Cefditoren pivoxil composition, its preparation method and application

Abstract

This invention discloses a ceftorpiril composition, its preparation method, and its application. The ceftorpiril composition of this invention comprises amorphous ceftorpiril and excipients containing a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer. The excipients further include at least one of water-soluble chitosan or acrylic resin. The ratio of the sum of the mass of the water-soluble chitosan and acrylic resin to the mass of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and the mass of the amorphous ceftorpiril is (1~5):(0.05~0.5):(5~15). The excipients in the ceftorpiril composition of this invention help maintain the stability of the amorphous ceftorpiril crystal form, and the granules prepared using the ceftorpiril composition exhibit good stability.

Description

Technical Field

[0001] This invention belongs to the technical field of cefotaxime, specifically relating to a cefotaxime composition, its preparation method, and its application. Background Technology

[0002] Ceftoranil is an oral cephalosporin antibiotic synthesized by Meiji Seika Co., Ltd. (now Meiji Seika Pharmaceutical Co., Ltd. Pharmaceutical Research Institute) in Japan. It was first marketed on April 1, 1994. It has broad-spectrum and highly effective antibacterial activity, especially against respiratory tract infections with strong bacterial resistance. Ceftoranil itself is inactive and exerts its effect after oral administration by esterases in the gastrointestinal tract to be metabolized into cefotaxime.

[0003] Cefditoren Pivoxil is a pale yellow to light yellow powder, odorless or with an off-taste, and bitter in taste. Its English name is Cefditoren Pivoxil, and its chemical name is (…). ) (6R, 7R) 2,2 Dimethylpropionyloxymethyl 7 [(Z) 2 (2 amino 4 (thiazolyl) 2 Methoxyiminoacetamido] 3 [(Z) 2 (4 methyl 5 [Thiazolyl)vinyl] 8 Oxygenation 5 thia 1 Azabicyclo[4.2.0]octyl 2 olefins 2 Carboxylic acid esters.

[0004] Ceftorampivoxil exists in two main forms: crystalline and amorphous. Crystalline cefotaxime is highly stable but has poor solubility, which is not conducive to clinical absorption. It also requires a complex pretreatment process to convert it into amorphous cefotaxime. Amorphous cefotaxime has better solubility and oral absorption is significantly better than that of crystalline cefotaxime. However, amorphous cefotaxime is sensitive to light, temperature, and humidity and is easily converted into crystalline cefotaxime, resulting in poor stability. Summary of the Invention The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the present invention provides a ceftorpiril composition, wherein the amorphous ceftorpiril contained therein has good stability, and when used in pharmaceutical preparations, the resulting ceftorpiril preparation has good stability. The present invention also provides a method for preparing a ceftoranil composition.

[0005] This invention also proposes a ceftoranil formulation.

[0006] In a first aspect, the present invention provides a ceftorpiril composition comprising amorphous ceftorpiril and an excipient containing a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, wherein the excipient further comprises at least one of water-soluble chitosan or acrylic resin material, wherein the ratio of the sum of the mass of the water-soluble chitosan and acrylic resin material to the mass of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and the mass of the amorphous ceftorpiril is (1~5):(0.05~0.5):(5~15).

[0007] The ceftoranil composition according to embodiments of the present invention has at least the following beneficial effects: In the cefotaxime composition of this invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, water-soluble chitosan, or acrylic resin material work synergistically to help maintain the stability of the amorphous cefotaxime crystal form. The granules prepared using the cefotaxime composition exhibit good stability while ensuring the absorption of the drug composition in the gastrointestinal tract. In some embodiments of the present invention, the ratio of the sum of the masses of the water-soluble chitosan and acrylic resin materials to the mass of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and the mass of amorphous cefotaxime is (1~5):(0.09~0.5):(5~15).

[0008] In some embodiments of the present invention, the ratio of the sum of the masses of the water-soluble chitosan and acrylic resin materials to the mass of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and the mass of amorphous cefotaxime is (1~3):(0.09~0.2):10.

[0009] In some embodiments of the present invention, the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer includes poloxamer 188.

[0010] Poloxamer 188 has low toxicity and minimal irritation and hemolytic activity. In this invention, poloxamer 188 not only has a solubilizing and wetting effect, but can also work synergistically with water-soluble chitosan or acrylic resin materials to maintain the stability of the amorphous cefotaxime crystal form.

[0011] In some embodiments of the present invention, the acrylic resin material comprises a copolymer of methacrylic acid and methyl methacrylate.

[0012] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the acrylic resin material is 100:(10~30).

[0013] In some embodiments of the present invention, the acrylic resin material includes at least one of Eutrich L-type or Eutrich S-type. Optionally, the Eutrich L-type includes at least one of L100, L100-55, and / or the Eutrich S-type includes S100.

[0014] In some embodiments of the present invention, the mass ratio of the Udoch L-type and the Udoch S-type is (0~3):(3~0).

[0015] Eudragit is a trade name for a synthetic pharmaceutical excipient, comprising methacrylic acid copolymers and methacrylate copolymers, commonly known as acrylic resins in my country. It can be used as a coating agent, a sustained-release matrix material, and a matrix adhesive for transdermal formulations. In this invention, Eudragit not only functions as a crystal stabilizer but also as an adhesive, capable of being used in combination with hydroxypropyl methylcellulose to achieve a bonding effect.

[0016] In some embodiments of the present invention, the water-soluble chitosan is carboxymethyl chitosan.

[0017] In some embodiments of the present invention, the degree of deacetylation of the carboxymethyl chitosan is 70% to 85%.

[0018] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to carboxymethyl chitosan is 100:(10~30).

[0019] Chitosan, as a natural cationic polysaccharide, has the characteristics of good biocompatibility, biodegradability, non-toxicity, strong adhesion and certain biological activity. It can optimize formulation performance by improving particle formability, regulating drug release behavior and improving bioavailability.

[0020] The performance of chitosan is greatly affected by its molecular weight and degree of deacetylation. In this invention, carboxymethyl chitosan is selected to play multiple roles. It not only acts as a natural binder, working in conjunction with hydroxypropyl methylcellulose to facilitate dry granulation, but also as a crystal stabilizer to maintain the stability of amorphous ceftriaxone. Furthermore, carboxymethyl chitosan is stable in acidic environments and swells or degrades after entering the intestines. It temporarily opens the tight junctions with anionic mucoproteins between intestinal mucosal cells, promoting drug absorption in the intestines. In addition, chitosan itself has antibacterial properties and can disrupt the integrity of microbial cell membranes, reducing microbial contamination during granule storage.

[0021] In some embodiments of the present invention, the excipients further include hydroxypropyl methylcellulose.

[0022] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the hydroxypropyl methylcellulose is (5~15):(1~7), such as optionally 10:(2~4).

[0023] In oral formulations, hydroxypropyl methylcellulose primarily serves as an adhesive, film coating material, and matrix for sustained-release tablets. In this invention, hydroxypropyl methylcellulose mainly functions as an adhesive. In some embodiments of the present invention, the excipients further include at least one of sucrose or lactose.

[0024] In some embodiments of the present invention, the ratio of the mass of the amorphous ceftriaxone to the sum of the masses of the sucrose and lactose is (5~15):(50~90), such as optionally 10:(60~80).

[0025] In some embodiments of the present invention, the excipients further include a disintegrant. Optionally, the disintegrant includes croscarmellose sodium.

[0026] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the cross-linked sodium carboxymethyl cellulose is (5~15):(0.5~5), such as 10:(1~3).

[0027] Through the above embodiments, croscarmellose sodium not only acts as a disintegrant, which is beneficial to drug dissolution, but also serves as an excipient for the desiccant in the ceftoranil composition.

[0028] In some embodiments of the present invention, the auxiliary material further includes silicon dioxide. In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the silica is (5~15):(0.5~5), such as 10:(1~2).

[0029] In some embodiments of the present invention, the excipients further include propylene glycol alginate.

[0030] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the propylene glycol alginate is (5~15):(0.01~0.5), such as optionally 10:(0.01~0.1).

[0031] Propylene glycol alginate is a derivative formed by the esterification of some carboxyl groups of alginate with propylene glycol. It combines water solubility, emulsification and acid resistance, and has unique value in pharmaceutical preparations containing ceftoranil. It can be used as a suspending agent and stabilizer for suspensions, an emulsifier for emulsions, a binder and sustained-release material for tablets, and as a taste mask for bitter drugs and a taste modifier for lozenges in pediatric oral preparations. It can reduce the strong bitterness of active ingredients and can synergistically improve the taste of aspartame.

[0032] In some embodiments of the present invention, the excipients further include flavoring agents.

[0033] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the flavoring agent is (5~15):(3~20), such as optionally 10:(9~14).

[0034] In some embodiments of the present invention, the flavoring agent includes at least one of a flavoring agent or a sweetener.

[0035] In some embodiments of the present invention, the fragrance is a flavoring.

[0036] In some embodiments of the present invention, the flavoring includes at least one selected from banana flavoring, strawberry flavoring, and orange flavoring. Optionally, the flavoring is banana flavoring.

[0037] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the fragrance is (5~15):(0.5~5), such as optionally 10:(1~2).

[0038] In some embodiments of the present invention, the sweetener includes at least one of aspartame or sucralose.

[0039] Aspartame, also known as aspartame, is a synthetic non-carbohydrate sweetener characterized by high sweetness and low calories. It can improve taste and mask the bitterness of drugs. This invention incorporates aspartame and propylene glycol alginate to synergistically improve the taste of the ceftoranil-pivoxil composition.

[0040] In some embodiments of the present invention, the mass ratio of the amorphous cefotaxime to the sweetener is (5~15):(2.5~15), such as optionally 10:(8~12).

[0041] In some embodiments of the present invention, the ceftoranil composition comprises, by mass fraction, the following components: Amorphous ceftriaxone 10% 1%~3% croscarmellose sodium cellulose Sucrose content: 63.7%~75.9% Poloxamer 1880.09%~0.2% Hydroxypropyl methylcellulose 2%~4% At least 1% to 3% of Eutrich L-type, Eutrich S-type, and carboxymethyl chitosan. 1%~2% silicon dioxide Banana powder flavoring 1%~2% Aspartame 8%~12% Propylene glycol alginate 0.01%~0.1%.

[0042] Through the above embodiments, the ceftoreprin composition provided by the present invention can maintain the amorphous ceftoreprin crystal form, improve the powder flowability, and the prepared granules have good stability, which can effectively exert the role of the active pharmaceutical ingredient. Moreover, no special requirements are required for the raw materials, and no crystallization pretreatment of the raw materials is required.

[0043] In some embodiments of the present invention, the ceftoranil composition is a granular composition.

[0044] A second aspect of the present invention provides a method for preparing a ceftorpirum ester composition, comprising the following steps: mixing raw materials containing amorphous ceftorpirum ester and excipients to obtain the ceftorpirum ester composition. Optionally, the mixing step may be performed by multiple mixing steps.

[0045] In some embodiments of the present invention, the preparation method includes the following steps: S1, a portion of amorphous ceftriaxone is mixed with hydroxypropyl methylcellulose, acrylic resin material and / or water-soluble chitosan, disintegrant, a portion of flavoring agent, and silicon dioxide, and then mixed with a portion of sucrose to obtain premix I; The remaining amorphous cefotaxime was mixed with another portion of the flavoring agent, polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and propylene glycol alginate, and then mixed with the remaining sucrose to obtain premix II. S2, take premix I and premix II and dry granulate them, pass them through a 30-200 mesh sieve for granulation, and then mix them with the remaining flavoring agent to obtain the ceftoranil composition.

[0046] In this invention, the use of suitable excipients helps maintain the crystal stability of amorphous cefotaxime. Granules can be prepared by granulation with suitable excipients, reducing the complex raw material crystal conversion pretreatment process in conventional formulation production (such as the preparation of original cefotaxime fine granules, which requires converting crystalline raw materials into amorphous raw materials for pretreatment before granulation), improving production efficiency, and the resulting granules have good stability, stable quality, and high industrialization potential.

[0047] Furthermore, the wet granulation process for pharmaceutical formulations in related technologies suffers from incomplete removal of introduced moisture and requires multiple operational units (such as material preparation, drying, and sieving). In contrast, this invention employs dry granulation, eliminating the need for water in the entire composition preparation process. This simplifies the preparation process, shortens the production cycle, and reduces moisture contact, which is beneficial for product stability. Dry granulation also improves powder flowability, enhances the synergistic effect of excipients, and improves process compliance. The ceftorepnitin composition prepared by this invention exhibits good stability in its amorphous ceftorepnitin form, and its crystal form remains unchanged after a period of storage.

[0048] In some embodiments of the present invention, in step S1, a portion of amorphous cefotaxime, eutectic L-type and / or eutectic S-type and / or carboxymethyl chitosan, hydroxypropyl methylcellulose, croscarmellose sodium, a portion of aspartame, and silica are mixed, and then a portion of sucrose is added and mixed to obtain premix 1. The remaining amorphous cefotaxime was mixed with the remaining aspartame, poloxamer 188, and propylene glycol alginate, and then mixed with the remaining sucrose in an equal increment. The mixture was then passed through a 60-mesh sieve to obtain premix II.

[0049] In some embodiments of the present invention, step S1 specifically includes: The excipients are sieved and set aside. Take 1 / 2 of the prescribed amount of amorphous cefotaxime, eutectic L-type or eutectic S-type or carboxymethyl chitosan, hydroxypropyl methylcellulose, croscarmellose sodium, part of the prescribed amount of aspartame, and silica, mix for 3 min, then add 40% of the prescribed amount of sucrose and mix for 3 min to obtain premix 1; mix the remaining amorphous cefotaxime with the remaining prescribed amount of aspartame, poloxamer 188, and propylene glycol alginate for 3 min, then mix with the remaining prescribed amount of sucrose in an equal increment for 3 min, and pass through a 60-mesh sieve to obtain premix II.

[0050] In some embodiments of the present invention, step S2 specifically includes: After mixing premix I and premix II, dry granulation is performed. The feeding speed is set to 8-30 rpm, the conveying speed to 20-40 rpm, the roller speed to 5-10 rpm, and the roller pressure to 5-15 MPa. The granulated material is then passed through a 30-mesh sieve to obtain pre-formed granules. The pre-formed granules between 35-200 mesh sieves are then mixed with banana powder flavoring to obtain the ceftoranil composition.

[0051] A third aspect of the present invention provides a ceftoranil formulation comprising the above-described ceftoranil composition.

[0052] In some embodiments of the present invention, the formulation includes at least one of tablets or granules.

[0053] In some embodiments of the present invention, the formulation is a granule. Attached Figure Description

[0054] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein: Figure 1 This is a schematic diagram of the preparation method of ceftoranil granules in an embodiment of the present invention. Detailed Implementation

[0055] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0056] Unless otherwise specified, the experimental methods used in the following examples and comparative examples are generally performed under conventional conditions in the art or as recommended by the manufacturer; the raw materials and reagents used are all commercially available from the conventional market unless otherwise specified.

[0057] Amorphous ceftoranil: pharmaceutical grade; All excipients used in the examples must meet pharmaceutical requirements, including: Silicon dioxide: Model 350FCP, purchased from Fuji Silicon Chemical Co., Ltd. Carboxymethyl chitosan: Degree of deacetylation is 70%~85%; Yutchi L-type: Yutchi L100, or Yutchi L100-55; Hydroxypropyl methylcellulose: viscosity of 4~8 mPa·s, purchased from Shin-Etsu Chemical Industry Co., Ltd. 2910-606, or hydroxypropyl methylcellulose with viscosity of 4~8 mPa·s produced by other manufacturers can also be used; Sucrose: pharmaceutical grade; purchased from COFCO Chongzuo Sugar Co., Ltd. Crosslinked sodium carboxymethyl cellulose: Lot number 2174259607, purchased from International N&H USA, Inc. Propylene glycol alginate: Batch number 4614542492, purchased from International N&H Manufacturing UK Limited; Banana powder flavoring: Model number 98AF4983, purchased from Senxin Flavor & Pigment Technology (China) Co., Ltd. Poloxamer 188: Lot number GNH20321C, purchased from BASF New Materials Co., Ltd.

[0058] Examples 1-8 Examples 1-8 disclose a series of ceftoranil granules, the composition of which is shown in Table 1 below. All of them were prepared by a method including the following steps: Preparation of premix 1: The excipients are passed through a 60-mesh sieve for later use. Take half of the prescription amount of amorphous cefotaxime, carboxymethyl chitosan or Utec L type or Utec S100, cross-linked sodium carboxymethyl cellulose, silicon dioxide, hydroxypropyl methylcellulose, and 11% of the prescription amount of aspartame and mix for 3 min. Then add 40% of the prescription amount of sucrose and mix for 3 min to obtain premix 1.

[0059] Preparation of premix 2: Take the remaining amorphous cefotaxime, propylene glycol alginate, poloxamer 188, and the remaining amount of aspartame and mix them evenly. Then mix them with the remaining amount of sucrose in an equal increment and pass them through a 60-mesh sieve to obtain premix 2.

[0060] Dry granulation: Take premix 1 and premix 2 and mix them in a mixer for 3 minutes (mixing speed 10~15 rpm). Add the materials to the hopper of the dry granulator, turn on the dry granulator, set the feeding speed to 20 rpm, the conveying speed (feeding speed) to 20 rpm, the roller speed to 8 rpm, and the working pressure (roller pressure) to 6 MPa. Perform dry granulation through a 30-mesh granulation screen. After granulation, collect all materials between 35 and 200 mesh, and then add the converted banana powder flavoring and mix for 5 minutes (mixing speed 10~15 rpm) to obtain a drug composition containing amorphous ceftriaxone, which is ceftriaxone granules.

[0061] Table 1. Ingredients of Ceftoranil Granules (Unit: Bag)

[0062] Note: The mass of each bag of material in Table 1 is 500mg.

[0063] Experimental Examples of Compatibility Study of Additives in Excipients To investigate the compatibility of the additives, samples 1-16 were prepared and their crystal stability was tested. Specifically, supersaturated suspensions were prepared using the formulations shown in Table 2, with purified water as the dispersion medium, to achieve a concentration of 10 mg / mL of amorphous cefotaxime (calculated as cefotaxime). The retention time of amorphous cefotaxime in the prepared suspensions was evaluated. Specifically, each suspension was stored at 25°C under sealed conditions, and samples were taken immediately after a specified time. The sampled suspensions were centrifuged, and the precipitate was dried under reduced pressure and subjected to powder X-ray diffraction analysis. The results are shown in Table 2.

[0064] Table 2. Results of Additive Compatibility and Crystal Form Examination

[0065] Note: Amorphous cefotaxime, the dosage shown is based on cefotaxime; A is amorphous cefotaxime, C is crystalline cefotaxime.

[0066] The results showed that the surfactant poloxamer 188 alone could not maintain the crystal stability of ceftoreprin. Carboxymethyl chitosan or eutectic alone could prolong the retention time of amorphous ceftoreprin. Adding carboxymethyl chitosan or eutectic while adding poloxamer 188 could further improve the retention time of amorphous ceftoreprin. Hydroxypropyl methylcellulose alone had no significant effect on maintaining amorphous ceftoreprin and was mainly used as a binder in ceftoreprin compositions.

[0067] Furthermore, banana flavoring is preferred as the fragrance agent in this invention, as it is more beneficial to the stability of ceftriaxone. For example, vanillin has poor compatibility with ceftriaxone and contains more impurities compared to banana powder flavoring. The content of vanillin mixed with ceftriaxone decreased from 78.5% on day 0 to 74.9% after being placed at 60°C for 10 days; the content of banana powder flavoring mixed with ceftriaxone decreased from 78.0% on day 0 to 76.3% after being placed at 60°C for 10 days, a smaller decrease. Therefore, banana powder flavoring is preferred as the fragrance agent in the ceftriaxone composition.

[0068] Test case This test example performed performance tests on the ceftoranil compositions and granule samples from the examples and comparative examples, including: (1) Evaluation of dissolution performance Dissolution evaluation was performed on different ceftorepnitin granule samples prepared in Examples 1-8 and the commercial product Meiji Seika Pharma Co., Ltd., where Meiji Seika is the original ceftorepnitin granule 50mg (potency) / 0.5g / bag imported from Meiji Seika Pharma Co., Ltd., and the commercial name is Meiji Seika.

[0069] Because amorphous cefotaxime has high solubility in pH 1.2 medium, the dissolution rate was determined using pH 1.2 medium according to the imported drug registration standard. At 5 minutes, the dissolution rate exceeded 90%, indicating rapid dissolution with no discriminative power. Therefore, this study, referring to Chinese Pharmacopoeia General Chapter 8004 and related guidelines, used pH 4.5 medium for dissolution curve comparison and employed high-performance liquid chromatography (HPLC) for detection. The dissolution curve results for pH 4.5 medium are shown in Table 3. Table 3. Results of dissolution curve determination in pH 4.5 medium (unit: %)

[0070] Table 3 shows that the dissolution curves of the granule samples from Examples 1-8 of this invention are similar to those of the MeiAike granules in pH 4.5 medium. Among them, the dissolution curve of Example 2 shows the highest similarity to MeiAike and is superior. Therefore, this invention can directly use amorphous cefotaxime raw material and related excipients in a granulation process to prepare products that meet the product quality requirements. The preparation process of the cefotaxime composition of this invention is feasible and relatively simple.

[0071] (2) Stability test The ceftoranil granule samples prepared in Examples 2 and 5 were subjected to stability testing together with the commercial product, Meiai Ke: an accelerated stability study was conducted for 3 months (40±2℃, RH 75±5%), referring to the drug registration standard approved by the National Medical Products Administration (standard number: YBY72422024). The test items included appearance, content, related substances, and loss on drying. The content and related substances were determined using high performance liquid chromatography.

[0072] The method for determining the content was as follows: The chromatographic conditions were as follows: an octadecylsilane-bonded silica gel column (4.6×150mm, 5μm) was used as the packing material, the mobile phase was acetic acid-ammonium acetate buffer-methanol-acetonitrile (450:275:275), the detection wavelength was 230nm, the column temperature was 30℃, and the flow rate was 0.9ml / min.

[0073] The determination method for related substances: Chromatographic conditions: An octadecylsilane-bonded silica gel column (4.6×150mm, 5μm) was used; mobile phase A was pH 3.0 citric acid-sodium citrate buffer-methanol-acetonitrile (90:5:5), mobile phase B was pH 3.0 citric acid-sodium citrate buffer-methanol-acetonitrile (10:45:45), column temperature was 30℃, detection wavelength was 254nm, flow rate was 1.0ml / min, and elution program is shown in Table 4 (the sensitivity solution and control solution can be selected according to the actual peak situation using gradient elution in Table 5).

[0074] Table 4 Elution Procedure

[0075] Table 5 Elution Procedure

[0076] The test results for samples after 0 days and after 3 months of accelerated testing are detailed in Table 6.

[0077] Table 6. Accelerated test (40±2℃, RH 75±5%) stability results

[0078] The results in Table 6 show that the properties, loss on drying, content, and related substances of the embodiments of the present invention and the comparative product—Mei'ai Ke—all meet the standard requirements. The formulation and preparation process of the present invention can achieve stable and controllable product.

[0079] This invention provides a ceftorpirum ester composition and its preparation method. The formulation and process provided in the examples can achieve the stability of amorphous ceftorpirum ester, and the prepared granules have good stability, with dissolution curves that fit the reference formulation. The granules are obtained by dry granulation, which is prepared by mixing amorphous ceftorpirum ester with excipients.

[0080] Unless otherwise specified, the term "about" in this invention actually means that the allowable error is within ±2%, for example, about 100 is actually 100 ± 2% × 100. The terms "room temperature" and "room temperature" in this invention, unless otherwise specified, are approximately 20~30℃. The phrase "between..." in this invention includes the number itself; for example, "between 2 and 3" includes the endpoints 2 and 3.

[0081] The embodiments of the present invention have been described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments, and various changes can be made within the scope of knowledge possessed by those skilled in the art without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A ceftoranil composition, characterized in that, The invention includes amorphous cefotaxime and an excipient containing a polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer. The excipient further includes at least one of water-soluble chitosan or acrylic resin material. The ratio of the sum of the mass of the water-soluble chitosan and acrylic resin material to the mass of the polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer and the mass of amorphous cefotaxime is (1~5):(0.05~0.5):(5~15).

2. The ceftoranil composition according to claim 1, characterized in that, The polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer includes poloxamer 188.

3. The ceftoranil composition according to claim 1, characterized in that, The acrylic resin material includes a copolymer of methacrylic acid and methyl methacrylate; Preferably, the acrylic resin material includes at least one of Eutrich L-type or Eutrich S-type.

4. The ceftoranil composition according to claim 1, characterized in that, The water-soluble chitosan is carboxymethyl chitosan; Preferably, the degree of deacetylation of the carboxymethyl chitosan is 70% to 85%; and / or, the mass ratio of the amorphous cefotaxime to the carboxymethyl chitosan is 100:(10 to 30).

5. The ceftoranil composition according to claim 1, characterized in that, The excipients further include hydroxypropyl methylcellulose; and / or, the excipients further include at least one of sucrose or lactose; and / or, the excipients further include a disintegrant. Preferably, the mass ratio of the amorphous cefotaxime to the hydroxypropyl methylcellulose is (5~15):(1~7); and / or, the mass ratio of the amorphous cefotaxime to the sum of the masses of the sucrose and lactose is (5~15):(50~90); and / or, the disintegrant comprises croscarmellose sodium. Preferably, the mass ratio of the amorphous cefotaxime to the cross-linked sodium carboxymethyl cellulose is (5~15):(0.5~5).

6. The ceftoranil composition according to claim 1, characterized in that, The excipients also include silica; and / or, the excipients also include propylene glycol alginate; Preferably, the mass ratio of the amorphous cefotaxime to the silica is (5~15):(0.5~5); and / or, the mass ratio of the amorphous cefotaxime to the propylene glycol alginate is (5~15):(0.01~0.5).

7. The ceftoranil composition according to claim 1, characterized in that, The excipients also include flavoring agents; Preferably, the mass ratio of the amorphous cefotaxime to the flavoring agent is (5~15):(3~20); and / or, the flavoring agent includes at least one of a flavoring agent or a sweetener; Preferably, the flavoring agent is a fragrance; and / or, the sweetener includes at least one of aspartame or sucralose; and / or, the mass ratio of the amorphous ceftriaxone to the sweetener is (5~15):(2.5~15).

8. The ceftoranil composition according to claim 1, characterized in that, The ceftoranil composition comprises, by mass fraction, the following components: Amorphous ceftriaxone 10% 1%~3% croscarmellose sodium cellulose Sucrose content: 63.7%~75.9% Poloxamer 1880.09%~0.2% Hydroxypropyl methylcellulose 2%~4% At least 1% to 3% of Eutrich L-type, Eutrich S-type, and carboxymethyl chitosan. 1%~2% silicon dioxide Banana powder flavoring 1%~2% Aspartame 8%~12% Propylene glycol alginate 0.01%~0.1%.

9. A method for preparing the ceftoranil composition according to claim 1, characterized in that, The process includes the following steps: mixing the raw materials containing amorphous cefotaxime and excipients to obtain the cefotaxime composition; Preferably, the preparation method includes the following steps: S1, a portion of amorphous ceftriaxone is mixed with hydroxypropyl methylcellulose, acrylic resin material and / or water-soluble chitosan, disintegrant, a portion of flavoring agent, and silicon dioxide, and then mixed with a portion of sucrose to obtain premix I; The remaining amorphous cefotaxime was mixed with another portion of the flavoring agent, polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, and propylene glycol alginate, and then mixed with the remaining sucrose to obtain premix II. S2, take premix I and premix II and dry granulate them, pass them through a 30-200 mesh sieve for granulation, and then mix them with the remaining flavoring agent to obtain the ceftoranil composition.

10. A ceftoranil formulation, characterized in that, Includes the ceftoranil composition according to any one of claims 1 to 8; Preferably, the formulation comprises at least one of tablets or granules.

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