Cefcapene pivoxil hydrochloride granule and preparation method therefor

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and in particular to, a cefcapene pivoxil hydrochloride granule and a preparation method therefor. The cefcapene pivoxil hydrochloride granule has a pellet core, an isolation layer, and a taste masking layer from inside to outside; the composition of the pellet core comprises cefcapene pivoxil hydrochloride; and the composition of the taste masking layer comprises a butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer. The cefcapene pivoxil hydrochloride granule can ensure complete taste masking in the administration stage, and can be quickly dissolved out after administration, thereby improving the medication experience of a patient and improving compliance, and maintaining the drug efficacy.

Description

A cefoperazone hydrochloride granule and its preparation method

[0001] Related applications

[0002] This application claims priority to Chinese patent application filed on August 26, 2024, application number 202411178612X, entitled "A cefoperazone hydrochloride granules and a method for preparing the same", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pharmaceutical formulation technology, specifically to a cefoperazone hydrochloride granule and its preparation method. Background Technology

[0004] Oral administration is a common method of drug delivery, and it is generally more readily accepted by patients compared to other methods such as injection. Among oral drug formulations, granules are easy to swallow and allow for convenient dosage adjustments, making them particularly suitable for children and elderly patients. However, many effective drug ingredients have a strong bitter taste, resulting in a poor oral experience for patients and significantly impacting their medication adherence.

[0005] Traditional methods for masking the bitterness of drugs aim to reduce the chance of the drug directly contacting the taste buds. One such method is encapsulation technology, which wraps the bitter-tasting drug in a core. The encapsulation layer is designed to reduce drug exudation during administration but dissolve rapidly in the body, thus striking a balance between reducing the perceived bitterness and ensuring effective drug release. This design presents significant challenges to the material design of the encapsulation layer. Furthermore, encapsulation technology also faces challenges such as complex formulation processes, increased costs, and potential impacts on drug dissolution rates.

[0006] Cefcaptin hydrochloride has a low bitterness threshold (70 μg / ml), meaning it can be detected by patients even at low concentrations. While methods have attempted to mask its bitterness through wax coating, these methods suffer from a narrow operational window and incomplete bitterness masking. For example, the wax-coated formulation proposed in patent CN100528233C, although reducing bitterness to some extent, still requires preparation and administration within a very short time, which is impractical for most patients.

[0007] Therefore, it is necessary to develop a cefoperazone hydrochloride formulation that can completely mask the bitterness without affecting its absorption in the body. Summary of the Invention

[0008] Based on this, one or more embodiments of this application provide cefoperazone hydrochloride granules and a method for preparing the same. These cefoperazone hydrochloride granules can completely mask the bitterness during the dissolving stage and dissolve rapidly after administration, thereby improving the patient's medication experience and compliance, without affecting the drug's efficacy.

[0009] The technical solution of this application includes the following:

[0010] A cefcapine hydrochloride granule, wherein the cefcapine hydrochloride granule has a core, an isolation layer and a flavor-masking layer from the inside out;

[0011] The core of the pellet comprises cefoperazone hydrochloride;

[0012] The flavor-masking layer comprises a copolymer of butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate.

[0013] Optionally, the weight percentage of each layer in the cefoperazone hydrochloride particles is as follows:

[0014] The pellet core contains 10% to 90% of the pellet.

[0015] The isolation layer comprises 3% to 60%.

[0016] The masking layer comprises 5% to 70%.

[0017] Optionally, the core pellet may further comprise cefoperazone hydrochloride, filler, binder, and first anti-adhesion agent;

[0018] The isolation layer comprises a first film-forming agent and a second anti-adhesion agent;

[0019] The flavor-masking layer comprises a second film-forming agent, an emulsifier, a neutralizing agent, and a third anti-adhesion agent, wherein the second film-forming agent is selected from the butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer.

[0020] Optionally, the weight percentage of each component in the pellet core is as follows:

[0021] Optionally, the weight percentage of each component in the isolation layer is as follows:

[0022] The first film-forming agent is 20%–90%.

[0023] The second anti-adhesion agent comprises 10% to 80%.

[0024] Optionally, the weight percentage of each component in the flavor-masking layer is as follows:

[0025] Optionally, the filler is selected from microcrystalline cellulose, sucrose, starch, or any combination of the above components.

[0026] Optionally, the adhesive is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, or any combination of the above components.

[0027] Optionally, the first anti-adhesion agent, the second anti-adhesion agent, and the third anti-adhesion agent are each independently selected from sodium dodecyl sulfate, talc, magnesium stearate, titanium dioxide, or any combination of the above components.

[0028] Optionally, the first film-forming agent is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, sucrose, or any combination of the above components.

[0029] Optionally, the emulsifier is selected from sodium dodecyl sulfate, polysorbate, or any combination of the above components.

[0030] Optionally, the neutralizing agent is selected from stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, or any combination of the above components.

[0031] Optionally, the cefoperazone hydrochloride granules have a drug exudation concentration of <40 μg / ml within 10 min in a solvent environment with pH 6.8 to 7.2; and the cefoperazone hydrochloride granules have a drug dissolution rate of >80% within 30 min in a solvent environment with pH ≤4.5.

[0032] A method for preparing cefoperazone hydrochloride granules according to any of the above technical solutions includes:

[0033] Prepare the first material, the second material, and the third material according to the composition of the pellet core, the isolation layer, and the flavor-masking layer, respectively;

[0034] Prepare pellet cores using the first material;

[0035] The second material is coated onto the pellet core and dried to form the isolation layer;

[0036] The third material is coated onto the isolation layer and dried to form the odor-masking layer.

[0037] Optionally, the method for preparing pellet cores using the first material includes fluidized bed granulation, high-efficiency wet granulation, extrusion spheronization granulation, and drying to obtain dry pellets.

[0038] Optionally, the method of coating the second material onto the pellet core includes fluidized bed coating.

[0039] Optionally, the method of coating the third material onto the isolation layer includes fluidized bed coating.

[0040] Traditional encapsulation techniques are not ideal for masking the taste of drugs with a low bitterness threshold, such as cefoperazone hydrochloride. This application, through in-depth research on the encapsulation principle, develops a cefoperazone hydrochloride granule formulation. After being mixed with water, the drug's exudate concentration remains below the bitterness threshold for a period of time. During this process, patients will not perceive the bitterness when taking the medication. After swallowing, it can quickly dissolve in the stomach without hindering the absorption of the drug in the body.

[0041] The cefcapine hydrochloride granules of this application have, from the inside out, a core, an isolation layer, and a taste-masking layer; the core contains cefcapine hydrochloride; the taste-masking layer is made of butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer. Based on its rational formulation and structural design, these cefcapine hydrochloride granules are insoluble or slightly soluble in water, and dissolve at pH < 5.5. Therefore, when taken orally, the drug is minimally leached, achieving a good taste-masking effect. After administration, they dissolve rapidly under the action of gastric acid, allowing for normal drug release and absorption.

[0042] The above description is only an overview of the technical solution of this application. In order to better understand the technical means of this application and to implement it in accordance with the contents of the specification, and to make the above and other objects, features and advantages of this application more obvious and understandable, the following are specific embodiments of this application. Attached Figure Description

[0043] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0044] Figure 1 shows the relationship between the drug exudation concentration and time in neutral aqueous solution for each granule corresponding to Table 7.

[0045] Figure 2 shows the relationship between the drug dissolution rate and time in an aqueous solution at pH 1.0 for each granule corresponding to those in Table 8.

[0046] Figure 3 shows the relationship between the drug dissolution rate and time in an aqueous solution at pH 4.5 for each granule corresponding to those in Table 9. Detailed Implementation

[0047] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0048] 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 herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0049] the term:

[0050] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0051] The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations encompass any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B.

[0052] In this application, terms such as "further," "even further," and "particularly" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0053] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0054] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, optional numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0055] In this application, weight can be a well-known unit of mass in the chemical industry, such as μg, mg, g, or kg.

[0056] One aspect of this application provides cefoperazone hydrochloride granules. Traditional oral cefoperazone hydrochloride formulations cannot completely eliminate bitterness, but can only reduce the perception of bitterness to a certain extent. This application, through in-depth research on the encapsulation principle, develops a cefoperazone hydrochloride granule formulation in which the drug's transdermal concentration remains below the bitterness threshold for a period of time after being mixed with water. During this process, the patient will not perceive bitterness when taking the medication. After swallowing, it can quickly dissolve in the stomach without hindering the absorption of the drug in the body.

[0057] One embodiment of the cefoperazone hydrochloride granules of this application comprises, from the inside out, a core, an isolation layer, and a taste-masking layer; the core is composed of cefoperazone hydrochloride; the taste-masking layer is composed of butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer. Based on its rational formulation and structural design, the cefoperazone hydrochloride granules of this application are insoluble or slightly soluble in water, and dissolve at pH < 5.5. Therefore, when taken orally, the drug is essentially not leached out, achieving a good taste-masking effect. After administration, it dissolves rapidly under the action of gastric acid, allowing for normal drug release and absorption.

[0058] Optionally, the weight percentage of each layer in the cefoperazone hydrochloride granules is as follows:

[0059] Core content 10%–90%,

[0060] The isolation layer is 3% to 60%.

[0061] The masking layer comprises 5% to 70%.

[0062] In one embodiment, the weight percentage of the pellet core in the cefoperazone hydrochloride granules can be 10% to 90%, further can be 40% to 80%, and even further can be 50% to 70%. For example, the weight percentage can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, etc.

[0063] In one embodiment, the weight percentage of the isolation layer in the cefoperazone hydrochloride particles can be 3% to 60%, further can be 10% to 40%, and even further can be 15% to 25%. For example, the weight percentage can be 3%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 40%, 50%, 60%, etc.

[0064] In one embodiment, the flavor-masking layer in the cefoperazone hydrochloride granules may be 5% to 70% by weight, further 15% to 50%, and even further 15% to 30%. For example, the weight percentage may be 5%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, etc.

[0065] In one embodiment, the cefcapine hydrochloride granules, by weight, comprise 200 parts of a core, 50-70 parts of an isolation layer, and 20-80 parts of a flavor-masking layer. The weight percentage of the isolation layer can be independently selected from 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, etc.; the weight percentage of the flavor-masking layer can be independently selected from 20, 22.75, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 74.75, 75, 80, etc.

[0066] Optionally, the pellet core also includes cefoperazone hydrochloride, filler, binder and first anti-adhesion agent;

[0067] The isolation layer consists of a first film-forming agent and a second anti-adhesion agent;

[0068] The flavor-masking layer consists of a second film-forming agent, an emulsifier, a neutralizer, and a third anti-adhesion agent. The second film-forming agent is selected from butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer.

[0069] Optionally, the weight percentages of each component in the pellet core are as follows:

[0070] In one embodiment, the weight percentage of cefoperazone hydrochloride in the pellet core can be 5% to 80%, more preferably 10% to 50%, more preferably 30% to 40%, and for example, the weight percentage can be 5%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, etc.

[0071] In one embodiment, the filler content in the pellet core can be 5% to 70% by weight, more preferably 40% to 70%, more preferably 50% to 60%, and for example, the weight percentage can be 5%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, etc.

[0072] In one embodiment, the adhesive content in the core pellet can be 0.2% to 20% by weight, more preferably 10% to 20%, more preferably 10% to 15%, and for example, the weight percentage can be 0.2%, 0.5%, 1%, 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, etc.

[0073] In one embodiment, the weight percentage of the first anti-adhesion agent in the pellet core can be 0.01% to 10%, more preferably 0.1% to 5%, more preferably 1% to 3%, and for example, the weight percentage can be 0.01%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%, 5%, 8%, 10%, etc.

[0074] In one embodiment, the pellet core comprises, by weight, 100 parts cefcapine hydrochloride, 100-200 parts filler, 20-40 parts adhesive, and 1-10 parts first anti-adhesion agent. The weight percentage of the filler can be independently selected from 100, 110, 120, 130, 140, 150, 160, 170, 180, 200, etc.; the weight percentage of the adhesive can be independently selected from 20, 22, 25, 28, 30, 32, 35, 38, 40, etc.; and the weight percentage of the first anti-adhesion agent can be independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0075] Optionally, the weight percentage of each component in the isolation layer is as follows:

[0076] The first film-forming agent is 20%–90%.

[0077] The second anti-adhesion agent comprises 10% to 80%.

[0078] In one embodiment, the weight percentage of the first film-forming agent in the isolation layer can be 20% to 90%, more specifically 40% to 60%, and for example, the weight percentage can be 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, etc.

[0079] In one embodiment, the weight percentage of the second anti-adhesion agent in the isolation layer can be 10% to 80%, more specifically 40% to 60%, and for example, the weight percentage can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, etc.

[0080] Preferably, the second anti-adhesion agent comprises talc and magnesium stearate in a weight ratio of (1 to 3):1, such as 1:1, 2:1, 3:1, etc.

[0081] Optionally, the weight percentage of each component in the odor-masking layer is as follows:

[0082] In one embodiment, the weight percentage of the second film-forming agent in the odor-masking layer can be 15% to 85%, more specifically 40% to 65%, and for example, the weight percentage can be 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, etc.

[0083] In one embodiment, the weight percentage of the emulsifier in the flavor-masking layer can be 0.2% to 8.5%, more specifically 1% to 8%, more specifically 5% to 8%, and for example, the weight percentage can be 0.2%, 0.5%, 1%, 1.5%, 2%, 3%, 5%, 6%, 8%, 8.5%, etc.

[0084] In one embodiment, the neutralizing agent in the odor-masking layer may be 0.3% to 13% by weight, more preferably 1% to 10%, more preferably 5% to 8%, and for example, the weight percentage may be 0.3%, 1%, 1.5%, 2%, 3%, 5%, 6%, 8%, 10%, 11%, 13%, etc.

[0085] In one embodiment, the weight percentage of the third anti-adhesion agent in the odor-masking layer can be 10% to 80%, more preferably 20% to 50%, more preferably 30% to 40%, and for example, the weight percentage can be 10%, 12%, 15%, 17%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, etc.

[0086] In one embodiment, the flavor-masking layer comprises, by weight, 30 parts of a second film-forming agent, 15-25 parts of a third anti-adhesion agent, 2-8 parts of an emulsifier, and 2-8 parts of a neutralizer. The weight percentage of the third anti-adhesion agent can be independently selected from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, etc.; the weight percentage of the emulsifier can be independently selected from 2, 3, 4, 5, 6, 7, 8, etc.; and the weight percentage of the neutralizer can be independently selected from 2, 3, 4, 5, 6, 7, 8, etc.

[0087] Optionally, the filler is selected from microcrystalline cellulose, sucrose, starch, or any combination of the above components.

[0088] Optionally, the adhesive is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, or any combination of the above components.

[0089] Optionally, the first anti-adhesion agent, the second anti-adhesion agent, and the third anti-adhesion agent are each independently selected from sodium dodecyl sulfate, talc, magnesium stearate, titanium dioxide, or any combination of the above components.

[0090] Optionally, the first film-forming agent is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, sucrose, or any combination of the above components.

[0091] Optionally, the emulsifier is selected from sodium dodecyl sulfate, polysorbate, or any combination of the above components.

[0092] Optionally, the neutralizing agent is selected from stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, or any combination of the above components.

[0093] In one embodiment, the cefoperazone hydrochloride granules of this application exhibit a drug transudate concentration of <40 μg / ml within 10 minutes in a solvent environment with pH 6.8–7.2; and the cefoperazone hydrochloride granules exhibit a drug dissolution rate of >80% within 30 minutes in a solvent environment with pH ≤4.5. This satisfies the requirement that the drug transudate amount is below the bitterness threshold (transudate concentration below 40 μg / ml) during patient administration, while simultaneously ensuring rapid dissolution of the drug in acidic gastric juice (pH below 4.5) after entering the stomach.

[0094] This application also provides a method for preparing cefoperazone hydrochloride granules according to any of the above technical solutions, comprising:

[0095] Prepare the first material, the second material, and the third material according to the composition of the core, the isolation layer, and the flavor-masking layer, respectively;

[0096] The pellet core was prepared using the first material;

[0097] The second material is coated onto the pellet core and dried to form an isolation layer;

[0098] The third material is wrapped around the isolation layer and dried to form a odor-masking layer.

[0099] Optionally, the method for preparing pellet cores using the first material includes fluidized bed granulation, high-efficiency wet granulation, extrusion spheronization granulation, and drying to obtain dry pellets.

[0100] Optionally, the method of coating the second material onto the pellet core includes fluidized bed coating.

[0101] Alternatively, the method of coating the isolation layer with a third material includes fluidized bed coating.

[0102] The following are some specific examples.

[0103] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0104] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0105] I. Preparation of cefoperazone hydrochloride granules

[0106] Example 1

[0107] This embodiment provides a method for preparing cefoperazone hydrochloride granules S1, the steps of which are as follows:

[0108] (1) Weigh the first material, the second material and the third material used to prepare the pellet core, the isolation layer and the flavor masking layer according to Table 1, Table 2 and Table 3.

[0109] Table 1. Material composition of the first material used to prepare pellet cores.

[0110] Table 2. Material composition of the second material used to prepare the isolation layer.

[0111] Table 3. Material composition of the third material used to prepare the flavor-masking layer.

[0112] (2) Take the weighed materials of the first material, mix all materials except microcrystalline cellulose pellets to form a first suspension, and then use microcrystalline cellulose pellet core as substrate, mix with the first suspension in a fluidized bed, dry, and obtain pellet core S1, take 200g for later use.

[0113] (3) Take the weighed materials of the second material, mix them to form a second suspension, and then use the 200g pellet core S1 obtained in step (2) as the substrate, mix it with the second suspension in a fluidized bed, dry it, and obtain the isolation layer particles. Take 200g for later use.

[0114] (4) Take the weighed materials of the third material, mix them to form a third suspension, and then use the 200g of the isolation layer particles obtained in step (3) as the substrate to mix with the third suspension in a fluidized bed and dry. The weight ratio of the core, isolation layer and flavor masking layer of the cefoperazone hydrochloride particles S1 obtained in this way is 200:60:74.75.

[0115] Example 2

[0116] Cefcaptin hydrochloride granules S2 were prepared using essentially the same method as in Example 1, except that the composition of the third material used to prepare the flavor-masking layer is shown in Table 4. All other operations, material compositions, and amounts were the same as in Example 1. The weight ratio of the core, isolation layer, and flavor-masking layer of the cefcaptin hydrochloride granules S2 obtained in this way was 200:60:22.75.

[0117] Table 4. Material composition of the third material used to prepare the flavor-masking layer.

[0118] Comparative Example 1

[0119] Cefcapine hydrochloride granules D1 were prepared using essentially the same method as in Example 1, except that the composition of the third material used to prepare the flavor-masking layer is shown in Table 5. All other operations, material compositions, and amounts were the same as in Example 1. The weight ratio of the core, isolation layer, and flavor-masking layer of the cefcapine hydrochloride granules D1 obtained in this way was 200:60:221.

[0120] Table 5. Material composition of the third material used to prepare the flavor-masking layer.

[0121] Comparative Example 2

[0122] Cefcapine hydrochloride granules D2 were prepared using essentially the same method as in Example 1, except that the composition of the third material used to prepare the flavor-masking layer is shown in Table 6. All other operations, material compositions, and amounts were the same as in Example 1. The weight ratio of the core, isolation layer, and flavor-masking layer of the cefcapine hydrochloride granules D2 obtained in this way was 200:60:208.

[0123] Table 6. Material composition of the third material used to prepare the flavor-masking layer.

[0124] Comparative Example 3

[0125] This comparative example provides a method for preparing cefoperazone hydrochloride particles D3, which, compared to Example 1, omits only the step of coating the isolation layer, as follows:

[0126] (1) Weigh the first material and the third material used to prepare the core and flavor masking layer according to Table 1 and Table 3 in Example 1.

[0127] (2) Take the weighed materials of the first material, mix all materials except microcrystalline cellulose pellets to form a first suspension, and then use microcrystalline cellulose pellet core as substrate, mix with the first suspension in a fluidized bed, dry, and obtain pellet core D3, take 200g for later use.

[0128] (3) Take the weighed materials of the third material, mix them to form the third suspension, and then use the 200g pellet core D3 obtained in step (2) as the substrate, mix it with the third suspension in a fluidized bed, and dry it. The weight ratio of the pellet core and the flavor masking layer of the cefoperazone hydrochloride granules D3 obtained in this way is 200:57.5.

[0129] Comparative Example 4

[0130] Cefcapine hydrochloride granules D4 were prepared using essentially the same method as in Example 1, the difference being that the weight ratios of the core, the isolation layer, and the flavor-masking layer were different, as detailed below:

[0131] (1) Prepare the first material, the second material, and the third material using the same steps as in Example 1;

[0132] (2) Prepare pellet core D4 using the same steps as in Example 1.

[0133] (3) Take the weighed materials of the second material, mix them to form a second suspension, and then take an appropriate amount of the pellet core D4 obtained in step (2) as the substrate, mix it with the second suspension in a fluidized bed, and dry it. The weight ratio of pellet core to isolation layer in the isolation layer particles D4 obtained in this way is 100:2.

[0134] (4) Take the weighed materials of the third material, mix them to form the third suspension, and then take an appropriate amount of the isolation layer particles D4 obtained in step (3) as the substrate, mix them with the third suspension in a fluidized bed, and dry them. The weight ratio of the core, isolation layer and flavor masking layer in the cefoperazone hydrochloride particles D4 obtained in this way is 100:2:1.

[0135] II. In vitro exudation and dissolution test of cefcapine hydrochloride particles

[0136] The cefcapine hydrochloride granules from Examples 1-2 and Comparative Examples 1-4, as well as the pellet core S1 and isolation layer particles S1 prepared in Example 1 (using cefcapine C... 17 H 19Samples (containing 50 mg of N5O6S2) were taken for leaching and dissolution tests, and the results are shown in Tables 7-9 and Figures 1-3.

[0137] Leakage method: Add 50mg API to each beaker, add 30ml of water, clamp onto a vibrating device, vibrate at a frequency of 3 times / minute, and take samples at 1, 5 and 10 minutes respectively to detect the API content by HPLC.

[0138] Dissolution method: API was added at a dose of 50 mg, and the dissolution rate of API was measured in aqueous solutions at pH 1.0 and pH 4.5 for different time periods using a paddle method at a speed of 75 rpm.

[0139] Table 7. Statistical results of drug exudation concentration of each granule formulation in neutral aqueous solution over time.

[0140] Table 8. Statistical results of drug dissolution rate over time in aqueous solution at pH 1.0 for each granule formulation.

[0141] Table 9. Statistical results of drug dissolution rate over time in aqueous solution at pH 4.5 for each granule formulation.

[0142] Figure 1 shows the relationship between the drug exudation concentration and time in a normal aqueous solution (neutral pH) for each granule corresponding to Table 7; Figure 2 shows the relationship between the drug dissolution rate and time in an aqueous solution at pH 1.0 for each granule corresponding to Table 8; Figure 3 shows the relationship between the drug dissolution rate and time in an aqueous solution at pH 4.5 for each granule corresponding to Table 9.

[0143] As shown in Figures 1-3, in the solution dissolution experiment, the drug dissolution concentrations of the individual pellet core (pill core S1) and the individual isolation layer particles (isolation layer particles S1) reached 253 μg / ml and 127 μg / ml respectively after one minute, far exceeding the bitterness threshold of 70 μg / ml. The finished granules of Examples 1 and 2 had dissolution concentrations of 21 μg / ml and 36 μg / ml respectively after 10 minutes, which were lower than the bitterness threshold of 70 μg / ml, and even lower than 40 μg / ml (this threshold has no bitterness). They achieved excellent taste masking effect during the 10-minute drug preparation process, allowing patients sufficient time for drug preparation and administration. The finished granules of Examples 1 and 2 had a dissolution rate of more than 80% after 30 minutes in dissolution media at pH 1.0 and pH 4.5, respectively, without hindering drug absorption in the body.

[0144] The finished granules of Comparative Example 1 and Comparative Example 2, coated with ethyl cellulose and acrylic resin (Eudragit L30D-55) respectively, achieved good taste masking effect in the solution exudation test (the exudation concentration was below the threshold of 40 μg / ml after 10 minutes). However, in the dissolution test, the cumulative dissolution amount did not exceed 20% after 30 minutes, which hindered the absorption of the drug in the body.

[0145] Comparative Examples 3 and 4 omitted the isolation layer and adopted different layer setting ratios, respectively. The finished granules could not achieve the expected effect in the liquid exudation test, which resulted in a relatively obvious bitter taste exudation during the dispensing stage.

[0146] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0147] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A cefoperazone hydrochloride granule, characterized in that, The cefoperazone hydrochloride granules have a core, an isolation layer, and a flavor-masking layer from the inside out. The core of the pellet comprises cefoperazone hydrochloride; The flavor-masking layer comprises a copolymer of butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate.

2. The cefoperazone hydrochloride granules according to claim 1, characterized in that, The weight percentages of each layer in the cefoperazone hydrochloride granules are as follows: the core is approximately 10% to 90%, the isolation layer is approximately 3% to 60%, and the flavor-masking layer is approximately 5% to 70%.

3. The cefoperazone hydrochloride granules according to claim 1 or 2, characterized in that, The core also includes a filler, a binder, and a first anti-adhesion agent; The isolation layer comprises a first film-forming agent and a second anti-adhesion agent; The flavor-masking layer comprises a second film-forming agent, an emulsifier, a neutralizer, and a third anti-adhesion agent. The second film-forming agent is selected from butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate copolymer.

4. The cefoperazone hydrochloride granules according to claim 3, characterized in that, The weight percentages of each component in the pellet core are as follows:

5. The cefoperazone hydrochloride granules according to claim 3 or 4, characterized in that, The weight percentages of the components in the isolation layer are as follows: the first film-forming agent is approximately 20% to 90%, and the second anti-adhesion agent is approximately 10% to 80%.

6. The cefoperazone hydrochloride granules according to any one of claims 3 to 5, characterized in that, The weight percentages of the components in the flavor-masking layer are as follows:

7. The cefoperazone hydrochloride granules according to any one of claims 3 to 6, characterized in that, The filler is selected from microcrystalline cellulose, sucrose, starch, or any combination of the above components.

8. The cefoperazone hydrochloride granules according to any one of claims 3 to 7, characterized in that, The adhesive is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch, or any combination of the above components.

9. The cefoperazone hydrochloride granules according to any one of claims 3 to 8, characterized in that, The first anti-adhesion agent, the second anti-adhesion agent, and the third anti-adhesion agent are each independently selected from sodium dodecyl sulfate, talc, magnesium stearate, titanium dioxide, or any combination of the above components.

10. The cefoperazone hydrochloride granules according to any one of claims 3 to 9, characterized in that, The first film-forming agent is selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, sucrose, or any combination of the above components.

11. The cefoperazone hydrochloride granules according to any one of claims 3 to 10, characterized in that, The emulsifier is selected from sodium dodecyl sulfate, polysorbate, or any combination of the above components.

12. The cefoperazone hydrochloride granules according to any one of claims 3 to 11, characterized in that, The neutralizing agent is selected from stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, or any combination of the above components.

13. The cefoperazone hydrochloride granules according to any one of claims 1 to 12, characterized in that, The cefoperazone hydrochloride granules, in a solvent environment with a pH of about 6.8 to 7.2, exhibit a drug exudation concentration of < about 40 μg / ml within about 10 minutes; and, in a solvent environment with a pH of about ≤4.5, the drug dissolution rate of the cefoperazone hydrochloride granules is > about 80% within about 30 minutes.

14. A method for preparing cefoperazone hydrochloride granules according to any one of claims 1 to 13, characterized in that, include: Prepare the first material, the second material, and the third material according to the composition of the pellet core, the isolation layer, and the flavor-masking layer, respectively; Prepare pellet cores using the first material; The second material is coated onto the pellet core and dried to form the isolation layer; and The third material is coated onto the isolation layer and dried to form the odor-masking layer.

15. The preparation method according to claim 14, characterized in that, Methods for preparing pellet cores using the first material include fluidized bed granulation, high-efficiency wet granulation, extrusion spheronization granulation, and drying to obtain dry pellets.

16. The preparation method according to claim 14 or 15, characterized in that, Methods for coating the pellet core with the second material include fluidized bed coating.

17. The preparation method according to any one of claims 14 to 16, characterized in that, The method of coating the third material onto the isolation layer includes fluidized bed coating.

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