A medicinal co-processing adjuvant, its preparation method and application

Abstract

This invention belongs to the field of biopharmaceutical technology, and relates to a pharmaceutical co-processed excipient, its preparation method, and its application. The raw materials for preparing the pharmaceutical co-processed excipient include mannitol, pregelatinized starch, and crospovidone. The co-processed excipient is prepared by co-processing mannitol, pregelatinized starch, and crospovidone through a fluidized bed drying process, forming spherical particles with a flocculent surface structure. This invention features a simple process, high yield, and low cost, making it suitable for industrial production. The resulting co-processed excipient exhibits good flowability, compressibility, and binding ability, and is suitable for preparing orally disintegrating tablets using direct compression processes.

Description

Technical Field

[0001] This invention belongs to the field of biopharmaceutical technology and relates to a pharmaceutical co-processing excipient, its preparation method, and its application. Background Technology

[0002] Tablets, as a classic and traditional dosage form, are stable, easy to carry and use, and their mechanized manufacturing results in low cost, high yield, and accurate dosage, making them one of the most commonly used dosage forms. Orally disintegrating tablets, as described in the 2020 edition of the *Pharmacopoeia of the People's Republic of China*, are tablets that rapidly disintegrate or dissolve in the oral cavity without the need for water, and should have a good taste, be easy to swallow, and be non-irritating to the oral mucosa. Travelers with limited access to water, the elderly with poor swallowing function, and children have a greater need for easily swallowable formulations.

[0003] Orally disintegrating tablets mainly consist of three excipients: fillers, disintegrants, and flavoring agents. These enable tablet formation, rapid disintegration, and masking of unpleasant odors from the active pharmaceutical ingredient. For ease of production, flow aids or lubricants are often added. Currently, commonly used disintegrants in orally disintegrating tablets, such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and crospovidone, have poor flowability, making them difficult to mix evenly with the active pharmaceutical ingredient and other excipients during production. This results in variations in tablet weight and disintegration time, and the finished product often has a heavy granular feel and poor taste after disintegration. Co-processed excipients, through specific physical processing, cause the excipients to react in a sub-particle state, producing a synergistic effect. They integrate multiple functions such as excipient formation and disintegration, while also masking the shortcomings of individual excipients, thus improving the key quality of orally disintegrating tablets and optimizing the production process.

[0004] To address this issue, CN101829333A provides a novel multifunctional excipient made from mannitol, isosorbide, and crospovidone. While this method improves the excipient's flowability and disintegration capacity, isosorbide still needs to be added as a binder during preparation. CN104645336A employs a co-crystallization process using mannitol and crospovidone, eliminating the need for a binder. The resulting co-treated excipient can be used in pharmaceutical formulations such as ibuprofen. However, the yield of this co-crystallization process is only about 60%, which is insufficient for large-scale industrial production. Summary of the Invention

[0005] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a pharmaceutical co-processing excipient, its preparation method and application.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides a pharmaceutical co-processing excipient, wherein the raw materials for preparing the pharmaceutical co-processing excipient include mannitol, pregelatinized starch and cross-linked polyvinylpyrrolidone.

[0008] The pharmaceutical co-processed excipient provided by this invention is obtained by co-processing mannitol, pregelatinized starch, and cross-linked polyvinylpyrrolidone through a fluidized bed drying process. The preparation method is simple, low-cost, and suitable for continuous industrial production, solving the problem of low yield in existing co-processed excipient preparation methods. The co-processed excipient is a near-spherical particle with a flocculent structure on its surface. The particles are uniform in size and have a large surface area, improving their binding ability with the active pharmaceutical ingredient and enhancing their flowability and compressibility, making them suitable for direct tableting processes.

[0009] Mannitol functions as both a filler and a flavoring agent, exhibiting advantages such as low hygroscopicity, high stability, low calories, and a refreshing sweetness. Croscinopovidone is a commonly used disintegrant in orally disintegrating tablets, offering a good taste without any gritty feeling. Adding pregelatinized starch simultaneously functions as a filler and disintegrant, reducing the amount of mannitol and croscinopovidone required while optimizing the taste. The co-treated excipients obtained in this invention meet the requirements of direct compression tableting in terms of flowability and compressibility. Tablets made using these co-treated excipients have moderate hardness, minimal weight variation, and disintegrate rapidly in the oral cavity using saliva, resulting in a good taste.

[0010] Co-processed excipients have optimized the specific functions of various excipients (such as flowability, compressibility, adhesion, and disintegration) at the microscopic level. They only need to be mixed with the active pharmaceutical ingredient (API) or a small amount of lubricant before direct tableting, eliminating the need for the traditional wet or dry granulation process required for tableting. This reduces equipment investment and energy consumption, significantly improving production efficiency; it also reduces losses caused by material transfer during operation, increasing product yield; it avoids the moisture, heat, and prolonged drying process required for wet granulation, which is particularly beneficial for maintaining the stability of heat- and moisture-sensitive drugs (such as antibiotics, biologics, or vitamins); and it simplifies process validation and cleaning validation procedures, reducing the risk of cross-contamination. Co-processed excipients are a key carrier for realizing direct tableting technology and promoting the development of continuous tablet manufacturing.

[0011] Preferably, the raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 20-96 parts mannitol, 2-60 parts pregelatinized starch, and 2-20 parts crospovidone.

[0012] At this ratio, the co-treatment of mannitol, pregelatinized starch and crospovidone showed good results. The resulting co-treated excipients had good flowability and compressibility, which met the requirements for direct tableting. The pregelatinized starch served as both a filler and a disintegrant, overcoming the shortcomings of crospovidone as a disintegrant alone.

[0013] Preferably, the raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 40-90 parts mannitol, 5-40 parts pregelatinized starch, and 5-20 parts crospovidone.

[0014] Preferably, the raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 55-80 parts mannitol, 10-30 parts pregelatinized starch, and 10-15 parts crospovidone.

[0015] The mass fractions of mannitol can be selected from 20, 30, 40, 50, 60, 70, 80, 90, and 96 parts, etc. The mass fractions of pregelatinized starch can be selected from 2, 5, 10, 20, 30, 40, 50, and 60 parts, etc. The mass fractions of crospovidone can be selected from 2, 5, 10, 12, 15, 18, and 20 parts, etc. Other specific values ​​within the above ranges can be selected, which will not be elaborated here.

[0016] Preferably, the surface structure of the pharmaceutical co-processed excipient is spherical, and the surface of the excipient has a flocculent appearance.

[0017] In a second aspect, the present invention provides a method for preparing a pharmaceutical co-processed excipient according to the first aspect, the method comprising:

[0018] Pregelatinized starch and cross-linked polyvinyl ketone are premixed in a fluidized bed to obtain a premixed material. Mannitol solution is sprayed onto the premixed material for coating, and then dried to obtain the final product.

[0019] The pregelatinized starch is premixed with cross-linked povidone, allowing the pregelatinized starch to encapsulate the cross-linked povidone in a fluidized bed. Mannitol solution is then sprayed into the fluidized bed to further encapsulate the pregelatinized starch and cross-linked povidone, followed by drying to obtain the co-treated excipient. The resulting co-treated excipient exhibits good flowability and compressibility. Tablets prepared using this co-treated excipient possess a certain degree of hardness, a smooth surface without powder shedding, and the prepared orally disintegrating tablets disintegrate rapidly with a good taste. The preparation method is simple and easy to operate, reducing costs and increasing yield through formula substitution, which is beneficial for industrial production. This method solves the problems of low yield and high cost caused by expensive excipient selection in existing technologies using co-crystallization to prepare co-treated excipients.

[0020] Preferably, the concentration of mannitol in the mannitol solution is 100-550 g / L, such as 100 g / L, 150 g / L, 200 g / L, 250 g / L, 300 g / L, 350 g / L, 400 g / L, 450 g / L, 500 g / L, 550 g / L, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0021] Preferably, the fluidized bed has a flow rate of 15-30 mL / min and an air volume of 50-70 m³ / min. 3 / h, solution temperature is 60-80℃.

[0022] The flow rate can be selected from 15 mL / min, 18 mL / min, 20 mL / min, 22 mL / min, 25 mL / min, 28 mL / min, 30 mL / min, etc., and the air volume can be selected from 50 m³ / min. 3 / h、52 m 3 / h、55 m 3 / h、58 m 3 / h、60 m 3 / h、62 m 3 / h、65m 3 / h、68 m 3 / h、70 m 3 / h, etc., the temperature can be selected as 60℃, 62℃, 65℃, 68℃, 70℃, 72℃, 75℃, 78℃, 80℃, etc. Other specific point values ​​within the above range can be selected, which will not be elaborated here.

[0023] Preferably, the temperature of the material is 30-45°C.

[0024] Temperatures can be selected from 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, 45℃, etc. Other specific values ​​within the above range can also be selected, which will not be elaborated here.

[0025] Preferably, the pressure of the gas injection in the fluidized bed is 2-3 kg / cm². 2 For example, 2 kg / cm 2 2.2 kg / cm 2 2.4kg / cm 2 2.6 kg / cm 2 2.8 kg / cm 2 3 kg / cm 2 Other specific point values ​​within the above range can also be selected, and will not be elaborated on here.

[0026] Preferably, the drying time is 10-30 min, such as 10 min, 12 min, 15 min, 18 min, 20 min, 22 min, 25 min, 28 min, 30 min, etc. Other specific values ​​within the above range can be selected, and will not be elaborated here.

[0027] Preferably, the fluidized bed outlet uses a 65-mesh sieve.

[0028] Preferably, the fluidized bed has a flow rate of 20-25 mL / min and an air volume of 55-70 m³ / min. 3 / h, solution temperature is 65-75℃.

[0029] Thirdly, the present invention provides the application of the pharmaceutical co-processed excipient according to the first aspect in the preparation of orally disintegrating tablets.

[0030] The orally disintegrating tablets prepared by this invention have a disintegration time of less than 1 minute, disintegrate quickly, have a good taste and no gritty feeling, and have suitable hardness, making them suitable for transportation and storage, with little difference in tablet weight.

[0031] Preferably, the orally disintegrating tablets include vitamin C orally disintegrating tablets or loratadine orally disintegrating tablets.

[0032] Preferably, in the orally disintegrating vitamin C tablets, the mass ratio of vitamin C to pharmaceutically co-processed excipients is 1:(3-10).

[0033] The specific point values ​​in (3-10) can all be selected from 3, 4, 5, 6, 7, 8, 9, 10, etc. Other specific point values ​​within the above range can also be selected, which will not be elaborated here.

[0034] Preferably, in the loratadine orally disintegrating tablets, the mass ratio of loratadine to pharmaceutically co-processed excipients is 1:(20-50).

[0035] The specific point values ​​in (20-50) can be selected from 20, 22, 25, 28, 30, 32, 35, 38, 40, 42, 45, 48, 50, etc. Other specific point values ​​within the above range can also be selected, which will not be elaborated here.

[0036] Preferably, the vitamin C orally disintegrating tablets are prepared by a method comprising the following steps: mixing vitamin C with pharmaceutically co-treated excipients and colloidal silica, and directly compressing the mixture into tablets.

[0037] Preferably, the loratadine orally disintegrating tablets are prepared by a method comprising the following steps: mixing loratadine with pharmaceutically co-treated excipients and magnesium stearate, and directly compressing the mixture into tablets.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] (1) The co-processed excipients prepared by the present invention retain the chemical properties of each individual excipient, while their overall physical properties change, thus meeting the quality control requirements for co-processed pharmaceutical excipients;

[0040] (2) The flowability, compressibility and other properties of the co-processed excipients prepared by the present invention can meet the requirements of the direct tableting process;

[0041] (3) The preparation method of the co-processing excipients obtained by the present invention is simple in operation, low in cost, and high in yield, which is conducive to industrial production;

[0042] (4) Orally disintegrating tablets were prepared using the co-treated excipients prepared in this invention. The disintegration time of the prepared orally disintegrating tablets met the requirements and the tablets had a good taste. Attached Figure Description

[0043] Figure 1 The image shows an electron scanning microscope image of the co-treated excipients obtained in Comparative Example 5 and Example 1.

[0044] Figure 2 The images are scanning electron microscope images of the co-treated excipients obtained in Examples 1 and 3.

[0045] Figure 3 Differential scanning calorimetry (DSC) spectra of the co-treated excipients obtained from Comparative Examples 1-3, Comparative Example 5, and Example 1.

[0046] Figure 4 The images show the Fourier transform infrared (FT-IR) spectra of the co-treated excipients obtained in Comparative Examples 1-3 and Example 1.

[0047] Figure 5 X-ray powder diffraction (XRD) curves of the co-treated excipients obtained in Comparative Examples 1-3 and Example 1. Detailed Implementation

[0048] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0049] The sources of the active ingredients in the products involved in the following examples and comparative examples are as follows (only the active ingredients are shown; other necessary excipients contained in commercially available raw materials are not described):

[0050] Mannitol was purchased from Roquette (France) under the product name P160C, from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. under the product name Mannitol, and from Shenzhen Youpuhui Pharmaceutical Co., Ltd. under the product name Mannitol.

[0051] Cross-linked polyvinylpyrrolidone was purchased from ASHLAND Corporation (USA) under the product names XL and XL-10, from Shanhe Pharmaceutical Excipients Co., Ltd. under the product name SH-SL10, and from Jianhua Nanhang Co., Ltd. under the product names XL and XL-10.

[0052] The pregelatinized starch was purchased from Asahi Kasei Corporation of Japan under the product name PC-10 and from Sankawa Pharmaceutical Excipients Co., Ltd. under the product name SH1500.

[0053] Experiment 1

[0054] This experiment provides a method for screening co-processed excipient formulations, including the following steps:

[0055] Commercially available fillers, binders, and disintegrants were selected, including lactose, mannitol, corn starch, pregelatinized starch, microcrystalline cellulose, povidone, crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose. The angle of repose was measured, and the Karl Fischer index was determined using bulk density and tapped density. The results of the angle of repose and Karl Fischer index tests are shown in Table 1. Each sample was tested three times.

[0056] Table 1

[0057]

[0058] As can be seen from Table 1, a repose angle of less than 30° can be used for direct tableting, and a Karl index between 15 and 25 generally indicates good compressibility. None of the components in Table 1 can be directly tableted. Lactose can easily cause gastrointestinal adverse reactions in people with intolerance. Pregelatinized starch has the dual functions of binder and filler and has a good taste. The preliminary screening of the prescription composition is: mannitol and pregelatinized starch.

[0059] Experiment 2

[0060] This experiment provides a method for screening disintegrants in co-processed excipient formulations, including the following steps:

[0061] Commercially available disintegrants, including corn starch, pregelatinized starch, microcrystalline cellulose, povidone, crospovidone, sodium carboxymethyl starch, and sodium crospovidone, were selected, and their swelling in water was measured.

[0062] The results of the expansion test are shown in Table 2. Each sample was tested three times.

[0063] Table 2

[0064]

[0065] As can be seen from Table 2, among commonly used disintegrants, crospovidone is significantly more prevalent than other varieties. Orally disintegrating tablets have clearly defined disintegration time limits; therefore, crospovidone was chosen as the disintegrant. The formulation composition for treating excipients includes: mannitol, pregelatinized starch, and crospovidone.

[0066] Example 1

[0067] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0068] Weigh 100 g of crospovidone (ASHLAND, USA, model XL, particle size approximately 150 μm) and 200 g of pregelatinized starch (Asahi Kasei, Japan, model PC-10) and premix them in a fluidized bed apparatus. Weigh 700 g of mannitol (Roquette, model P160C) and dissolve it completely in water to prepare a solution with a concentration of 150 g / L. Add the mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 20 mL / min and an air volume of 60 m³ / min. 3 / h, temperature 65 ℃, material temperature 40 ℃, pressure 2kg / cm 2 The mixture was prepared by drying under specific conditions, with a 65-mesh sieve installed at the outlet. After the mannitol solution was completely added, drying continued for 20 minutes to obtain the co-processed excipient, which consisted of near-spherical particles with a uniform particle size of approximately 230 μm and a yield of 96%.

[0069] Example 2

[0070] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0071] Weigh 150 g of crospovidone (ASHLAND, USA, model XL, particle size approximately 150 μm) and 250 g of pregelatinized starch (Asahi Kasei, Japan, model PC-10) and premix them in a fluidized bed apparatus. Weigh 600 g of mannitol (Roquette, model P160C) and dissolve it completely in water to prepare a 200 g / L solution. Add the mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 20 mL / min and an air volume of 60 m³ / min. 3 / h, temperature 65 ℃, material temperature 40 ℃, pressure 2kg / cm 2 The mixture was prepared by drying under specific conditions, with a 65-mesh sieve installed at the outlet. After the mannitol solution was completely added, drying continued for 20 minutes to obtain the co-processed excipient, which consisted of near-spherical particles with a uniform particle size of approximately 230 μm and a yield of 95%.

[0072] Example 3

[0073] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0074] Weigh 100 g of crospovidone (Jianhua Nanhang Company, model XL, particle size approximately 70 μm) and 200 g of pregelatinized starch (Shanhe Pharmaceutical Excipients Company, model SH1500), and premix them in a fluidized bed apparatus. Weigh 700 g of mannitol (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.), add water to completely dissolve it, and prepare a solution with a concentration of 150 g / L. Add the mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 20 mL / min and an air volume of 60 m³ / min. 3 / h, temperature 65 ℃, material temperature 40 ℃, pressure 2 kg / cm 2 The mixture was prepared by drying under specific conditions, with a 65-mesh sieve installed at the outlet. After the mannitol solution was completely added, drying continued for 20 minutes to obtain the co-processed excipient, which consisted of near-spherical particles with a uniform particle size of approximately 150 μm and a yield of 98%.

[0075] Example 4

[0076] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0077] Weigh 150 g of crospovidone (Jianhua Nanhang Company, model XL, particle size approximately 70 μm) and 250 g of pregelatinized starch (Shanhe Pharmaceutical Excipients Company, model SH1500) and premix them in a fluidized bed apparatus. Weigh 600 g of mannitol (Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.) and dissolve it completely in water to prepare a solution with a concentration of 200 g / L. Add the mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 20 mL / min and an air volume of 60 m³ / min. 3 / h, temperature 65 ℃, material temperature 40 ℃, pressure 2 kg / cm 2 The mixture was prepared by drying under specific conditions, with a 65-mesh sieve installed at the outlet. After the mannitol solution was completely added, drying continued for 20 minutes to obtain the co-processed excipient, which consisted of near-spherical particles with a uniform particle size of approximately 150 μm and a yield of 98%.

[0078] Example 5

[0079] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0080] Weigh 50 g of crospovidone (ASHLAND, USA, model XL, particle size approximately 150 μm) and 150 g of pregelatinized starch (Shanhe Pharmaceutical Excipients Co., Ltd., model SH1500) and premix them in a fluidized bed apparatus. Weigh 800 g of mannitol (Shenzhen Youpuhui Pharmaceutical Co., Ltd.) and dissolve it completely in 80 °C hot water to prepare a saturated solution. Add the saturated mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 25 mL / min and an air volume of 55 m³ / min. 3 / h, temperature 65 ℃, material temperature 35 ℃, pressure 3 kg / cm 2 The mixture was prepared by drying under specific conditions, with a 65-mesh sieve installed at the outlet. After the mannitol solution was completely added, drying continued for 20 minutes to obtain the co-processed excipient, which consisted of near-spherical particles with uniform particle size and a yield of 94%.

[0081] Example 6

[0082] This embodiment provides a method for preparing co-processing excipients, including the following steps:

[0083] Weigh 100 g of crospovidone (ASHLAND, USA, model XL, particle size approximately 150 μm) and 400 g of pregelatinized starch (Asahi Kasei Corporation, Japan, model PC-10) and premix them in a fluidized bed apparatus. Weigh 500 g of mannitol (Shenzhen Youpuhui Pharmaceutical Co., Ltd.) and dissolve it completely in water to prepare a solution with a concentration of 150 g / L. Add the mannitol solution to the fluidized bed apparatus using a top spray method at a flow rate of 30 mL / min and an air volume of 70 m³ / min. 3 The material was dried at 70 °C / h, with a material temperature of 40 °C and a pressure of 30 psi. A 65-mesh sieve was installed at the outlet. After the mannitol solution was completely added, drying continued for 10 minutes to obtain the co-processed excipient, which consisted of spherical particles with uniform particle size and a yield of 91%.

[0084] Comparative Example 1

[0085] Mannitol mononitrate (Roquette, model P160C).

[0086] Comparative Example 2

[0087] Single pregelatinized starch (Asahi Kasei Corporation, Japan, model PC-10).

[0088] Comparative Example 3

[0089] Single cross-linked polyvinylpyrrolidone (ASHLAND, USA, model XL, particle size approximately 150 μm).

[0090] Comparative Example 4

[0091] Single cross-linked polyvinylpyrrolidone (Jianhua Nanhang Company, model XL, particle size approximately 70 μm).

[0092] Comparative Example 5

[0093] This comparative example provides a method for preparing an excipient, comprising the following steps:

[0094] Weigh out 70 g of mannitol (Roquette, model P160C), 20 g of pregelatinized starch (Asahi Kasei Corporation, Japan, model PC-10), and 10 g of crospovidone (ASHLAND, USA, model XL, particle size approximately 150 μm), mix them evenly to prepare a physical mixture excipient, and then test it.

[0095] Comparative Example 6

[0096] This comparative example provides a method for preparing an excipient, comprising the following steps:

[0097] Weigh out 70 g of mannitol (Shenzhen Youpuhui Pharmaceutical Co., Ltd.), 20 g of pregelatinized starch (Shanhe Pharmaceutical Excipients Co., Ltd., model SH1500) and 10 g of cross-linked polyvinylpyrrolidone (Jianhua Nanhang Co., Ltd., model XL, particle size approximately 70 μm), mix them evenly to prepare a physical mixed excipient, and then test it.

[0098] Comparative Example 7

[0099] This comparative example provides a method for preparing a co-processed excipient, which differs from Example 1 only in that crosslinked polyvinylpyrrolidone is replaced in equal amounts with polyvinylpyrrolidone (BASF, Germany, polyvinylpyrrolidone K30, particle size approximately 60 μm), while other operations remain unchanged.

[0100] Test Example 1

[0101] The Chinese Pharmacopoeia, Volume IV, "9603 Guidelines for Quality Control of Premixed and Co-processed Pharmaceutical Excipients," requires that co-processed excipients be mixed excipients prepared from two or more pharmaceutical excipients through specific physical processing techniques (such as spray drying, granulation, etc.) to achieve specific functions. Co-processed excipients should not form new chemical covalent bonds during processing. The difference between co-processed excipients and premixed excipients is that co-processed excipients cannot be prepared through simple physical mixing. Therefore, the binding mechanism and characterization state of the co-processed excipients prepared in this invention are studied and explained.

[0102] The products of Comparative Examples 1-6, the co-treated excipients obtained in Example 1, and the co-treated excipients obtained in Example 3 will be compared and analyzed. The specific analysis is as follows.

[0103] 1. Scanning electron microscopy analysis

[0104] Characterization studies were conducted on the co-treated excipients prepared in Comparative Example 5 and Example 1:

[0105] The surface structure was observed using the sputtering method. The co-processing excipients (F) prepared in Comparative Example 5 and Example 1 were placed on conductive tape in a glass dish. After ion sputtering, the surface structure of the sample was observed by SEM with an accelerating voltage of 25.0 kV.

[0106] Figure 1 Scanning electron microscope images of the co-processed excipients prepared in Comparative Example 5 and Example 1. Figure 1 The image above shows the physical mixture of excipients (Comparative Example 5). The individual characteristics of mannitol block crystals, pregelatinized starch clumps, and cross-linked polyvinylpyrrolidone can be observed, with each exhibiting its own morphology. Figure 1The figure below shows the co-processed excipient obtained in Example 1. The co-processed excipient, obtained by fluidized bed processing of mannitol, pregelatinized starch, and crospovidone, is a single, spherical particle with a "popcorn" flocculent structure on its surface, thus increasing its surface area. No individual structural characteristics of mannitol, pregelatinized starch, and crospovidone were observed. This demonstrates that the preparation method of the present invention effectively integrates the three excipients organically, rather than simply mixing them, explaining the improved physical properties.

[0107] Figure 2 Scanning electron microscope images of the co-processed excipients prepared in Examples 1 (left) and 3 (right). The particle size of the co-processed pharmaceutical excipients prepared by the fluidized bed process is related to the original particle size of the pregelatinized starch, with smaller particle size (Example 3) showing less flocculent structure on the surface.

[0108] 2. Differential Calorimetry Analysis

[0109] The co-processed excipients prepared in Comparative Examples 1, 2, 3, 5, and 1 were placed in aluminum crucibles, respectively, with an empty crucible as a reference. The heating rate was 10.00 ℃•min. -1 Heating range: 0-500℃; record the differential calorimetry curves for each sample. Figure 3 Differential scanning calorimetry spectra of Comparative Examples 1-3, Comparative Example 5, and Example 1.

[0110] from Figure 3 It can be seen that, by comparing the DSC spectra of the physically mixed excipients in Comparative Example 5 and the co-treated excipients in Example 1, it can be seen that mannitol and cross-linked polyvinylpyrrolidone in the co-treated excipients did not produce new endothermic peaks, indicating that the chemical composition of the three excipients in the co-treated excipients did not change during the processing.

[0111] 3. Infrared spectroscopy analysis

[0112] 0.1 g of the co-treated excipients prepared in Comparative Examples 1, 2, 3 and 1 were mixed with potassium bromide powder under a dry environment to form tablets, which were then heated at 400-4000 cm⁻¹. -1 Infrared spectroscopy measurements were performed within the specified range, and the results are as follows: Figure 4 As shown.

[0113] Figure 4 The infrared spectra of Comparative Examples 1-3 and Example 1 are shown. Compared with the single excipient, no new absorption peaks were observed in the spectrum of the co-treated excipient, suggesting that no new chemical bonds were formed among the three.

[0114] 4. X-ray powder diffraction analysis

[0115] X-ray powder diffraction analysis was performed on appropriate amounts of the co-treated excipients prepared in Comparative Examples 1, 2, 3, and 1. Test conditions: Cu target (40 kV, 40 mV), 0.02° / step scan, scan range 5°-90°, 0.02°min. -1 Scanning speed and X-ray powder diffraction curves of the acquired samples are shown in the appendix. Figure 5 .

[0116] from Figure 5 It can be seen that mannitol has multiple strong diffraction peaks with crystallization characteristics in the range of 10°-55°. Pregelatinized starch and cross-linked polyvinylpyrrolidone do not have obvious diffraction peaks and are non-crystalline compounds. However, mannitol crystallization diffraction peaks are present in the spectrum of co-processed excipients, but the overall signal is weakened. Continuous diffraction peaks appear in the original mannitol characteristic crystallization diffraction peaks in the range of 10°-50°. It is speculated that some mannitol crystals are retained, and new crystalline states are formed in the co-processed excipients in spherical or near-spherical state during the process.

[0117] In summary, the co-processed excipients obtained by co-processing mannitol, pregelatinized starch, and cross-linked polyvinylpyrrolidone using a fluidized bed process are integral particles with a spherical or near-spherical appearance. No individual characteristics of the excipients were observed. The chemical composition of the co-processed excipients did not change, and no chemical reaction occurred between the three excipients to form new chemical bonds. However, the processing resulted in a slight change in the crystal structure.

[0118] Test Example 2

[0119] The co-processed pharmaceutical excipients developed in this invention are mainly used for the preparation of orally disintegrating tablets, and the direct compression method is mostly adopted. There are specific requirements for the functionality of pharmaceutical excipients. The products of Comparative Examples 1-7 and the pharmaceutical excipients prepared in Examples 1-4 are subjected to performance tests such as powder flowability and compressibility.

[0120] The angle of repose is often used to indicate the flowability of powders. When the angle of repose is ≤35°, the flowability requirements during production can be met. Loose density and tapped density can be used to calculate the Karl Fischer index, reflecting the compressibility and filling performance of powders. When the Karl Fischer index is between 15% and 25%, the requirements for direct tableting of powders using a rotary tablet press can be met. The loose density, tapped density, and Karl Fischer index of the products from Comparative Examples 1-7 and the co-treated excipients obtained in Examples 1-4 were measured. The functionality of the co-treated pharmaceutical excipients and single pharmaceutical excipients were compared. Each test was repeated three times in parallel, and the results are shown in Table 3.

[0121] Table 3

[0122]

[0123] The results in Table 3 show that the angle of repose and Karl elliptic index of the co-processed excipients prepared in this invention meet the requirements for excipients in the direct tableting method. Comparing the flowability of the co-processed excipients prepared in Examples 1-4 with the products of Comparative Examples 1-7, the powder properties of the co-processed excipients prepared in this invention are superior to any single excipient (Comparative Examples 1-4) and the excipients obtained by simple physical mixing (Comparative Examples 5-7). This indicates that the performance of the co-processed excipients prepared in this invention is not a simple summation of the performance of individual excipients; the powder properties of the co-processed excipients with an integral morphology prepared in this invention are more advantageous.

[0124] Test Example 3

[0125] The co-processed excipients obtained in Examples 1-4 were directly compressed into blank orally disintegrating tablets without the addition of active pharmaceutical ingredients. According to the requirements of the Chinese Pharmacopoeia, Part IV (General Chapter 0101 Tablets), the tablets should have a complete and smooth appearance, uniform color, and suitable hardness and abrasion resistance to prevent wear or breakage during packaging and transportation. Unless otherwise specified, uncoated tablets should meet the requirements of the tablet friability test method (General Chapter 0923). Simultaneously, for orally disintegrating tablets (tablets that rapidly disintegrate or dissolve in the oral cavity without the need for water), a disintegration time test (General Chapter 0921) should be performed. For compliance requirements, the taste was evaluated. The following test items were set:

[0126] Tablet appearance: visual inspection.

[0127] Friability: Tested in accordance with Part IV of the Chinese Pharmacopoeia (General Chapter 0923 Friability Test Method).

[0128] Disintegration time limit: In accordance with Part IV of the Chinese Pharmacopoeia (General Chapter 0921 Disintegration Time Limit Test).

[0129] Taste: Six healthy volunteers (3 men and 3 women) aged 22-40 were selected and given a three-level rating system: good, average, and poor.

[0130] Table 4

[0131]

[0132] The results are shown in Table 4. The blank orally disintegrating tablets prepared from the co-treated excipients in Examples 1-4 had smooth surfaces, disintegration times of less than 1 minute, and a certain degree of hardness, making them suitable for transportation and storage. They also had a good taste and no gritty feel. However, the comparative example 7 using povidone had a disintegration time that exceeded the requirements and did not meet the requirements for orally disintegrating tablets.

[0133] Test Example 4

[0134] Vitamin C orally disintegrating tablets were prepared using the co-treated excipients obtained in Examples 1 and 3. Vitamin C is a heat-labile and easily degraded drug. The preparation methods are as follows:

[0135] Take 16 g of vitamin C, add 48 g of the co-treated excipients obtained in Example 1 or Example 3, add 0.2 g of colloidal silica, mix well, and prepare by direct powder compression method. Press into shape using an 8 mm die and an elliptical irregular die respectively, each tablet weighing 0.2 g, with hardness controlled at 80~90 N, to obtain 150 vitamin C orally disintegrating tablets respectively.

[0136] The two types of orally disintegrating vitamin C tablets prepared above were tested: the test results showed that the tablets were all intact and smooth in appearance, with uniform color, and the tablet hardness was 80-90 N. The disintegration time was between 50-55 s and within 1 min. The tablets had a slightly sweet and slightly sour taste, no gritty feeling, and a good mouthfeel. The tablet weight difference was controlled within 0.75%.

[0137] Loratadine orally disintegrating tablets were prepared using the co-treated excipients obtained in Example 4. Loratadine is a poorly soluble drug used clinically to relieve allergies, requiring rapid efficacy. Orally disintegrating tablets offer rapid release and multiple absorption pathways, enabling them to act quickly. The preparation method is as follows:

[0138] Take 3 g of loratadine, add 41.5 g of the co-processed excipients obtained in Example 4 above, add 0.5 g of magnesium stearate, mix well, and prepare by direct powder compression method. Press into shape with elliptical irregular die, each tablet is 0.15 g, and the hardness is controlled at 80~90N, to obtain 280 loratadine orally disintegrating tablets.

[0139] The loratadine orally disintegrating tablets prepared above were tested: the results showed that the tablets were intact, smooth, and uniform in color, with a hardness of 85-92 N, a disintegration time of 52-57 s, a sweet taste, no gritty feeling, and a good mouthfeel. The tablet weight difference was controlled within 0.60%.

[0140] In summary, the co-treated excipients obtained in this invention exhibit superior flowability and compressibility compared to simple physical mixtures of single excipients, meeting the requirements for direct tableting. Orally disintegrating tablets prepared using this co-treated excipient have disintegration times not exceeding 1 minute. This co-treated excipient can be directly tableted after uniform mixing with other excipients and the active pharmaceutical ingredient, resulting in faster processing speeds compared to traditional granulation followed by tableting, significantly improving production efficiency. It also solves the problem of easy degradation in the processing of thermally unstable active pharmaceutical ingredients, producing tablets with minimal weight variation, a smooth surface, no gritty texture, excellent taste, and suitable hardness to meet the hardness requirements during transportation and storage.

[0141] The above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A pharmaceutical co-processed excipient, characterized in that, The raw materials for preparing the pharmaceutical co-processed excipients include mannitol, pregelatinized starch, and crospovidone.

2. The pharmaceutical co-processed excipient according to claim 1, characterized in that, The raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 20-96 parts mannitol, 2-60 parts pregelatinized starch, and 2-20 parts crospovidone; Preferably, the raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 40-90 parts mannitol, 5-40 parts pregelatinized starch, and 5-20 parts crospovidone; Preferably, the raw materials for preparing the pharmaceutical co-processed excipients include, by mass parts, 55-80 parts mannitol, 10-30 parts pregelatinized starch, and 10-15 parts crospovidone.

3. The pharmaceutical co-processed excipient according to claim 1 or 2, characterized in that, The surface structure of the pharmaceutical co-processed excipient is spherical, and the surface of the excipient has a flocculent appearance.

4. The method for preparing pharmaceutical co-processed excipients according to any one of claims 1-3, characterized in that, The preparation method includes: Pregelatinized starch and cross-linked polyvinyl ketone are premixed in a fluidized bed to obtain a premixed material. Mannitol solution is sprayed onto the premixed material for coating, and then dried to obtain the final product.

5. The method for preparing pharmaceutical co-processed excipients according to claim 4, characterized in that, The concentration of mannitol in the mannitol solution is 100-550 g / L.

6. The method for preparing pharmaceutical co-processed excipients according to claim 4 or 5, characterized in that, The fluidized bed has a flow rate of 15-30 mL / min, air volume of 50-70 m 3 / h, and solution temperature of 60-80℃; Preferably, the temperature of the material is 30-45°C; Preferably, the pressure of the gas injection in the fluidized bed is comprised between 2 and 3 kg / cm2 2 ; Preferably, the drying time is 10-30 min; Preferably, the fluidized bed has a flow rate of 20-25 mL / min and an air volume of 55-70 m³ / min. 3 / h, temperature is 65-75 ℃.

7. The use of the pharmaceutical co-processed excipient according to any one of claims 1-3 in the preparation of orally disintegrating tablets.

8. The application according to claim 7, characterized in that, The orally disintegrating tablets include vitamin C orally disintegrating tablets or loratadine orally disintegrating tablets.

9. The application according to claim 8, characterized in that, In the oral disintegrating vitamin C tablets, the mass ratio of vitamin C to pharmaceutically co-processed excipients is 1:(3-10).

10. The application according to claim 8, characterized in that, In the loratadine orally disintegrating tablets, the mass ratio of loratadine to pharmaceutically co-processed excipients is 1:(20-50).

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