Sorbitol-povidone compound as well as preparation method and application thereof

Abstract

The invention provides a sorbitol-povidone compound as well as a preparation method and application thereof. The compound can be used as a filling agent for adjusting the dissolution speed of a corrosion type medicinal preparation. According to the invention, sorbitol powder and povidone are mixed, granulated by a fluidized bed and dried to obtain a new compound, and the new compound can be used as a new compound auxiliary material, is applied to a slowly-corroded medicinal preparation, and is mixed with other pharmaceutically acceptable auxiliary materials, and the mixture is tableted to prepare a tablet; the quick release preparation can be applied to the field of preparations, can also be applied to common quick release preparations, has good compressibility and high flexibility, can be customized according to variety requirements, and is wide in application range. The sorbitol-povidone compound replaces a traditional direct-mixing type auxiliary material, so that the preparation cost is greatly reduced, the preparation process is simplified, and the quality of the prepared medicinal preparation product is stable and controllable.

Description

Technical Field

[0001] The invention relates to a sorbitol-polyvidone complex and a preparation method and application thereof, belonging to the field of pharmaceutical preparations. The complex can be used as a filler and can be widely used in the preparation of erosion-type pharmaceutical preparations and the adjustment of dissolution curves. Background Art

[0002] The drug dissolution rate and degree of solid preparations are affected by many factors such as the preparation of raw materials and excipients, and the preparation process. The dissolution type is a common disintegration dissolution mode for drug preparations. Its mechanism is that the soluble components contained in the drug preparations dissolve when they come into contact with water, forming dissolution holes, and the drugs are released. The dissolution type can be used for immediate-release preparations or skeleton-type sustained-release preparations, and is generally used for immediate-release preparations.

[0003] In the preparation process of dissolving drug preparations, the type, amount and aggregation state of the soluble components have a great influence on the dissolution process, especially the adjustment of the drug dissolution curve, which requires the use of appropriate types, amounts and aggregation states of the soluble components.

[0004] Sorbitol is a D-glucose alcohol that is easily soluble in water, an odorless, white or almost colorless crystalline, hygroscopic powder with a pleasant sweet taste and a cool mouthfeel. Sorbitol can be used as a dissolving filler in the preparation process of wet granulation or direct compression. Its structural formula is as follows:

[0005]

[0006] The Drug Review Center of the State Food and Drug Administration of my country has collected 14 registration numbers for pharmaceutical-grade sorbitol, of which only 4 are activated and only 1 is domestically produced.

[0007] For example, according to the Chinese patent CN200880007597.5 of Boehringer-Ingelheim, the original developer of Telmisartan Tablets, the main filler of Telmisartan Tablets - a filler with a specific surface area of ​​0.75 to 3.5 m 2 / g direct compression type sorbitol is used in this preparation. Compared with ordinary sorbitol, this type of sorbitol can bring more ideal dissolution characteristics. However, according to market research, the average selling price of this type of sorbitol is more than 5 times that of ordinary sorbitol, and the amount of sorbitol in this preparation accounts for as much as 70%, which leads to higher preparation costs.

[0008] In addition, most imported direct-compression sorbitol is prepared by spray drying, which requires large equipment and is difficult to clean manually. The production process consumes huge amounts of energy, produces large amounts of waste gas, and has high industrial processing costs. These shortcomings are also the reason why the market price remains high, further leading to rising prices for pharmaceutical preparations using this type of sorbitol.

[0009] Therefore, it is necessary to develop new fillers to ensure that drug preparations obtain appropriate dissolution characteristics on the one hand, and to maintain low prices on the other hand, thereby reducing drug prices and the medication burden on patients. Summary of the invention

[0010] In order to solve the defects and shortcomings of the prior art and replace the imported direct-compression type of sorbitol, the inventor provides a new sorbitol-povidone complex as a filler for pharmaceutical preparations. The sorbitol-povidone complex is a composite excipient in which sorbitol and povidone are mixed, granulated and dried in a fluidized bed according to a certain ratio, and the prepared composite has uniform particle size and good fluidity, and is suitable for direct powder compression. In addition, the ratio and particle size of the two materials can be flexibly controlled to meet the preparation requirements of different varieties of preparations.

[0011] Povidone is a white to milky white, odorless or almost odorless hygroscopic powder, which is widely used in solid preparations. Povidone is a synthetic polymer, mainly composed of linear 1-vinyl-2-pyrrolidone groups. Different degrees of polymerization lead to different molecular weights of polymers. The molecular weight can be characterized by the viscosity of the aqueous solution of povidone relative to water, expressed as the K value, which is between 10 and 120. Its structural formula is as follows:

[0012]

[0013] The present invention provides a sorbitol-polyvidone complex, characterized in that the complex contains 50-98% (by weight) sorbitol and 2-50% (by weight) polyvidone. The larger the proportion of polyvidone, the slower the dissolution rate of the drug preparation, and the proportion can be flexibly adjusted according to the requirements of the drug dissolution rate.

[0014] The above-mentioned sorbitol-polyvidone complex, preferably the polyvidone includes: polyvidone K25 or polyvidone K30. The K value of polyvidone K30 ranges from 27.0 to 32.0, and the K value of polyvidone K25 ranges from 24.0 to 27.0. Our comparative studies have shown that polyvidones with other K values ​​have low viscosity and poor bonding effect when the K value is too small; when the K value is too large, it is not suitable for use as an adhesive, for example, it will lead to adverse consequences such as too hard particles, poor compressibility, and slow release.

[0015] The above-mentioned sorbitol-povidone complex preferably has an average particle size (D50) of 100 to 300 μm; for example, 100 to 150 μm; or 150 to 200 μm; or 200 to 250 μm; or 250 to 300 μm; as a preferred embodiment, the average particle size (D50) is preferably 150 to 250 μm. Our research shows that when the average particle size (D50) is below 100 μm, the compressibility of the particles is poor; when D50 exceeds 300 μm, the mixing uniformity is poor. Specifically for different pharmaceutical preparations, it is necessary to select a suitable value within the above range according to the particle size and fluidity of the raw materials and other excipients.

[0016] The present invention provides a method for preparing the above-mentioned sorbitol-povidone complex, which is characterized by comprising the following steps:

[0017] (a) sorbitol is crushed and sieved to form a uniform sorbitol powder;

[0018] (b) mixing sorbitol powder and povidone in a certain proportion through a fluidized bed, wherein the sorbitol accounts for 50-98% and the povidone accounts for 2-50%, adding a wetting agent in a top spraying manner until particles of uniform size and good fluidity are formed, and then drying;

[0019] (c) The dried granules are sized by passing through a sieve with a suitable aperture to control the particle size of the complex, thereby obtaining a sorbitol-povidone complex.

[0020] In the above-mentioned method for preparing the sorbitol-povidone complex, the povidone preferably comprises: povidone K25 or povidone K30, which acts as an adhesive during the preparation of the complex.

[0021] In the above-mentioned method for preparing the sorbitol-povidone complex, the average particle size (D50) of the sorbitol-povidone complex is preferably 100-300 μm; as a preferred embodiment, the average particle size (D50) of the sorbitol-povidone complex is 150-250 μm.

[0022] The present invention also provides use of the sorbitol-povidone complex in preparing pharmaceutical preparation products.

[0023] The use is characterized by comprising the following steps:

[0024] (a) mixing the complex with a pharmaceutically active ingredient, a pharmaceutical excipient, etc. to obtain a final mixture;

[0025] (b) The final mixture is compressed into tablets or tablet layers.

[0026] Studies have shown that in the above-mentioned sorbitol complex, the choice of adhesive has a significant impact on the properties of the complex, and polyvidone is the most suitable. If polyvidone is replaced with other types of adhesives, such as polyethylene glycol, the effect will be significantly reduced.

[0027] The viscosity K value of povidone also has a significant effect on the properties of the composite. Povidone K25 or povidone K30 is the most suitable. If it is out of range, the performance will be significantly reduced.

[0028] The technical advantages of the present invention are as follows:

[0029] According to Chinese patent CN200880007597.5 of Boehringer-Ingelheim, the original developer of telmisartan tablets, a specific surface area of ​​0.75 to 3.5 m 2 / g of sorbitol is used as the main filler. According to market research, the average selling price of this type of sorbitol is more than 5 times that of ordinary sorbitol, and the amount of sorbitol used in the preparation accounts for as much as 70%, and the cost remains high. Using ordinary sorbitol, through conventional pulverization technology, even if the specific surface area is 0.75 to 3.5m 2 / g, and the same effect cannot be achieved when used for direct compression of powders. The starting material used by the inventors is ordinary sorbitol, and a sorbitol-povidone complex of a specific ratio can be obtained by one-step granulation, and the complex is particularly suitable for direct compression of powders. For example, the sorbitol-povidone complex is used as a new filler, and the powder properties of the obtained sorbitol-povidone complex are similar to those of direct compression sorbitol, and the particles have similar fluidity and compressibility; the dissolution of the obtained telmisartan tablets or sheets is similar to that of the original research, and the perfect replacement greatly reduces the material cost, which is only slightly higher than the ordinary sorbitol. In addition, we found that after granulation of sorbitol fine powders of different particle sizes after crushing, the powder properties of the obtained composite particles are relatively small, and all have good fluidity and compressibility; and the particle size difference of sorbitol fine powder has no obvious effect on the dissolution rate of the final preparation product, indicating that the compatibility of the production process is very good.

[0030] Sorbitol is a commonly used filler in pharmaceutical preparations, and povidone is also a commonly used adhesive, both of which are very cheap. Our research has proved that the two have good compatibility. The sorbitol-povidone complex prepared by the method of the present invention has no change in its key quality attributes during storage, and can be used as a new type of composite pharmaceutical excipient with stability.

[0031] The sorbitol-polyvidone complex of the present invention is a direct compression excipient, which simplifies the production process of the drug and enables more drug preparations to choose the powder direct compression process. Powder direct compression is a convenient production and ultra-low energy consumption preparation process, and is the first choice for many drug preparations. This patent provides very meaningful help.

[0032] Pharmaceutical solid preparations have high requirements for excipients, and different types of pharmaceutical preparations have different requirements for the same type of excipients. In order to meet different requirements, the sorbitol-povidone complex of the present invention can achieve control of key quality attributes by adjusting the material ratio and controlling the production parameters to meet the customized requirements of different drugs for excipients. DETAILED DESCRIPTION

[0033] Example 1: Effect of different material ratios on sorbitol-polyvidone compounding

[0034] Prescription composition table (weight ratio)

[0035]

[0036] Brief description of preparation process

[0037] ① Crushing of sorbitol: Take sorbitol and crush it through a 0.5mm sieve before use

[0038] ②Material weighing: According to the material ratio design of samples 1 to 3, weigh the crushed sorbitol and povidone

[0039] ③ Granulation: Place the material in a fluidized bed, mix the material evenly, spray add a certain amount of purified water, until the material is evenly granulated, and then directly dry it in the fluidized bed, controlling the end point moisture content ≤3.0%.

[0040] ④ Granulation: The prepared dry granules are granulated by a high-speed granulator, and a 1.5 mm sieve is selected.

[0041] Test results

[0042] Compare the differences in powder properties:

[0043] 1. Use BT-1000 powder comprehensive property tester of Dandong Better Instrument Co., Ltd. to measure bulk density and repose angle;

[0044] Angle of repose: In a static equilibrium state, the acute angle between the inclined surface of the powder accumulation and the bottom horizontal plane is called the angle of repose. It is formed by allowing the powder to fall naturally onto a specific platform in a specific way. The size of the angle of repose directly reflects the flow of the powder. The smaller the angle of repose, the better the flowability of the powder.

[0045] Bulk density: refers to the density of the powder in a naturally filled state in a specific container. It is measured using the fixed volume method. The particles are poured into a measuring cup of solid volume and the bulk density is calculated after weighing.

[0046] 2. Particle size: The particle size was measured using the HELOS laser particle size analyzer produced by Sympatec of Germany.

[0047] Principle of measurement: The pulse light emitted from a high-frequency pulse light source passes through a beam diffuser to obtain parallel pulse light. In the test area, the pulse light irradiates the dispersed single particles, and the parallel light will be scattered. A part of the light will form a certain angle with the optical axis and propagate outward. The scattering angle caused by large particles is small. The smaller the particle, the larger the angle between the scattered light and the axis. These scattered lights at different angles will form a series of light rings with different radii on the focal plane after passing through the Fuchs lens. The light spots of alternating light and dark composed of these light rings are called Airy spots. The Airy spots contain rich particle size information. We place a series of photoelectric receivers on the focal plane to convert the light signals scattered by particles of different particle sizes into electrical signals and transmit them to the computer. By mathematically processing these signals through the Mie scattering theory, the particle size distribution results can be obtained. In the present invention, we use D50 to illustrate the particle size.

[0048] The measurement results are shown in the following table:

[0049]

[0050] Summary: The addition ratio of povidone as a binder affects the particle size, density and angle of repose of the particles. When the povidone content is 2-50% (weight ratio), the particle size is appropriate, the angle of repose is less than 35°, and the bulk density is less than 0.5g / ml, indicating that the obtained particles have good fluidity and compressibility.

[0051] Example 2: Effect of different preparation parameters on the particle size of sorbitol-povidone complex

[0052] Prescription composition table

[0053]

[0054] Brief description of preparation process

[0055] ① Crushing of sorbitol: Take sorbitol (sorbitol produced by Hubei Gedian Renfu, batch number F303C201102), crush it through a 0.5mm sieve and use

[0056] ②Material weighing: According to the material ratio design, weigh the crushed sorbitol and povidone

[0057] ③ Granulation: Place the material in a fluidized bed, mix the material evenly, spray add purified water in an amount of 5% of the weight of the whole material, the obtained sample is named sample 4-1; spray add purified water in an amount of 10% of the weight of the whole material, the obtained sample is named sample 4-2; after drying respectively, control the overall moisture content to ≤3.0%.

[0058] The comparative investigation of the particle powder properties is as follows:

[0059]

[0060] ④ Granulation: The prepared dried granules of sample 4-1 were granulated by a high-speed granulator, and a 1.0 mm sieve was selected to obtain granulated sample 4-3. A 1.5 mm sieve was selected to obtain granulated sample 4-4.

[0061] The prepared sample 4-2 dried granules were granulated by a high-speed granulator, and a 1.0 mm sieve was selected to obtain a granulated granule sample 4-5. A 1.5 mm sieve was selected to obtain a granulated granule sample 4-6.

[0062] The test results of comparing the differences in powder properties are as follows:

[0063]

[0064] Test conclusion: In this study, purified water was used as a wetting agent for top spray granulation. The amount of purified water sprayed had a significant effect on the powder physics of the particles, mainly in terms of particle size and bulk density. Within a certain range, the granulation screen had little effect on the powder physics of the particles, and its main purpose was to remove possible agglomerates.

[0065] Example 3: Effect of Povidone Type

[0066] Povidone, also known as polyvinyl pyrrolidone, is mainly composed of linear 1-vinyl-2-pyrrolidone groups. Different degrees of polymerization lead to different molecular weights of polymers. The molecular weight can be characterized by the viscosity of the aqueous solution of povidone relative to water, expressed as the K value, which is between 10-120 and calculated using the Fikentscher's equation. The K value of povidone K30 ranges from 27.0 to 32.0, and the K value of povidone K25 ranges from 24.0 to 27.0. Experiments have shown that when using povidone with other K values, the K value is too small and the bonding effect is poor, and the K value is too large, it is not suitable for use as an adhesive, for example, it will lead to adverse consequences such as hard particles, poor compressibility, and slow release.

[0067] List of prescription ingredients

[0068]

[0069] Brief description of preparation process

[0070] ① Crushing of sorbitol: Take sorbitol (sorbitol produced by Hubei Gedian Renfu, batch number F303C201102), crush it through a 0.5mm sieve and use

[0071] ②Material weighing: According to the material ratio design, weigh the crushed sorbitol and povidone

[0072] ③ Granulation: Place the material in a fluidized bed, mix the material evenly, then spray 5% of the weight of the whole material with purified water to control the overall moisture content to ≤3.0%.

[0073] ④ Granulation: Use a high-speed granulation machine and select a 1.5mm screen for granulation;

[0074] The test results of the powder properties of the above composite particles are as follows:

[0075]

[0076] Test conclusion: Our company uses K30 and K25, the molecular weight difference between the two is not large, the viscosity is appropriate, and the prepared particles have no significant difference in powder properties, and both have good fluidity and compressibility. For povidone with other K values, when the K value is too small, the viscosity is low, the bonding effect is not good, the particles are not hard enough and are easy to break; when the K value is too large, it is not suitable for use as an adhesive, for example, it will lead to adverse consequences such as too hard particles, poor compressibility, slow release, etc.

[0077] Example 4: Application of sorbitol-povidone complex in telmisartan tablets

[0078] Prescription composition table

[0079]

[0080] Note [1]: The formula composition of Telmisartan Complex: Each tablet contains 80 mg of Telmisartan, 6.72 mg of Sodium Hydroxide, 24 mg of Povidone, and 24 mg of Meglumine.

[0081] Brief description of preparation process

[0082] ① Preparation of Telmisartan Complex: Telmisartan, sodium hydroxide, meglumine and povidone K25 are dissolved in an appropriate amount of hot water, and the mixture is spray-dried and sieved to obtain the Telmisartan Complex.

[0083] ② Preparation of sorbitol-povidone complex: Weigh the crushed sorbitol and povidone K25 in a ratio of 9:1, mix, granulate and dry in a fluidized bed, and then select a 1.2-2.0 mm aperture sieve for granulation according to the particle size of the telmisartan complex to obtain uniform sorbitol-povidone complex particles.

[0084] ③ According to the prescription ratio, weigh the telmisartan complex and the sorbitol-povidone complex, complete premixing in a three-dimensional motion mixer, and then add magnesium stearate to complete the total mixing.

[0085] ④ The total mixed granules are compressed into tablets by a tablet press to obtain telmisartan tablets or tablet layers.

[0086] Experimental results:

[0087] The mixing uniformity of telmisartan complex and sorbitol-povidone complex in the premixing and total mixing stages was summarized, proving that the established prescription was reasonable, the process parameters were properly controlled, and the product quality was controllable. The tablet core obtained by the above prescription and process showed slow dissolution during the dissolution study. The homemade preparation was similar to the original research, and both were completely dissolved between 18 and 25 minutes. The dissolution data similarity was very high, and the calculated similarity factor f2 = 86.

[0088] Sorbitol-Polyvidone Complex Particle Size Test Results:

[0089]

[0090] The results of semi-finished product mixing uniformity are as follows:

[0091]

[0092] Dissolution curve test:

[0093] This product uses the paddle method specified in the Chinese Pharmacopoeia to test the dissolution curve, the rotation speed is 75rpm, the dissolution liquid is pH7.5 phosphate buffer, and the dissolution liquid volume is 900ml. The results are as follows:

[0094]

[0095] Note: The reference preparation refers to the "Catalogue of Reference Preparations for Generic Drugs" issued by CDE, and the imported telmisartan tablets produced by Boehringer Ingelheim are selected, with batch number 844257.

[0096] Summary: The results of the investigation of the key quality attributes of the semi-finished products and finished products show that the quality of the telmisartan tablets can be controlled after mixing and tableting using the sorbitol-povidone complex of the present invention, and has good similarity with the reference preparation.

[0097] Example 5: Application of sorbitol-povidone complex in bisoprolol fumarate tablets

[0098] Prescription composition

[0099]

[0100]

[0101] Brief description of preparation process:

[0102] ① Preparation of sorbitol-povidone complex: Weigh the crushed sorbitol and povidone K30 in a ratio of 8:2, mix, granulate and dry in a fluidized bed, select a 1.0 mm pore size screen for granulation, and obtain sorbitol-povidone complex particles. Sorbitol-povidone complex particle size requirement: 100≤D50≤200μm

[0103] ② Weigh bisoprolol fumarate, microcrystalline cellulose and silicon dioxide in the prescribed proportion and premix them in a hopper mixer, and then add magnesium stearate to complete the total mixing.

[0104] ③ Take the total mixed granules and complete tableting through a tablet press, and control the tableting hardness at 50-80N.

[0105] Experimental results:

[0106] In view of the small proportion of raw materials in this product, the composition ratio of sorbitol and povidone K30 was adjusted, and the mesh size of the whole granule sieve was controlled to enable the sorbitol-povidone complex to obtain a more suitable particle size distribution. The mixing uniformity of the semi-finished product was examined to ensure that it met the quality standard requirements.

[0107] Sorbitol-Polyvidone Complex Particle Size Test Results:

[0108]

[0109] Results of the inspection on the uniformity of semi-finished product mixing:

[0110]

[0111] Segmentation uniformity inspection:

[0112]

[0113] Note [1]: The reference preparation was selected from the “Catalogue of Reference Preparations” published by CDE, and was an imported product produced by Merck in Germany, with batch number 22006A.

[0114] Summary: After adjusting the prescription ratio and whole granulation parameters of sorbitol-povidone complex, the semi-finished product test results meet the quality standard requirements, thus ensuring the quality of the finished product. In addition, bisoprolol fumarate tablets are scored tablets, which involve tablet segmentation during the patient's medication process. By using a special new excipient sorbitol-povidone complex as a filler, due to its good plastic deformation, the tablet core is guaranteed to be compressible, the segmentation weight loss is reduced, and the medication compliance is improved.

[0115] Example 6: Effect of Sorbitol Powder Particle Size

[0116] As an important component of fluidized bed granulation, sorbitol needs to be crushed during the preparation production process. Therefore, the effect of different particle sizes of sorbitol on the powder properties of sorbitol-povidone complex after fluidized bed granulation was studied. The same batch of sorbitol was crushed with different particle size screens to make sorbitol-povidone complex, which was then applied to a specific variety of telmisartan tablets. The differences in the powder properties of sorbitol-povidone complex were compared, and the effect of this change on the dissolution curve of telmisartan tablets was compared.

[0117] Prescription composition table

[0118]

[0119] Note [1]: The formula composition of Telmisartan Complex: Each tablet contains 80 mg of Telmisartan, 6.72 mg of Sodium Hydroxide, 24 mg of Povidone, and 24 mg of Meglumine.

[0120] Brief description of preparation process

[0121] ① Preparation of Telmisartan Complex: Telmisartan, sodium hydroxide, meglumine and povidone K25 are dissolved in an appropriate amount of hot water, and the mixture is spray-dried and sieved to obtain the Telmisartan Complex.

[0122] ② Sorbitol crushing: Sorbitol (batch number: F303C240101) produced by Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. was crushed with a hammer mill with an 80-mesh screen and used to prepare sample 9. Sorbitol was crushed with a hammer mill with a 120-mesh screen and used to prepare sample 10.

[0123] ③ Preparation of sorbitol-povidone complex: Weigh the crushed sorbitol and povidone K25 in a ratio of 9:1, mix, granulate and dry in a fluidized bed, and pass the obtained sorbitol-povidone complex through a 20-mesh ternary rotary vibrating sieve to maintain the particle size. Using the same prescription ratio and preparation process parameters, prepare the sorbitol-povidone complex required for sample 9 and sample 10.

[0124] ④ According to the prescription ratio, weigh the telmisartan complex and sorbitol-povidone complex, complete premixing in a three-dimensional motion mixer, and then add magnesium stearate to complete the total mixing.

[0125] ⑤ The total mixed granules are compressed into tablets by a tablet press to obtain telmisartan tablets or tablet layers.

[0126] Experimental results:

[0127] ① Difference in particle size of sorbitol powder after crushing using different sieves:

[0128]

[0129] Summary: The particle sizes of sorbitol obtained by different crushing methods are significantly different.

[0130] ② Differences in powder properties of sorbitol-povidone complex after granulation and sieving:

[0131]

[0132] Summary: After granulation of sorbitol of different particle sizes, the obtained composite particles have little difference in powder properties and all have good fluidity and compressibility.

[0133] ③Dissolution curve detection:

[0134] This product uses the paddle method specified in the Chinese Pharmacopoeia to test the dissolution curve, the rotation speed is 75rpm, the dissolution liquid is pH7.5 phosphate buffer, and the dissolution liquid volume is 900ml. The results are as follows:

[0135]

[0136] Note: The reference preparation refers to the "Catalogue of Reference Preparations for Generic Drugs" issued by CDE, and the imported telmisartan tablets produced by Boehringer Ingelheim are selected, with batch number 844257.

[0137] Summary: There is no significant difference in the tablet dissolution curves of Sample 9 and Sample 10, which proves that the prescription composition is well tolerated. The difference in particle size of sorbitol fine powder has no significant effect on the dissolution rate of the product. The ratio of sorbitol-povidone is the key means to adjust the dissolution rate of the tablet core.

[0138] Example 7: Advantages of sorbitol-povidone complex over original sorbitol SI150

[0139] The original manufacturer of telmisartan tablets is Boehringer Ingelheim. Literature shows that directly compressible sorbitol is used for prescription preparation in its preparation process. Therefore, directly compressible sorbitol SI150 was purchased to prepare telmisartan tablets, and sorbitol-povidone complex was used to prepare telmisartan tablets in parallel to compare the difference in their economic benefits.

[0140] Prescription composition table

[0141]

[0142]

[0143] Note [1]: The formula composition of Telmisartan Complex: Each tablet contains 80 mg of Telmisartan, 6.72 mg of Sodium Hydroxide, 24 mg of Povidone, and 24 mg of Meglumine.

[0144] Brief description of preparation process

[0145] ① Preparation of Telmisartan Complex: Telmisartan, sodium hydroxide, meglumine and povidone K25 are dissolved in an appropriate amount of hot water, and the mixture is spray-dried and sieved to obtain the Telmisartan Complex.

[0146] ② Application of sorbitol-povidone complex: Sorbitol (batch number: F303C240101) produced by Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. was crushed with a hammer mill with an 80-mesh sieve. The crushed sorbitol and povidone K25 were weighed in a ratio of 9:1, mixed, granulated and dried in a fluidized bed, and the obtained sorbitol-povidone complex was passed through a 20-mesh ternary vibrating sieve. Telmisartan complex and sorbitol-povidone complex were weighed according to the prescription ratio, premixed in a three-dimensional motion mixer, and then magnesium stearate was added to complete the total mixing. The total mixed granules were tableted, and the tablet core hardness was controlled to 100-120N to obtain sample 11.

[0147] ③ Application of sorbitol SI150: Telmisartan complex and sorbitol SI150 were weighed according to the prescription ratio, pre-mixed in a three-dimensional motion mixer, and then magnesium stearate was added to complete the total mixing. The total mixed particles were tableted, and the tablet core hardness was controlled to 100-120N to obtain sample 12.

[0148] Experimental results:

[0149] ① Comparison of the powder physics differences between sorbitol SI150 and sorbitol-povidone complex:

[0150]

[0151] Summary: The powder properties of the prepared sorbitol-povidone complex are similar to those of direct compression sorbitol SI150, and the particles have similar fluidity and compressibility.

[0152] ②Comparison of dissolution curves:

[0153] This product uses the paddle method specified in the Chinese Pharmacopoeia to test the dissolution curve, the rotation speed is 75rpm, the dissolution liquid is pH7.5 phosphate buffer, and the dissolution liquid volume is 900ml. The results are as follows:

[0154]

[0155]

[0156] Note: The reference preparation refers to the "Catalogue of Reference Preparations for Generic Drugs" issued by CDE, and the imported telmisartan tablets produced by Boehringer Ingelheim are selected, with batch number 844257.

[0157] Summary: The dissolution curves of Sample 11 and Sample 12 were compared with the original product, and the similarity factors were calculated to be ≥50, so they are similar to the original product.

[0158] ③ Comparison of the costs of different prescriptions for Sample 11 and Sample 12:

[0159]

[0160] Note: The cost per tablet is calculated based on the theoretical prescription quantity and the price of commercially available excipients.

[0161] Summary: The cost difference of a single tablet is 0.0135 yuan / tablet. When the product is scaled up, it can be scaled up to 1 million tablets / batch according to the smaller batch size. The cost difference per batch will be expanded to 13,500 yuan / batch, reflecting the economic benefits of sorbitol-povidone complex. Example 8: Study on the stability of sorbitol-povidone complex

[0162] The sample preparation was repeated three times with a sorbitol:povidone ratio of 8:2. The changes in particle size, moisture, density, angle of repose and other parameters during storage were studied.

[0163] Prescription composition table

[0164]

[0165] Brief description of preparation process

[0166] ① Grinding of sorbitol: Take sorbitol (sorbitol produced by Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd., batch number: F303C240101), grind it through an 80-mesh sieve before use.

[0167] ②Material weighing: According to the material ratio design, weigh the crushed sorbitol and povidone

[0168] ③ Granulation: Place the materials in a fluidized bed, mix the materials evenly, spray and add purified water in an amount of 8% of the weight of the entire materials, and obtain a sorbitol-povidone complex after fluidized bed drying. Repeat the granulation process for 3 batches.

[0169] ④ Sieving: After the obtained dry granules were passed through a 20-mesh sieve, three parallel batches were named Sample 13, Sample 14, and Sample 15.

[0170] Experimental results:

[0171] Three batches of samples were prepared in parallel, and after being packaged in low-density polyethylene bags and paper-aluminum composite bags, accelerated tests (40°C / 75%RH) and long-term tests (30°C / 65%RH) were carried out to investigate the changes in the relevant indicators of the sorbitol-povidone complex during storage. The detailed results are as follows:

[0172] Stability test results of sample 13

[0173]

[0174] Stability test results of sample 14

[0175]

[0176] Stability test results of sample 15

[0177]

[0178] Test conclusion: The repeatability study showed that the batch-to-batch differences were small, and the stability study also proved that the moisture and particle state of the sorbitol-povidone complex did not change significantly during storage. This proves that the new complex can be stably produced and can meet storage requirements.

Claims

1. A sorbitol-povidone complex, characterized in that The composite contains 50-98% sorbitol and 2-50% povidone by weight.

2. The sorbitol-povidone complex according to claim 1, characterized in that The polyvidone includes: polyvidone K25 or K30.

3. The sorbitol-povidone complex according to claim 1, characterized in that The average particle size D50 of the sorbitol is 100 to 300 μm.

4. The sorbitol-povidone complex according to claim 1, characterized in that The average particle size D50 of the sorbitol is 150 to 250 μm.

5. The method for preparing the sorbitol-povidone complex according to claim 1, characterized in that The steps include: (a) sorbitol is crushed and sieved to obtain sorbitol powder; (b) mixing sorbitol powder and povidone in a fluidized bed, wherein the weight ratio of sorbitol is 50-98% and the weight ratio of povidone is 2-50%, adding a wetting agent by spraying to form particles of uniform size and good fluidity, and drying in a fluidized bed; (c) The dried granules are sized by passing through a sieve with a suitable aperture to obtain a sorbitol-povidone complex.

6. The method for preparing the sorbitol-povidone complex according to claim 5, characterized in that The polyvidone includes polyvidone K25 or polyvidone K30, which acts as an adhesive during the preparation of the composite.

7. The method for preparing the sorbitol-povidone complex according to claim 5, characterized in that The average particle size D50 of the sorbitol is 100 to 300 μm.

8. The method for preparing the sorbitol-povidone complex according to claim 5, characterized in that The average particle size D50 of the sorbitol is 150 to 250 μm.

9. Use of the sorbitol-povidone complex according to claim 1 in the preparation of a pharmaceutical preparation product, wherein the complex is used as a filler in a pharmaceutical preparation to effectively control the key quality attributes of the preparation.

10. The use according to claim 9, characterized in that The steps include: (a) mixing the complex with a pharmaceutically active ingredient, a pharmaceutical excipient, etc. to obtain a final mixture; (b) The final mixture is compressed into tablets or tablet layers.

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