Cefcapene pivoxil hydrochloride granules as well as preparation method and application thereof

Abstract

The invention discloses cefcapene pivoxil hydrochloride particles as well as a preparation method and application thereof. The cefcapene pivoxil hydrochloride particles comprise hydrophobic taste-masking particles, a hydrophilic taste-modifying layer and a hydrophilic surface modification layer, the hydrophilic taste-modifying layer is coated on at least part of the surface of the hydrophobic taste-masking particles; the hydrophilic surface modification layer is coated on at least part of the surface of the hydrophilic flavoring layer. By optimizing the particle structure design and adopting a multi-layer coated composite particle form, the hydrophilic outer layer is arranged on the basis of keeping the hydrophobic taste-masking function of the core, so that the wettability and the dispersity of the particles are remarkably improved, and the gravel feeling when the particles are taken after being mixed with water is eliminated; moreover, the sweet filler and the water-soluble adhesive are adopted in the granules, so that better dispersion of all the components can be promoted, a good taste masking effect can be ensured, and on the premise of ensuring the curative effect of the medicine, the medication compliance of child patients is remarkably improved by improving the taste, the safety and the convenience; the compound has a good application prospect in preparation of medicines for children.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a cefoperazone hydrochloride granule, its preparation method, and its application. Background Technology

[0002] In the field of pediatric medication, granules are widely considered one of the preferred solid oral dosage forms. This is mainly based on their significant advantages over tablets or capsules: ease of swallowing, dosage flexibility, and the ability to mask taste. Therefore, formulating drugs (especially bitter drugs that require taste masking) into granules is a common and preferred solution in the existing technology to meet the needs of pediatric medication.

[0003] Cefcaptin hydrochloride is known to have a strong, unpleasant bitter taste. For pediatric patients, palatability is crucial. A strong bitter taste can significantly reduce medication adherence in children, leading to vomiting, refusal to take the medication, and thus affecting treatment efficacy, potentially even delaying treatment due to insufficient dosage. Therefore, effective taste masking of cefcaptin hydrochloride is a key technological challenge and a necessary condition for its successful development into a child-friendly granule formulation.

[0004] To overcome the bitterness of cefcaptin hydrochloride, a common masking strategy in existing technologies is to establish a physical barrier to prevent drug molecules from dissolving prematurely in the mouth and coming into contact with taste buds. One key approach to achieving this physical barrier is increasing the hydrophobicity of the drug particles or their surface, such as through coating, adsorption, melt extrusion / hot melt coating, etc. These hydrophobic materials or structures effectively slow down the penetration of water molecules and the dissolution rate of the drug in saliva, thereby reducing the perception of bitterness in the mouth (the drug is mainly released in the stomach / intestine). However, significantly increased hydrophobicity has a noticeable negative effect: when these masking particles are added to water for oral administration, the particles are not easily wetted and have poor dispersibility. The resulting suspension has a severe "gritty" feel, and the particles tend to settle and clump, resulting in an unpleasant taste, which greatly reduces children's compliance and acceptance of the medication. Adding surfactants can help improve wetting and dispersibility, but may introduce safety and irritation risks.

[0005] In existing technologies, a physical barrier is created for cefoperazone hydrochloride particles to achieve a masking effect, and polyoxyethylene (160) polyoxypropylene (30) glycol and hydrated silica are added to improve the suspending and wettability of the particles in water. However, polyoxyethylene (160) polyoxypropylene (30) glycol has a low melting point and is unstable during accelerated stabilization, posing a risk to product quality.

[0006] In summary, current methods for masking the taste of bitter drugs in pediatric medications have the following limitations: ① The contradiction between masking performance and mouthfeel: There is a fundamental conflict between establishing an effective physical barrier (strong hydrophobicity) and achieving good dispersibility / mouthfeel (low gritty feel). ② Safety challenges: Surfactants introduced to improve mouthfeel may pose safety and irritation risks, especially for children with sensitive skin. ③ Potential performance conflicts: The wetting effect of surfactants may weaken the masking effect of the physical barrier because they promote particle wetting in the mouth, which in turn increases the risk of drug dissolution and exposure to taste buds; in addition, some surfactants themselves have unpleasant tastes or strong foaming properties, which will further affect the medication experience. ④ Increased complexity and cost of excipients: The need for additional surfactants and the need to solve the new problems they bring increases the complexity and cost of formulation, process optimization, and safety evaluation. Summary of the Invention

[0007] In order to overcome at least one of the problems existing in the prior art, one of the objectives of the present invention is to provide cefoperazone hydrochloride granules, which have good wetting and dissolving properties, good palatability, low impurity content, high solubility, and good stability.

[0008] The second objective of this invention is to provide a method for preparing the above-mentioned cefoperazone hydrochloride granules.

[0009] The third objective of this invention is to provide an application of the above-mentioned cefoperazone hydrochloride granules.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A first aspect of the present invention provides cefoperazone hydrochloride particles, comprising hydrophobic flavor-masking particles, a hydrophilic flavor-enhancing layer, and a hydrophilic surface-modifying layer; the hydrophilic flavor-enhancing layer covers at least a portion of the surface of the hydrophobic flavor-masking particles; the hydrophilic surface-modifying layer covers at least a portion of the surface of the hydrophilic flavor-enhancing layer. The hydrophobic flavor-masking particles comprise the following components: cefcapine hydrochloride, waxy flavor-masking material, disintegrant, first sweetener, and first water-soluble binder; the hydrophilic flavor-correcting layer comprises the following components: second sweetener and second water-soluble binder; the hydrophilic surface-modifying layer comprises the following components: hydrophilic modifier.

[0011] In this invention, the first sweetener and the second sweetener may be the same or different; the first water-soluble binder and the second water-soluble binder may be the same or different.

[0012] In some embodiments of the present invention, the waxy odor-masking material includes at least one of hydrogenated vegetable oil, hydrogenated castor oil, glyceryl distearate, or glyceryl behenate; in some specific embodiments of the present invention, the waxy odor-masking material includes hydrogenated vegetable oil, hydrogenated castor oil, or a combination thereof.

[0013] In some embodiments of the present invention, the disintegrant includes at least one of low-substituted hydroxypropyl cellulose, crospovidone, or crospovidone sodium carboxymethyl starch; in some specific embodiments of the present invention, the disintegrant is selected from low-substituted hydroxypropyl cellulose.

[0014] In some embodiments of the present invention, the first sweetener and the second sweetener each independently comprise at least one selected from sucrose, lactose, mannitol, sorbitol, pregelatinized starch, or xylitol; in some specific embodiments of the present invention, the first sweetener and the second sweetener each independently comprise sucrose, mannitol, or a combination thereof. In some embodiments of the present invention, the first sweetener comprises sucrose and mannitol; further, in the first sweetener, the mass ratio of sucrose to mannitol is 1:(0.5~2).

[0015] In some embodiments of the present invention, the second sweetener is selected from sucrose.

[0016] In some embodiments of the present invention, the first water-soluble adhesive and the second water-soluble adhesive each independently include at least one of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), methylcellulose (MC), or povidone (PVP); in some specific embodiments of the present invention, both the first water-soluble adhesive and the second water-soluble adhesive are selected from hydroxypropyl cellulose.

[0017] This invention uses safe sweeteners such as sucrose and mannitol, as well as water-soluble binders such as hydroxypropyl cellulose. This not only promotes better dispersion of the components and avoids the use of surfactants, thus improving the safety of the formulation, but also ensures a good taste masking effect and improves the palatability of the formulation.

[0018] In some embodiments of the present invention, the hydrophilic modifier includes at least one of gum arabic, xanthan gum, guar gum, carrageenan, or hydroxypropyl methylcellulose; in some specific embodiments of the present invention, the hydrophilic modifier is selected from gum arabic.

[0019] This invention uses conventional auxiliary materials and simplifies the production process, which not only reduces production costs but also makes it more conducive to industrial-scale production.

[0020] In some embodiments of the present invention, the mass of the hydrophobic odor-masking particles accounts for 50-80% of the total mass of the cefoperazone hydrochloride particles; in some specific embodiments of the present invention, the mass of the hydrophobic odor-masking particles accounts for 55-70% of the total mass of the cefoperazone hydrochloride particles.

[0021] In some embodiments of the present invention, the mass of the hydrophilic flavoring layer accounts for 10-40% of the total mass of the cefoperazone hydrochloride particles; for example, it can be any value or a range between 10%, 13.5%, 15%, 20%, 25%, 30%, 35% or 40%; in some specific embodiments of the present invention, the mass of the hydrophilic flavoring layer accounts for 15-35% of the total mass of the cefoperazone hydrochloride particles.

[0022] In some embodiments of the present invention, the mass of the hydrophilic surface modified layer accounts for 0.5-5% of the total mass of the cefoperazone hydrochloride particles; in some embodiments of the present invention, the mass of the hydrophilic surface modified layer accounts for 0.8-2.5% of the total mass of the cefoperazone hydrochloride particles.

[0023] In some embodiments of the present invention, the hydrophobic flavor-masking particles comprise the following components in parts by weight: 100-150 parts cefcaptin hydrochloride, 100-200 parts waxy flavor-masking material, 50-150 parts disintegrant, 150-300 parts first sweetener, and 5-15 parts first binder.

[0024] In some embodiments of the present invention, the hydrophilic flavoring layer comprises the following components in parts by weight: 200-400 parts of a second sweetener and 5-30 parts of a second binder.

[0025] This invention ensures that the drug can effectively block bitterness in the oral cavity and can be released in a timely manner in the gastrointestinal environment by precisely controlling the ratio of excipients and coating parameters, without affecting the bioavailability of the drug.

[0026] In some embodiments of the present invention, the cefoperazone hydrochloride particles do not contain surfactants.

[0027] This invention, through specific excipient selection and formulation design, can effectively improve the wettability and taste of hydrophobic particles without relying on surfactants, solving the technical problem that existing solutions require the simultaneous use of hydrophobic materials and surfactants. The cefoperazone hydrochloride granules of this invention not only reduce the complexity of the formulation but also reduce production costs.

[0028] In some embodiments of the present invention, the cefoperazone hydrochloride granules further include an added flavoring agent.

[0029] In some embodiments of the present invention, the added flavoring agent includes aspartame, flavoring, or a combination thereof.

[0030] In some embodiments of the present invention, the mass of the added flavoring agent accounts for 0.5 to 10% of the total mass of the cefoperazone hydrochloride granules; in some specific embodiments of the present invention, the mass of the added flavoring agent accounts for 1 to 8% of the total mass of the cefoperazone hydrochloride granules.

[0031] A second aspect of the present invention provides a method for preparing cefoperazone hydrochloride granules as described in the first aspect of the present invention, comprising the following steps: granulation and coating by melt method to obtain the cefoperazone hydrochloride granules.

[0032] In some embodiments of the present invention, the preparation method of the cefoperazone hydrochloride granules specifically includes the following steps: mixing the components of the hydrophobic flavor-masking granules at 50-100°C, melting and granulating, and cooling to obtain hydrophobic flavor-masking granules; mixing the hydrophobic flavor-masking granules with the components of the hydrophilic flavor-correcting layer at 50-100°C, drying to obtain the hydrophilic flavor-correcting layer; then adding the components of the hydrophilic surface modification layer, mixing at 50-100°C, drying to obtain the hydrophilic surface modification layer.

[0033] In some embodiments of the present invention, during melt granulation, the reaction temperature does not exceed the melting point of the wax-based odor-masking material.

[0034] In some specific embodiments of the present invention, the preparation method of the cefoperazone hydrochloride granules specifically includes the following steps: mixing the components of the hydrophobic flavor-masking granules at 60~70°C, melting and granulating, and cooling to obtain hydrophobic flavor-masking granules; mixing the hydrophobic flavor-masking granules with the components of the hydrophilic flavor-correcting layer at 60~90°C, drying to obtain the hydrophilic flavor-correcting layer; then adding the components of the hydrophilic surface modification layer, mixing at 60~70°C, drying to obtain the hydrophilic surface modification layer.

[0035] In some embodiments of the present invention, the method for preparing the cefoperazone hydrochloride particles further includes the following steps: after obtaining the hydrophilic surface modified layer, cooling is performed, and then an external flavoring agent is added and mixed.

[0036] A third aspect of the present invention is the use of cefoperazone hydrochloride granules as described in the first aspect of the present invention in the preparation of pediatric medicines.

[0037] Compared with existing technologies, the cefoperazone hydrochloride granules provided by this invention have better safety, better medication compliance and lower production costs, and are particularly suitable for the special requirements of pediatric medication.

[0038] The beneficial effects of this invention are as follows: By optimizing the particle structure design and adopting a multi-layered coated composite particle form, this invention significantly improves the wettability and dispersibility of the particles and eliminates the gritty feeling when dissolved in water while maintaining the core hydrophobic and taste-masking function. Furthermore, the use of sweeteners and water-soluble binders in the particles can promote better dispersion of each component and ensure a good taste-masking effect. Under the premise of ensuring the efficacy of the drug, this invention significantly improves the medication compliance of children by improving the taste, enhancing safety and convenience. It has good application prospects in the preparation of pediatric medicines. Attached Figure Description

[0039] Figure 1 This is a flowchart of the preparation process in Example 1 of the present invention. Detailed Implementation

[0040] The following specific embodiments further illustrate the content of the present invention in detail. It should also be understood that the following embodiments are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the principles described herein are all within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below. Unless otherwise specified, the raw materials, reagents, or apparatus used in the following embodiments and comparative examples can be obtained from conventional commercial sources or by existing known methods.

[0041] In the following examples and comparative examples, the D90 particle size of the raw material cefoperazone hydrochloride was less than 10 μm.

[0042] Example 1 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 1: Table 1 Raw material composition of Example 1

[0043] like Figure 1 The preparation flow chart shown illustrates the preparation of cefoperazone hydrochloride granules for this example, based on the raw materials listed in Table 1, using the following method: Preparation of hydrophobic odor-masking granules: Sieve all raw and auxiliary materials; except for hydroxypropyl cellulose, premix all raw and auxiliary materials for hydrophobic odor-masking granules and mix evenly to obtain premixed powder; place the premixed powder in a fluidized bed, set the inlet air temperature to 65℃, and when the material temperature reaches 40℃, use an atomizing spray gun to spray the binder hydroxypropyl cellulose into the premix for hot melt granulation. After spraying the binder, start drying. Heat until the material temperature reaches the hot melt temperature and maintain it for 10 minutes, then start cooling. Cool to 40℃ to obtain hydrophobic odor-masking granules.

[0044] Preparation of the hydrophilic flavoring layer: Add the prescribed amount of sucrose to a fluidized bed containing hydrophobic flavor-masking particles, set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray in the binder hydroxypropyl cellulose for one-step granulation, and then fluidize and dry until the moisture content is below 1.4%.

[0045] Preparation of hydrophilic surface modified layer: Set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray in the prescribed amount of gum arabic aqueous solution, carry out hydrophilic modification, fluidize and dry until the moisture content is below 1.4%, cool to the material temperature of 40℃, and take out the granules.

[0046] The particles that passed through a 35-mesh sieve were collected, and aspartame and orange powder flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride particles with a particle size of about 350 μm.

[0047] Example 2 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 2: Table 2 Raw material composition of Example 2

[0048] Based on the raw materials listed in Table 2, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hydrophobic odor-masking granules: The inlet air temperature is set to 65℃. When the material temperature reaches 40℃, hydroxypropyl cellulose is sprayed into the premix using an atomizing spray gun to form granules. After the adhesive is sprayed, drying begins. The material temperature is heated until it reaches the hot melt temperature and maintained for 10 minutes. Then, cooling begins. The hydrophobic odor-masking granules are obtained when the temperature is cooled to 40℃.

[0049] Preparation of hydrophilic flavoring layer: Add the prescribed amount of sucrose to a fluidized bed containing hydrophobic flavor-masking particles, set the inlet air temperature to 85℃, adjust the appropriate atomization pressure, spray in hydroxypropyl methylcellulose for granulation, and then fluidize and dry until the moisture content is below 1.4%.

[0050] Preparation of hydrophilic surface modified layer: Set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray in the prescribed amount of gum arabic aqueous solution, and after completion, fluidize and dry until the moisture content is below 1.4%, cool to the material temperature of 40℃, and take out the granules.

[0051] The particles that passed through a 35-mesh sieve were collected, and aspartame and orange powder flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0052] Example 3 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 3: Table 3 Raw material composition of Example 3

[0053] Based on the raw materials listed in Table 3, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hydrophobic odor-masking granules: The inlet air temperature is set to 65℃. When the material temperature reaches 40℃, hydroxypropyl cellulose is sprayed into the premix using an atomizing spray gun to form granules. After the adhesive is sprayed, drying begins. The material temperature is heated until it reaches the hot melt temperature and maintained for 10 minutes. Then, cooling begins. The hydrophobic odor-masking granules are obtained when the temperature is cooled to 40℃.

[0054] Preparation of hydrophilic flavoring layer: Add the prescribed amount of sucrose to a fluidized bed containing hydrophobic flavor-masking particles, set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray in hydroxypropyl cellulose for granulation, and then fluidize and dry until the moisture content is below 1.4%.

[0055] Preparation of hydrophilic surface modified layer: Set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray in the prescribed amount of gum arabic aqueous solution, and after completion, fluidize and dry until the moisture content is below 1.4%, cool to the material temperature of 40℃, and take out the granules.

[0056] The particles that passed through a 35-mesh sieve were collected, and aspartame and orange powder flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0057] Comparative Example 1 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 4: Table 4 Raw material composition of Comparative Example 1

[0058] Based on the raw materials listed in Table 4, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hot melt granules: Hot melt granulation is used. The inlet air temperature is set to 65℃. When the material temperature reaches 40℃, hydroxypropyl methylcellulose is sprayed into the premix using an atomizing spray gun to form granules. After the adhesive is sprayed, drying begins. The inlet air temperature is set to 85℃. The material temperature is heated until it reaches the hot melt temperature and maintained for 10 minutes. Then, cooling begins. The hot melt granules are obtained by cooling to 40℃.

[0059] The particles that passed through a 35-mesh sieve were collected, and aspartame and flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0060] Comparative Example 2 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 5: Table 5 Raw material composition of Comparative Example 2

[0061] Based on the raw materials listed in Table 5, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hot melt granules: Hot melt granulation is used. The inlet air temperature is set to 65℃. When the material temperature reaches 40℃, hydroxypropyl methylcellulose is sprayed into the premix using an atomizing spray gun to form granules. After the adhesive is sprayed, drying begins. The inlet air temperature is set to 85℃. The material temperature is heated until it reaches the hot melt temperature and maintained for 10 minutes. Then, cooling begins. The hot melt granules are obtained by cooling to 40℃.

[0062] The particles that passed through a 35-mesh sieve were collected, and aspartame, fragrance, and sodium lauryl sulfate were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0063] Comparative Example 3 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 6: Table 6 Raw material composition of Comparative Example 3

[0064] Based on the raw materials listed in Table 6, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of one-step granules: One-step granulation is adopted, with the inlet air temperature set at 65℃. When the material temperature reaches 40℃, hydroxypropyl methylcellulose is sprayed into the premix to form granules. Then, drying is started until the moisture content is below 1.4%. The granules are removed after cooling to a material temperature of 40℃.

[0065] The particles that passed through a 35-mesh sieve were collected, and aspartame and flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0066] Comparative Example 4 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 7: Table 7 Raw material composition of Comparative Example 4

[0067] Based on the raw materials listed in Table 7, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hydrophobic odor-masking granules: The inlet air temperature was set to 65℃. When the material temperature reached 40℃, hydroxypropyl cellulose was sprayed into the premix using an atomizing spray gun to form granules. After spraying the binder, drying was started. The material temperature was heated until it reached the hot melt temperature and maintained for 10 minutes. Then, cooling was started, and the hydrophobic odor-masking granules were obtained by cooling to 40℃. The granules were collected and passed through a 35-mesh sieve.

[0068] Preparation of flavored granules: Add the prescribed amount of sucrose and gum arabic to a fluidized bed, set the inlet air temperature to 85℃, adjust the appropriate atomization pressure, spray in hydroxypropyl cellulose for granulation, and after completion, fluidize and dry until the moisture content is below 1.4%, then remove the granules. Collect the granules that pass through a 35-mesh sieve.

[0069] The hydrophobic flavor-masking granules and flavor-correcting granules were mixed, and the prescribed amount of aspartame and orange powder flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0070] Comparative Example 5 A cefoperazone hydrochloride granule formulation has the following raw material composition as shown in Table 8: Table 8 Raw material composition of Comparative Example 5

[0071] Based on the raw materials listed in Table 8, the cefoperazone hydrochloride granules in this example were prepared according to the following method: Preparation of hydrophobic odor-masking granules: The inlet air temperature is set to 65℃. When the material temperature reaches 40℃, hydroxypropyl cellulose is sprayed into the premix using an atomizing spray gun to form granules. After the adhesive is sprayed, drying begins. The material temperature is heated until it reaches the hot melt temperature and maintained for 10 minutes. Then, cooling begins. The hydrophobic odor-masking granules are obtained when the temperature is cooled to 40℃.

[0072] Preparation of hydrophilic surface modified layer: Set the inlet air temperature to 65℃, adjust the appropriate atomization pressure, spray the prescribed amount of gum arabic aqueous solution into the fluidized bed containing hydrophobic odor-masking particles, and after completion, fluidize and dry until the moisture content is below 1.4%, cool to the material temperature of 40℃, and take out the particles.

[0073] The particles that passed through a 35-mesh sieve were collected, and aspartame and orange powder flavoring were added and mixed for 5 minutes to obtain cefcaptin hydrochloride granules.

[0074] Experimental Example 1 Particle settling state and palatability evaluation Approximately 0.5g of cefoperazone hydrochloride granules prepared in each example and comparative example were placed in a cup, and then 150mL of purified water was poured in. The suspension and sedimentation of the fine granules were observed visually. Six healthy volunteers with normal taste were selected, and four parallel samples were set up in each group. An appropriate amount was taken for the volunteers to taste, and the solution was left in the mouth for 10 seconds. After tasting, the volunteers spat it out and rinsed their mouths. The taste of each volunteer was recorded.

[0075] Palatability evaluation criteria: 1. Overall palatability ① Taste: Very bad (0 points), Poor (20 points), Neutral (50 points), Good (80 points), Excellent (100 points); ② Aftertaste: Very bad (0 points), Poor (20 points), Neutral (50 points), Good (80 points), Excellent (100 points); ③ Smell: Very bad (0 points), Poor (20 points), Neutral (50 points), Good (80 points), Excellent (100 points).

[0076] 2. Grainy sensation: Very obvious gritty sensation, unacceptable (0 points); Obvious gritty sensation, poor medication experience (20 points); Slight gritty sensation, slightly affects medication experience, but acceptable (50 points); Slight gritty sensation, but does not affect medication experience at all (80 points); No gritty sensation (100 points).

[0077] The experimental results are shown in Table 9. The results show that the hydrophilicity of the particles in Examples 1-3 was significantly improved, while achieving a good flavor-masking effect. Specifically, the proportion of the hydrophilic flavor-correcting layer in Example 3 was lower than that in Example 1, resulting in a decrease in particle hydrophilicity and mouthfeel compared to Example 1. This indicates that using a certain proportion of hydrophilic flavor-correcting layer in this invention is beneficial for further improving particle hydrophilicity and mouthfeel. Comparative Example 1 did not have a hydrophilic layer to improve sweetness hydrophilicity; the particles had poor wettability and a noticeable gritty texture. Comparative Example 2 added a surfactant, which significantly improved sedimentation, but easily caused raw material dissolution, destroying the flavor-masking effect. Comparative Example 3 did not use a physical barrier to mask the flavor; the particles had good sedimentation, but the bitterness was more pronounced. Comparative Example 4 did not coat the particles but mixed the flavor-correcting particles with the flavor-masking particles; the particles had poor hydrophilicity and a noticeable gritty texture. Comparative Example 5 had no hydrophilic flavor-correcting layer, and the particle mouthfeel was significantly reduced.

[0078] Table 9. Particle settling state and palatability evaluation results for each embodiment and comparative example.

[0079] Experimental Example 2 Evaluation of key quality attributes of particles According to the determination method for related substances and polymers in the import registration standard (JX20190125) for cefcapine hydrochloride granules, the content of related substances, polymer content and dissolution rate of cefcapine hydrochloride granules in the test examples and comparative examples were determined.

[0080] The experimental results are shown in Table 10. The results show that the contents of related substances and polymers in Examples 1-2 and Comparative Examples 1-4 all meet the standard requirements. However, the contents of Examples 1-2 are significantly lower than those in Comparative Examples 1-4. Examples 1-2 also have higher dissolution rates, meeting the standard requirements, while the dissolution rates of Comparative Examples 1 and 4 are lower than the standard requirements.

[0081] Table 10 Evaluation results of key particle quality attributes for each embodiment and comparative example.

[0082] Experimental Example 3 Particle stability evaluation Accelerated testing was conducted on the commercially available packaging of Examples 1-2 and Comparative Examples 1-2. The samples were placed under accelerated testing conditions (40°C / 75% RH) for 6 months, and the contents of related substances and polymers were tested. The experimental results are shown in Table 11 below. The results show that the variation range and amount of related substances and polymers in Examples 1-2 were significantly better than those in Comparative Examples 1-2.

[0083] Table 11. Particle stability evaluation results for each embodiment and comparative example.

[0084] In terms of performance optimization, this invention effectively eliminates the gritty feeling of traditional hydrophobic particles when taken orally, significantly improving the taste and suspension stability while maintaining good oral masking effect and ensuring normal drug release in the gastrointestinal tract without affecting therapeutic efficacy. From a production cost perspective, this invention uses conventional pharmaceutical excipients instead of expensive specialized coating materials, simplifying the production process, significantly reducing costs, and making it more suitable for industrial-scale production.

[0085] Of particular note is that this invention has been comprehensively optimized to meet the specific needs of pediatric medication. While ensuring efficacy, it significantly improves medication adherence in children by enhancing taste, safety, and convenience. This technology allows for flexible dosage adjustments based on the medication characteristics of children of different age groups, achieving an optimal balance between taste, safety, and efficacy, and providing a more ideal taste-masked granule solution for pediatric medication.

[0086] In this embodiment of the invention, firstly, regarding the taste-masking technology, to improve problems such as poor particle wettability, drug floating on the water surface during patient administration, and poor drug compliance of taste-masked granules, highly safe sweeteners such as sucrose and mannitol are used in combination with specific pharmaceutical binders (such as HPC, HPMC, PVP, etc.) to completely replace traditional surfactants. This fundamentally avoids the gastrointestinal irritation and allergy risks that surfactants may cause, making the formulation particularly compliant with the safety requirements for pediatric medication. Secondly, in terms of particle structure design, a composite particle structure of "hydrophobic core-hydrophilic shell" has been developed. The core maintains hydrophobicity to ensure the taste-masking effect, while the shell imparts hydrophilicity, significantly improving the wettability and dispersibility of the particles, achieving a good balance between taste-masking effect and drug release.

[0087] In summary, this invention optimizes the particle structure design by employing a multi-layered coated composite particle form. While maintaining the core hydrophobic and taste-masking function, it incorporates a hydrophilic outer layer, thereby significantly improving the wettability and dispersibility of the particles and eliminating the gritty feeling when dissolved in water. Furthermore, the use of sweeteners and water-soluble binders in the particles promotes better dispersion of the components and ensures a good taste-masking effect. By improving taste, safety, and convenience while maintaining the efficacy of the drug, this invention significantly improves medication compliance in children, demonstrating promising application prospects in the preparation of pediatric medications.

Claims

1. A cefoperazone hydrochloride granule, characterized in that, It includes hydrophobic flavor-masking particles, a hydrophilic flavor-enhancing layer, and a hydrophilic surface-modifying layer; the hydrophilic flavor-enhancing layer covers at least a portion of the surface of the hydrophobic flavor-masking particles; the hydrophilic surface-modifying layer covers at least a portion of the surface of the hydrophilic flavor-enhancing layer; The hydrophobic flavor-masking particles comprise the following components: cefcapine hydrochloride, waxy flavor-masking material, disintegrant, first sweetener, and first water-soluble binder; the hydrophilic flavor-correcting layer comprises the following components: second sweetener and second water-soluble binder; the hydrophilic surface-modifying layer comprises the following components: hydrophilic modifier.

2. The cefoperazone hydrochloride granules according to claim 1, characterized in that, The waxy odor-masking material includes at least one of hydrogenated vegetable oil, hydrogenated castor oil, glyceryl distearate, or glyceryl behenate. And / or, the disintegrant includes at least one of low-substituted hydroxypropyl cellulose, crospovidone, or crospovidone sodium carboxymethyl starch; And / or, the first sweetener and the second sweetener each independently comprise at least one of sucrose, lactose, mannitol, sorbitol, pregelatinized starch, or xylitol; And / or, the first water-soluble adhesive and the second water-soluble adhesive each independently comprise at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, methylcellulose or povidone; And / or, the hydrophilic modifier includes at least one of gum arabic, xanthan gum, guar gum, carrageenan, or hydroxypropyl methylcellulose.

3. The cefoperazone hydrochloride granules according to claim 1, characterized in that, The hydrophobic taste-masking particles account for 50-80% of the total mass of the cefoperazone hydrochloride particles; And / or, the mass of the hydrophilic flavoring layer accounts for 10-40% of the total mass of the cefoperazone hydrochloride particles; And / or, the mass of the hydrophilic surface-modified layer accounts for 0.5 to 5% of the total mass of the cefoperazone hydrochloride particles.

4. The cefoperazone hydrochloride granules according to claim 1, characterized in that, The hydrophobic flavor-masking particles comprise the following components in parts by weight: 100-150 parts cefcaptin hydrochloride, 100-200 parts waxy flavor-masking material, 50-150 parts disintegrant, 150-300 parts first sweetener, and 5-15 parts first binder. And / or, the hydrophilic flavoring layer comprises the following components in parts by weight: 200-400 parts of a second sweetener and 5-30 parts of a second binder.

5. The cefoperazone hydrochloride granules according to claim 1, characterized in that, The cefoperazone hydrochloride particles do not contain surfactants; And / or, the cefoperazone hydrochloride granules may also include an added flavoring agent.

6. The cefoperazone hydrochloride granules according to claim 5, characterized in that, The added flavoring agents include aspartame, flavorings, or combinations thereof; And / or, the added flavoring agent accounts for 0.5 to 10% of the total mass of the cefoperazone hydrochloride granules.

7. A method for preparing cefoperazone hydrochloride granules as described in any one of claims 1 to 6, characterized in that, Includes the following steps: The cefoperazone hydrochloride granules were obtained by melt granulation and coating.

8. The preparation method according to claim 7, characterized in that, The preparation method of the cefcapine hydrochloride granules specifically includes the following steps: mixing the components of the hydrophobic flavor-masking granules at 50~100℃, melting and granulating, and cooling to obtain hydrophobic flavor-masking granules; mixing the hydrophobic flavor-masking granules with the components of the hydrophilic flavor-correcting layer at 50~100℃, drying to obtain the hydrophilic flavor-correcting layer; then adding the components of the hydrophilic surface modification layer, mixing at 50~100℃, drying to obtain the hydrophilic surface modification layer.

9. The preparation method according to claim 8, characterized in that, The preparation method of the cefcapine hydrochloride granules further includes the following steps: after obtaining the hydrophilic surface modified layer, cooling is performed, and then an external flavoring agent is added and mixed.

10. The use of cefoperazone hydrochloride granules as described in any one of claims 1 to 6 in the preparation of pediatric medicines.

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