to boiling, cooling to a water temperature not lower than 55°C, then mixing the purified water with polyoxyl 40 stearate, stirring evenly to form a polyoxyl 40 stearate aqueous solution, mixing microcrystalline cellulose, colloidal silicon dioxide, 2-hydroxyethyl methacrylate, a pharmaceutical adhesive and lactose evenly, adding the polyoxyl 40 stearate aqueous solution, granulating, drying and sieving to obtain the combination auxiliary materials.

[0015] By adopting the above technical solution, the heated purified water and polyoxyl 40 stearate are mixed to form a polyoxyl 40 stearate aqueous solution, which can promote the uniform dispersion of polyoxyl 40 stearate at a suitable temperature, replacing the traditional method of hot melting after crushing polyoxyl 40 stearate, and reducing the sticking phenomenon of polyoxyl 40 stearate. Controlling the temperature of the polyoxyl 40 stearate aqueous solution to not less than 55° C. can promote the polyoxyl 40 stearate to have good solubility and dissolution rate, promote the uniform dispersion of polyoxyl 40 stearate, and reduce the precipitation or aggregation caused by local oversaturation of polyoxyl 40 stearate.

[0016] Preferably, the mass ratio of the purified water to polyoxyl 40 stearate is (4-6):1.

[0017] In the third aspect, the present application provides an application of a combination of excipients in a cefdinir preparation, using the following technical solution: The invention discloses an application of a combination of auxiliary materials in a cefdinir preparation. The combination of auxiliary materials and cefdinir are uniformly mixed, and granulated to obtain the cefdinir preparation. The mass fraction of the combination of auxiliary materials in the cefdinir preparation is (0.2-0.3)%.

[0018] By adopting the above technical scheme and adjusting the appropriate ratio of the combined excipients in the cefdinir preparation, the concentration of polyoxyl 40 stearate can be reduced, the cefdinir preparation can be promoted to have both good solubility and dispersibility, and the absorption effect of the cefdinir preparation can be improved.

[0019] Preferably, the cefdinir preparation is one of a capsule and a granule.

[0020] In summary, this application has the following beneficial effects: 1. Since the present application adopts the use of an excess of microcrystalline cellulose and a small amount of polyoxyl 40 stearate, lactose, and colloidal silicon dioxide to compound, the proportion of polyoxyl 40 stearate in the combined excipients is reduced, the polyoxyl 40 stearate is adsorbed through a porous structure and a high specific surface area, the aggregation of polyoxyl 40 stearate is reduced, and the sticking phenomenon caused by excessively high concentrations of polyoxyl 40 stearate in drug preparations is reduced, thereby improving the solubility and bioavailability of cefdinir preparations.

[0021] 2. In the present application, heated purified water and polyoxyl 40 stearate are mixed to form a polyoxyl 40 stearate aqueous solution, which replaces the traditional polyoxyl 40 stearate crushing, heating and melting process, can promote the uniform dispersion of polyoxyl 40 stearate and reduce the sticking phenomenon caused by excessive local concentration of polyoxyl 40 stearate. DETAILED DESCRIPTION

[0022] The present application is further described in detail below with reference to the embodiments.

[0023] All raw materials in the examples are commercially available. Example

[0024] Example 1 This embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: Purified water is heated to boiling, cooled to a water temperature of 55°C, and then the purified water is mixed with 2g of polyoxyl 40 stearate, the mass ratio of purified water to polyoxyl 40 stearate is 5:1, and stirred evenly to form an aqueous solution of polyoxyl 40 stearate, 100g of microcrystalline cellulose, 0.04g of colloidal silicon dioxide, 2g of 2-hydroxyethyl methacrylate, 0.6g of a pharmaceutical adhesive and 4g of lactose are mixed evenly, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150nm, and the average width of the microcrystalline cellulose is 15nm, the aqueous solution of polyoxyl 40 stearate is added, granulated, dried at 60°C, passed through a 600-mesh sieve, collected in a plastic bag, and sealed to obtain a combined excipient.

[0025] The invention discloses an application of a combination of auxiliary materials in a cefdinir preparation. The combination of auxiliary materials prepared above is mixed evenly with cefdinir, granulated and filled into capsules to obtain the cefdinir preparation. The mass fraction of the combination of auxiliary materials in the cefdinir preparation is 0.25%.

[0026] Example 2 The present embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: heating purified water to boiling, cooling to a water temperature of 55° C., then mixing the purified water with 1 g of polyoxyl 40 stearate, wherein the mass ratio of purified water to polyoxyl 40 stearate is 5:1, stirring evenly to form an aqueous solution of polyoxyl 40 stearate, mixing 50 g of microcrystalline cellulose, 0.03 g of colloidal silicon dioxide, 1 g of 2-hydroxyethyl methacrylate, 0.5 g of a pharmaceutical adhesive and 3 g of lactose, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150 nm, and the average width of the microcrystalline cellulose is 15 nm, mixing evenly, adding the aqueous solution of polyoxyl 40 stearate, granulating, drying at 60° C., passing through a 600-mesh sieve, collecting in a plastic bag, and sealing to obtain the combination of excipients.

[0027] Example 3 The present embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: heating purified water to boiling, cooling to a water temperature of 55° C., then mixing the purified water with 3 g of polyoxyl 40 stearate, wherein the mass ratio of purified water to polyoxyl 40 stearate is 5:1, stirring evenly to form an aqueous solution of polyoxyl 40 stearate, mixing 150 g of microcrystalline cellulose, 0.05 g of colloidal silicon dioxide, 3 g of 2-hydroxyethyl methacrylate, 0.8 g of a pharmaceutical adhesive and 5 g of lactose, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150 nm, and the average width of the microcrystalline cellulose is 15 nm, mixing evenly, adding the aqueous solution of polyoxyl 40 stearate, granulating, drying at 60° C., passing through a 600-mesh sieve, collecting in a plastic bag, and sealing to obtain the combination of excipients.

[0028] Example 4 The present embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: heating purified water to boiling, cooling to a water temperature of 55° C., then mixing the purified water with 3 g of polyoxyl 40 stearate, wherein the mass ratio of purified water to polyoxyl 40 stearate is 4:1, stirring evenly to form an aqueous solution of polyoxyl 40 stearate, and mixing 150 g of microcrystalline cellulose, 0.05 g of colloidal silicon dioxide, 3 g of 2-hydroxyethyl methacrylate, 0.8 g of a pharmaceutical adhesive and 5 g of lactose, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150 nm, and the average width of the microcrystalline cellulose is 15 nm, evenly mixing, adding the aqueous solution of polyoxyl 40 stearate, granulating, drying at 60° C., passing through a 600-mesh sieve, collecting in a plastic bag, and sealing to obtain the combination of excipients.

[0029] Example 5 The present embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: heating purified water to boiling, cooling to a water temperature of 55° C., then mixing the purified water with 3 g of polyoxyl 40 stearate, wherein the mass ratio of purified water to polyoxyl 40 stearate is 6:1, stirring evenly to form an aqueous solution of polyoxyl 40 stearate, and mixing 150 g of microcrystalline cellulose, 0.05 g of colloidal silicon dioxide, 3 g of 2-hydroxyethyl methacrylate, 0.8 g of a pharmaceutical adhesive and 5 g of lactose, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150 nm, and the average width of the microcrystalline cellulose is 15 nm, evenly mixing, adding the aqueous solution of polyoxyl 40 stearate, granulating, drying at 60° C., passing through a 600-mesh sieve, collecting in a plastic bag, and sealing to obtain the combination of excipients.

[0030] Example 6 This embodiment provides an application of a combination of excipients in a cefdinir preparation. The combination of excipients prepared above is uniformly mixed with cefdinir, granulated and filled into capsules to obtain a cefdinir preparation. The mass fraction of the combination of excipients in the cefdinir preparation is 0.2%.

[0031] Example 7 This embodiment provides an application of a combination of excipients in a cefdinir preparation. The combination of excipients prepared above is uniformly mixed with cefdinir, granulated and filled into capsules to obtain a cefdinir preparation. The mass fraction of the combination of excipients in the cefdinir preparation is 0.3%.

[0032] Example 8 This embodiment provides a method for preparing a combination of excipients used in a cefdinir preparation, comprising the following specific steps: S1: Mix microcrystalline cellulose and ammonium persulfate in a mass ratio of 1:1 between microcrystalline cellulose and ammonium persulfate, with an average length of 150 nm and an average width of 15 nm of microcrystalline cellulose. Heat to 70°C and stir ultrasonically for 12 min. Add water to stop the reaction and obtain a suspension in a mass ratio of 0.3:1 between water and microcrystalline cellulose. Wash the suspension by centrifugation at 9000 r / min until it is neutral to obtain carboxylated microcrystalline cellulose.

[0033] S2: Heat purified water to boiling, cool to a water temperature of 55°C, then mix the purified water with 3g of polyoxyl 40 stearate, the mass ratio of purified water to polyoxyl 40 stearate being 6:1, stir evenly to form an aqueous solution of polyoxyl 40 stearate, add 150g of carboxylated microcrystalline cellulose, 0.05g of colloidal silicon dioxide, 3g of 2-hydroxyethyl methacrylate, 0.8g of a pharmaceutical adhesive and 5g of lactose, wherein the pharmaceutical adhesive is sucrose stearate, mix evenly, add the aqueous solution of polyoxyl 40 stearate, granulate, dry at 60°C, pass through a 600-mesh sieve, collect in a plastic bag, and seal to obtain a combined excipient.

[0034] Example 9 The difference between Example 9 and Example 8 is that the mass ratio of microcrystalline cellulose to ammonium cellulose in the raw material for preparing the combined auxiliary material carboxylated microcrystalline cellulose is 1:0.8.

[0035] Example 10 The difference between Example 10 and Example 8 is that the mass ratio of microcrystalline cellulose to ammonium cellulose in the raw material for preparing the combined auxiliary material carboxylated microcrystalline cellulose is 1:1.2.

[0036] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the amount of microcrystalline cellulose used in the combined auxiliary material raw material is 30 g.

[0037] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the preparation method of the combination excipients used in the cefdinir preparation comprises the following specific steps: Pulverize and heat polyoxyl 40 stearate until it is melted, then evenly mix 100g microcrystalline cellulose, 0.04g colloidal silicon dioxide, 2g 2-hydroxyethyl methacrylate, 0.6g pharmaceutical adhesive and 4g lactose, wherein the pharmaceutical adhesive is sucrose stearate, the average length of the microcrystalline cellulose is 150nm, and the average width of the microcrystalline cellulose is 15nm, add molten polyoxyl 40 stearate, granulate, dry at 60°C, pass through a 600-mesh sieve, collect in a plastic bag, and seal to obtain a combined excipient.

[0038] Performance testing Clinical trials were conducted on the cefdinir preparations produced using the combination of excipients provided in Examples 1-10 and Comparative Examples 1-2 of the present application. The specific test results are shown in Table 1.

[0039] Cefdinir preparations were administered to 24 subjects on an empty stomach and after meals, respectively. The administration sequence was TR for the first cycle, RT for the second cycle, and a washout period of 3 days. Blood was collected at 18 points, including -1 hour before administration, 0.5, 1, 1.5, 2, 2.5, 3, 3.33, 3.67, 4, 4.33, 4.67, 5, 5.5, 6, 8, 10, 12, and 24 hours after administration, and the average maximum plasma concentration was calculated.

[0040] Table 1: Test results data Table 1: Test results data Table 1: Test results data As can be seen from the performance test results, the combination excipients prepared by the present application are applied in the cefdinir preparation by the embodiments, and the absorption of cefdinir in vivo is significantly improved, and Cmax is significantly improved. By comparative examples 1-2, it can be seen that the content of microcrystalline cellulose is reduced, and the concentration of polyoxyl 40 stearates is excessively improved, which reduces Cmax on the contrary. In comparative example 2, polyoxyl 40 stearates are directly heated, and in the cefdinir preparation test produced, whether it is fasting or after meals, Cmax is all on the low side, which does not meet the requirement of bioequivalence. And by comparing with embodiment 8 and embodiment 1, it can be seen that in embodiment 8, microcrystalline cellulose is carboxylated and modified, and the dispersibility of polyoxyl 40 stearates in pharmaceutical preparations is improved, and the absorption of cefdinir in the system can be significantly enhanced.

[0041] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A combination of excipients used in cefdinir preparations, characterized in that: The invention comprises the following raw materials in parts by weight: 1-3 parts of polyoxyethylene 40 stearate, 50-150 parts of microcrystalline cellulose, 0.03-0.05 parts of colloidal silicon dioxide, 1-3 parts of 2-hydroxyethyl methacrylate, 3-5 parts of lactose and 0.5-0.8 parts of a pharmaceutical adhesive.

2. The combination excipient used in the cefdinir preparation according to claim 1, characterized in that: The pharmaceutical adhesive is at least one of sucrose stearate, povidone, and hydroxypropyl cellulose.

3. The combination excipient used in the cefdinir preparation according to claim 1, characterized in that: The length of the microcrystalline cellulose is 100-200 nm, and the width of the microcrystalline cellulose is 1-30 nm.

4. The combination excipient used in the cefdinir preparation according to claim 3, characterized in that: The microcrystalline cellulose is carboxylated and modified, and the preparation method of the carboxylated microcrystalline cellulose comprises the following specific steps: mixing the microcrystalline cellulose with ammonium persulfate, heating to 60-80°C, ultrasonically stirring, adding water to obtain a suspension, and centrifuging and washing the suspension to obtain the carboxylated microcrystalline cellulose.

5. The combination excipient used in the cefdinir preparation according to claim 4, characterized in that: The mass ratio of the microcrystalline cellulose to ammonium filtrate is 1:(0.8-1.2).

6. A method for preparing a combination of excipients used in a cefdinir preparation as claimed in claim 1, characterized in that: The method comprises the following specific steps: heating purified water to boiling, cooling the water to a water temperature not lower than 55°C, then mixing the purified water with polyoxyl 40 stearate, stirring evenly to form a polyoxyl 40 stearate aqueous solution, mixing microcrystalline cellulose, colloidal silicon dioxide, 2-hydroxyethyl methacrylate, a pharmaceutical adhesive and lactose evenly, adding the polyoxyl 40 stearate aqueous solution, granulating, drying and sieving to obtain a combined auxiliary material.

7. The method for preparing the combination excipients used in the cefdinir preparation according to claim 6, characterized in that: The mass ratio of the purified water to polyoxyethylene 40 stearate is (4-6):

1.

8. An application of the combination excipient according to any one of claims 1 to 7 in a cefdinir preparation, characterized in that: The combination of excipients and cefdinir are uniformly mixed, and granulated to obtain a cefdinir preparation. The mass fraction of the combination of excipients in the cefdinir preparation is (0.2-0.3)%.

9. The application of the combination adjuvant according to claim 8 in a cefdinir preparation, characterized in that: The cefdinir preparation is one of capsules and granules.

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