Ceftoranil sustained-release tablets and their preparation method

Abstract

This invention proposes a ceftorpirum ester sustained-release tablet, which comprises ceftorpirum ester, a crystal transformation inhibitor, a matrix material, a pore-forming agent, a binder, an antioxidant, and a lubricant. The crystal transformation inhibitor, matrix material, and binder are all polyethylene oxide, and the pore-forming agent is polyethylene glycol 8000. This invention effectively solves the drawback of the current ceftorpirum ester formulations requiring multiple doses and reduces the types of excipients in the formulation while ensuring the crystal stability of ceftorpirum ester, making it suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to cefotaxime sustained-release tablets and their preparation method. Background Technology

[0002] Ceftoranil is a novel oral third-generation broad-spectrum antibiotic developed by Meiji Seika Co., Ltd. (now Meiji Seika Pharmaceutical Co., Ltd. Research Institute) in Japan. It was first marketed on April 1, 1994, and can be used to treat various infections, such as respiratory infections.

[0003] Common adverse reactions to ceftriaxone include allergic reactions such as rash, itching, urticaria, and fever; gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain, and indigestion; eosinophilia and leukopenia; and occasionally, elevated blood urea nitrogen and serum creatinine levels, and transient increases in transaminase levels. Furthermore, long-term use of ceftriaxone can cause overgrowth of non-susceptible microorganisms, altering the normal intestinal flora and inducing superinfections, especially pseudomembranous colitis. Therefore, patients with gastrointestinal diseases, especially enteritis, should use ceftriaxone with caution. Considering the wide clinical application of ceftriaxone, it is crucial to research and develop a sustained-release ceftriaxone tablet to improve patient compliance and reduce the incidence of adverse reactions. Summary of the Invention

[0004] One object of the present invention is to provide a ceftorpirum ester sustained-release tablet, which can achieve both crystal form stability and sustained release of ceftorpirum ester.

[0005] Another object of the present invention is to provide a method for preparing ceftoranil sustained-release tablets.

[0006] The problem described in this invention is solved by the following technical solution:

[0007] A ceftoranil sustained-release tablet comprises ceftoranil, a crystallization inhibitor, a matrix material, a pore-forming agent, a binder, an antioxidant, and a lubricant.

[0008] Furthermore, the ceftoranil sustained-release tablets comprise 50-70 wt% ceftoranil, 1-5 wt% of a crystallization inhibitor, 10-30 wt% of a matrix material, 5-18 wt% of a pore-forming agent, 0-5 wt% of a binder, 0-3 wt% of an antioxidant, and 0-2 wt% of a lubricant.

[0009] Furthermore, the material inhibiting crystal transformation, the skeleton material, and the adhesive are all polyoxyethylene.

[0010] Furthermore, the anti-transformation material and adhesive are polyethylene oxide with a molecular weight distribution of 100,000 to 900,000, and the skeleton material is polyethylene oxide with a molecular weight distribution of 4,000,000 to 7,000,000.

[0011] Polyoxyethylene is formed by the ring-opening polymerization of ethylene oxide under the catalysis of a metal catalyst, and its molecular formula is HO(CH2CH2O). n H. The non-shared electron pairs of the ether oxygen bonds in this material have an affinity for hydrogen bonds. During the experiment, it was unexpectedly discovered that polyoxyethylene can combine with ceftoreprin to form a complex. Furthermore, due to its long molecular chain, it can fully bind ceftoreprin, thus achieving the stability of the amorphous crystalline form of ceftoreprin at room temperature. Polyoxyethylene can swell upon contact with water or gastrointestinal fluids, forming a gel barrier. Drug release is controlled through the diffusion of the gel layer and the dissolution of the gel.

[0012] Furthermore, the amount of ceftoreprin is 55-65 wt%, and the amount of the anti-crystallization material is 3-4 wt%.

[0013] Furthermore, the amount of the skeleton material used is 15~25wt%.

[0014] Furthermore, the amount of the skeleton material used is 18~22wt%.

[0015] Furthermore, the porogen is at least one of polyethylene glycol 8000, lactose, and sucrose, and the amount of the porogen is 8-16 wt%.

[0016] Furthermore, the pore-forming agent is polyethylene glycol 8000.

[0017] Polyethylene glycol 8000 is a mixture formed by the condensation polymerization of ethylene oxide and water, with the molecular formula HO(CH2CH2O). n H, with a molecular weight of 7000~9000, polyethylene glycol dissolves or detaches upon contact with water or gastrointestinal fluids, forming a microporous or sponge-like structure, thereby increasing the permeability of drugs and media.

[0018] Furthermore, the amount of adhesive used is 2.5~3.5wt%.

[0019] Furthermore, the antioxidant is one or more of butylated hydroxytoluene, butylated hydroxyanisole, and tocopherol, and the amount used is 0-1 wt%.

[0020] Furthermore, the amount of the antioxidant is 0~0.5wt%.

[0021] Furthermore, the antioxidant is butylated hydroxytoluene.

[0022] Furthermore, the lubricant is one or more of magnesium stearate, stearic acid, and sodium stearate fumarate, and the amount used is 0.5~1.5wt%.

[0023] Furthermore, the amount of lubricant used is 0.8~1.2wt%.

[0024] Furthermore, the lubricant is magnesium stearate.

[0025] Furthermore, the ceftoranil sustained-release tablets comprise 60 wt% ceftoranil, 3.6 wt% of a transcrystallization inhibitor, 20 wt% of a matrix material, 12.2 wt% polyethylene glycol, 3 wt% of a binder, 0.2 wt% butylated hydroxytoluene, and 1 wt% magnesium stearate.

[0026] A second aspect of the present invention provides a method for preparing ceftoranil sustained-release tablets, comprising the following steps:

[0027] Dissolve one-third of the crystallization inhibitor in 1M hydrochloric acid (10L of 1M hydrochloric acid solution for 1kg of ceftriaxone), keep the temperature at 0~5℃, cool down and add ceftriaxone until completely dissolved, then slowly add 1M ammonia water (9~11L of 1M ammonia water solution for 1kg of ceftriaxone) to adjust the pH to 6~7, and precipitates will gradually appear in the solution.

[0028] Under a nitrogen atmosphere, the precipitate and solution were centrifuged, and two-thirds of the amount of the inhibitory crystallization material was prepared into a 5wt% aqueous solution. The precipitate was then centrifuged and washed, dried, and granulated to obtain a mixture of active pharmaceutical ingredients.

[0029] The active pharmaceutical ingredient mixture, matrix material, and pore-forming agent are added to a granulator for premixing. Then, a 2wt% concentration of polyoxyethylene binder aqueous solution is added for wet granulation. After drying and sieving, dry granules are obtained.

[0030] The dry granules are mixed with antioxidants and lubricants until homogeneous, then compressed into tablets to obtain the final product.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) Polyoxyethylene with a molecular weight distribution of 100,000 to 900,000 is used as a material to inhibit crystal transformation. Because of its long molecular chain, it can fully combine with ceftoreprin, thereby achieving the stability of the amorphous crystal form of ceftoreprin at room temperature. Furthermore, it can form a complex with ceftoreprin, thereby regulating the release rate of ceftoreprin.

[0033] (2) Polyoxyethylene with a molecular weight distribution of 4,000,000 to 7,000,000 is used as the skeleton material of the sustained-release tablets. It can swell upon contact with gastrointestinal fluid and form a gel barrier. At the same time, polyethylene glycol 8000 is added as a pore-forming agent, which enables ceftoranil to be released evenly, reducing the initial burst release of the drug and allowing for more complete drug release in the later stage.

[0034] (3) Polyethylene glycol 8000 is used as a pore-forming agent. It has the same molecular formula as polyoxyethylene, only the molecular weight is different, which reduces the number of excipients that patients need to take and effectively reduces the incidence of adverse reactions. Detailed Implementation

[0035] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0036] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0037] Example 1

[0038] A ceftoranil sustained-release tablet comprises the following components: 60% ceftoranil, 3.6% polyoxyethylene (molecular weight 100,000~900,000) as an inhibitor of crystal transformation, 20% polyoxyethylene (molecular weight 4,000,000~7,000,000) as a skeleton material, 12.2% polyethylene glycol 8000 as a porogen, 3% polyoxyethylene (molecular weight 100,000~900,000) as a binder, 0.2% butylated hydroxytoluene as an antioxidant, and 1% magnesium stearate as a lubricant.

[0039] Its preparation method is as follows:

[0040] Weigh one-third of the polyoxyethylene (PE) material used to inhibit crystallization and dissolve it in approximately 1M hydrochloric acid solution (10L of 1M hydrochloric acid solution for 1kg of ceftriaxone). Maintain the temperature at 0-5℃, then add ceftriaxone and stir until completely dissolved. While stirring, slowly add 1M ammonia solution at 0-5℃ to adjust the pH to 6.5-7.0. Centrifuge the solution under a nitrogen atmosphere. Then, use two-thirds of the PE to prepare a 5wt% PE aqueous solution and centrifuge and wash twice. Dry the centrifuged material at a temperature ≤45℃. After drying, granulate the centrifuged material to obtain the active pharmaceutical ingredient composition.

[0041] The active pharmaceutical ingredient composition obtained in the above steps was premixed with the matrix material polyoxyethylene and the pore-forming agent polyethylene glycol. Then, a 2wt% concentration of the binder polyoxyethylene aqueous solution was added for wet granulation. The resulting wet granules were dried at 45°C and then sieved. The sieved dry granules and dibutylhydroxytoluene were added to a mixer for mixing and sieving. Then, magnesium stearate was added and the mixture was compressed into tablets to obtain ceftorpiloxetine sustained-release tablets.

[0042] Examples 2-6

[0043] Referring to the types of raw materials and preparation process in Example 1, ceftoranil sustained-release tablets with different amounts of excipients were prepared.

[0044] Table 1. Raw material and auxiliary material usage for each embodiment

[0045] raw materials Example 1 (%) Example 2 (%) Example 3 (%) Example 4 (%) Example 5 (%) Example 6 (%) Ceftoranil (active ingredient) 60 60 60 72.1 53.6 60 Polyoxyethylene (a material that inhibits crystal transformation) 3.6 1 5 4.8 5 3.6 Polyoxyethylene (skeleton material) 20 22.6 18.6 10.1 30.4 14.2 Polyethylene glycol 8000 (porogen) 12.2 12.2 12.2 6.7 5 18 Polyoxyethylene (adhesive) 3 3 3 4.8 5 3 Butylated hydroxytoluene (antioxidant) 0.2 0.2 0.2 0.2 0.2 0.2 Magnesium stearate (lubricant) 1 1 1 1.2 0.9 1 total 100 100 100 100 100 100

[0046] Comparative Example 1

[0047] Referring to Embodiment 1, without adding any material that inhibits crystallization (the reduced dosage is adjusted to include a pore-forming agent), the active pharmaceutical ingredient composition and ceftorepnitin sustained-release tablets were prepared.

[0048] Comparative Example 2

[0049] Ceftoramphenicol (50 g) was dissolved in an acidic aqueous solution (350 ml) containing dissolved hydroxypropyl methylcellulose (500 mg) and 1 N hydrochloric acid for 45 minutes at or below 5 °C. The resulting aqueous solution containing ceftoramphenicol was filtered through a microporous (1 μm) membrane filter to remove insoluble solids. This yielded an acidic aqueous solution containing ceftoramphenicol, hydroxypropyl methylcellulose, and hydrochloric acid completely dissolved in the solution. The resulting acidic aqueous solution was then neutralized to pH 7.0 by slow dropwise addition of 1 M ammonia solution, while maintaining the temperature of the acidic aqueous solution at or below 5 °C. During this neutralization reaction, a precipitate slowly formed. The resulting neutralization reaction mixture was filtered to recover the precipitate. The precipitate was thoroughly washed with a 0.5% wt hydroxypropyl cellulose aqueous solution. The washed precipitate was then dried under reduced pressure to obtain a yellow powder.

[0050] Comparative Example 3

[0051] (1) Mix 42g of xanthan gum and 10g of silk fibroin, stir and melt at 57°C and keep warm. While stirring, slowly add 10g of micronized silica gel to disperse the micronized silica gel evenly and obtain the composition for later use.

[0052] (2) A microemulsion was prepared by using 30g of propoxylated methyl glucoside, 10ml of isobutanol and 80ml of ethyl acetate. 372g of ceftriaxone was added to the emulsion and placed in a water bath at 50℃.

[0053] (3) Add the composition obtained in (1) to the microemulsion and stir until uniform. Use this solution as the reaction solution, adjust the pH of the reaction solution to 9.0 with 10% NaOH solution, add an appropriate amount of methanol, and react at a constant temperature for 1.5 hours.

[0054] (4) Cool the reaction solution to 0°C, add 0.1 times the volume of glutaraldehyde to the reaction solution and continue stirring for 30 minutes. Then slowly raise the temperature to 50°C and add glacial acetic acid to make the pH value 3.0 to obtain a suspension.

[0055] (5) After settling completely, pour off the supernatant, filter, wash with water until there is no aldehyde odor, dry and set aside.

[0056] (6) Take 300g of the precipitate ceftorepidoxime obtained in step (4), 35g of hydrogenated vegetable oil, 22g of sodium carboxymethyl starch and 5g of micronized silica gel, and compress them into tablets to obtain ceftorepidoxime tablets with a specification of 100mg / tablet.

[0057] Test Example 1

[0058] Crystal form determination: The active pharmaceutical ingredient composition from Example 1, the active pharmaceutical ingredient from Comparative Example 1, and the composition prepared from Comparative Example 2 were placed in an X-ray powder diffractometer for determination. The above compositions were placed in sealed containers and their stability was investigated at 40°C. Samples were then taken at 1 month, 3 months, and 4 months and determined using an X-ray powder diffractometer. The results are as follows:

[0059] Table 2. Results of X-ray powder diffraction measurements

[0060] 0 days 40℃, 1 month 40℃, 3 months 40℃, 4 months Example 1: Active Pharmaceutical Ingredient Composition Amorphous crystal form Amorphous crystal form Amorphous crystal form Amorphous crystal form Comparative Example 1: Active Pharmaceutical Ingredient Composition Amorphous crystal form and mixture of orthorhombic crystal forms Orthorhombic crystal form N / A N / A Comparative Example 2 Composition Amorphous crystal form Amorphous crystal form Amorphous crystal form Amorphous crystal form

[0061] The above results indicate that, in Comparative Example 1, without the addition of a crystal transformation inhibitor, the prepared composition contained both amorphous and orthorhombic crystal forms, and completely transformed into the orthorhombic crystal form after one month. The active pharmaceutical ingredient composition of Example 1, using polyoxyethylene as the crystal transformation inhibitor, was able to completely transform the cefotaxime crystal form into an amorphous form and maintain crystal stability for up to four months, which is beneficial for patient absorption of the drug.

[0062] Test Example 2

[0063] Dissolution (paddle method) test: Example 1, Comparative Example 1, Comparative Example 3, and ceftorepnitin tablets (production batch number: CFNTCV1021) produced by Meiji Seika Pharma Co., Ltd. were used as control groups for in vitro dissolution testing in different dissolution media.

[0064] (1) The dissolution medium was 900 ml of degassed pH 1.2 hydrochloric acid medium, the rotation speed was 50 r / min, and the temperature was 37.0℃±0.5℃. 5 ml of sample was taken after 5, 15, 30, 45, 60, 120, 240, 360 and 480 min respectively, filtered with a microporous membrane, and an equal amount of medium was added. The dissolution rate of the filtrate was measured at a wavelength of 321 nm.

[0065] (2) The dissolution medium was 900 ml of pH 4.5 acetic acid medium after degassing, the rotation speed was 50 r / min, and the temperature was 37.0℃±0.5℃. 5 ml of sample was taken after 5, 15, 30, 45, 60, 120, 240, 360 and 480 min respectively, filtered with a microporous membrane, and an equal amount of medium was added. The dissolution rate of the filtrate was measured at a wavelength of 321 nm.

[0066] (3) The dissolution medium was 900 ml of degassed pH 6.8 phosphate buffer, the rotation speed was 50 r / min, and the temperature was 37.0℃ ±0.5℃. 5 ml of sample was taken after 5, 15, 30, 45, 60, 120, 240, 360 and 480 min respectively, filtered with a microporous membrane, and an equal amount of medium was added. The dissolution rate of the filtrate was measured at a wavelength of 321 nm.

[0067] Table 3. Results of in vitro dissolution experiments using hydrochloric acid buffer solution at pH 1.2 as the dissolution medium.

[0068] Time (min) Example 1 (%) Example 2 (%) Example 3 (%) Example 4 (%) Example 5 (%) Example 6 (%) Comparative Example 1 (%) Comparative Example 3 (%) Commercially available drugs (%) 5 0 0 0 0 0 0 0 18 65 15 0 0 0 5 0 3 0 32 91 30 8 9 8 13 4 10 6 48 100 45 19 16 18 25 16 22 10 62 / 60 26 23 25 34 20 28 17 75 / 120 42 39 41 48 39 45 31 88 / 240 73 71 74 78 68 75 48 92 / 360 98 98 98 98 89 99 55 99 / 480 100 100 100 100 99 99 58 99 / F2 (using Example 1) / 75.4 84.5 58.5 54.2 79.3 31.2 22.7 /

[0069] Table 4. Results of in vitro dissolution experiments using acetate buffer solution at pH 4.5 as the dissolution medium.

[0070] Time (min) Example 1 (%) Example 2 (%) Example 3 (%) Example 4 (%) Example 5 (%) Example 6 (%) Comparative Example 1 (%) Comparative Example 3 (%) Commercially available drugs (%) 5 0 0 0 0 0 0 0 0 0 15 0 0 0 0 0 0 0 6 7 30 0 0 0 0 0 0 0 16 23 45 0 2 1 6 0 4 3 25 37 60 11 10 11 19 7 15 5 34 45 120 20 19 21 26 14 23 8 40 52 240 35 33 37 43 27 40 13 52 59 360 49 46 50 55 41 53 19 58 63 480 61 60 62 64 56 63 26 63 68 F2 (using Example 1) / 84.4 90.5 59.2 59.4 77.2 31.3 39.6 /

[0071] Table 5. Results of in vitro dissolution experiments using phosphate buffer solution at pH 6.8 as the dissolution medium.

[0072] Time (min) Example 1 (%) Example 2 (%) Example 3 (%) Example 4 (%) Example 5 (%) Example 6 (%) Comparative Example 1 (%) Comparative Example 3 (%) Commercially available drugs (%) 5 0 0 0 0 0 0 0 0 22 15 0 0 0 0 0 0 0 13 32 30 0 0 0 0 0 2 0 19 34 45 4 2 2 8 0 8 3 26 36 60 9 7 8 15 6 13 6 35 38 120 16 13 15 23 14 18 8 46 39 240 27 25 28 36 25 30 8 58 40 360 39 36 41 48 37 45 9 61 42 480 48 46 50 53 45 52 9 65 44 F2 (using Example 1) / 79.4 86.4 57.7 76.6 70.3 33.0 30.0 /

[0073] The above dissolution results show that the dissolution curves of the ceftorepnitin sustained-release tablets (Examples 1-6) prepared in this invention are similar in multiple media (F2>50), and are lower than those of Comparative Example 1, Comparative Example 3 and commercially available drugs, with a longer duration of action and obvious sustained-release effect, effectively reducing the frequency of medication for patients and improving patient compliance.

Claims

1. A ceftoranil sustained-release tablet, characterized in that, It comprises 55-65 wt% ceftriaxone, 3-4 wt% of a crystal transformation inhibitor, 15-25 wt% of a framework material, 8-16 wt% of a porogen, 2.5-3.5 wt% of a binder, 0-0.5 wt% of an antioxidant, and 0.8-1.2 wt% of a lubricant; the crystal transformation inhibitor and binder are polyethylene oxide with a molecular weight distribution of 100,000-900,000; the framework material is polyethylene oxide with a molecular weight distribution of 4,000,000-7,000,000; and the porogen is polyethylene glycol 8000.

2. The ceftoranolpidem sustained-release tablet as described in claim 1, characterized in that, The antioxidant is one or more of butylated hydroxytoluene, butylated hydroxyanisole, and tocopherol; the lubricant is one or more of magnesium stearate, stearic acid, and sodium stearate fumarate.

3. The ceftoranil sustained-release tablet as described in claim 1, characterized in that, The antioxidant is butylated hydroxytoluene, and the lubricant is magnesium stearate.

4. The method for preparing ceftoranil sustained-release tablets according to any one of claims 1 to 3, comprising the following steps: (1) Dissolve one-third of the material used to inhibit crystallization in 1M hydrochloric acid. Determine the amount of hydrochloric acid according to 10L of 1M hydrochloric acid solution for 1kg of ceftriaxone. Keep the temperature at 0~5℃. After cooling, add ceftriaxone to dissolve completely. Then slowly add 1M ammonia water to adjust the pH to 6~7. Precipitates will gradually appear in the solution. (2) Under a nitrogen atmosphere, the precipitate and solution were centrifuged, and two-thirds of the amount of the inhibitory crystallization material was prepared into a 5wt% aqueous solution. The precipitate was centrifuged and washed, and the centrifuged material was dried and granulated to obtain a mixture of raw materials. (3) Add the raw material mixture, matrix material and pore-forming agent to the granulator for premixing, then add 2wt% of the binder aqueous solution for wet granulation, and dry and sieve to obtain dry granules; (4) Add the dry granules to the antioxidant and lubricant, mix evenly, compress into tablets, and the product is obtained.