Method for improving dissolution rate of pioglitazone hydrochloride tablets

Abstract

The invention provides a method for improving the dissolution rate of pioglitazone hydrochloride tablets, and belongs to the technical field of medicines. The method for improving the dissolution rate of the pioglitazone hydrochloride tablet comprises the step of preparing the pioglitazone hydrochloride tablet from a pioglitazone hydrochloride solid dispersion, an adhesive and a pharmaceutically acceptable carrier through wet granulation. The amphiphilic carrier is selected and blended into water to form a hydrophobic cavity, so that hydrophobic pioglitazone hydrochloride is contained, the pioglitazone hydrochloride raw material medicine is highly dispersed under the ultrasonic or mechanical acting force through Van der Waals acting force, simple physical mixing in the prior art is avoided, and by controlling the using amount of an adhesive, the preparation process is simplified, and the preparation cost is reduced. And the effect that the dissolution of pioglitazone hydrochloride is consistent with that of the original drug is achieved.

Description

Technical Field

[0001] This invention application belongs to the field of pharmaceutical technology and relates to a method for improving the dissolution rate of pioglitazone hydrochloride tablets. Background Art

[0002] Pioglitazone hydrochloride (PGH) is a thiazolidinedione (TZD) - type oral antidiabetic drug and is an agonist of highly selective peroxisome proliferative activated receptor γ (PPARγ). It controls blood glucose levels by enhancing insulin sensitivity in the periphery and liver, reducing glucose output in the liver, decreasing hepatic glycogenolysis, and increasing the sensitivity of insulin receptors. Clinically, it is applicable to patients with type 2 diabetes mellitus (T2DM).

[0003] Pioglitazone hydrochloride is a white crystal or crystalline powder, highly soluble in organic solvents such as methanol and N, N - dimethylformamide, and almost insoluble in water and phosphate buffer solution (pH 6.8). Its powder is fine, the texture is loose, the drying and viscosity are poor, its absorption and bioavailability are relatively low, belonging to BCS class II drugs with the property of low solubility and high permeability. Thus, improving the dissolution rate of pioglitazone tablets is the key to the formulation process.

[0004] Due to the extremely poor water solubility of pioglitazone hydrochloride, in the prior art, it needs to be dissolved in organic solvents such as methanol, and then mixed with an aqueous solution of water - soluble carriers such as povidone, surfactant, crospovidone, cellulose, or organic acid to obtain a mixed solution. Subsequently, the solvent is removed and dried to obtain a pioglitazone hydrochloride solid dispersion. This introduces unnecessary organic solvents, affects the quality of subsequent preparations, and also requires additional impurity removal steps. At the same time, the active pharmaceutical ingredient and the carrier are in a physical blending form, with limited uniformity. The particle size of the active pharmaceutical ingredient is large (40 - 70 μm), and the requirements for micronization technology are high.

[0005] The invention patent application CN101269040A discloses a sustained - release dropping pill of pioglitazone hydrochloride and its preparation method. Using hydrophilic matrix materials and hydrophobic matrix materials as the matrix, they are mixed with the pioglitazone hydrochloride active pharmaceutical ingredient to form a solid dispersant, enabling the drug to be dispersed in the matrix in a molecular, colloidal, or microcrystalline state, increasing the total surface area of the drug, with high bioavailability and a long onset time.

[0006] The invention patent CN113116837 B discloses a pioglitazone hydrochloride sustained-release tablet and a preparation method thereof. The pioglitazone hydrochloride raw material drug is dispersed in an organic solvent such as methanol, and a mixed water-soluble carrier of hydroxypropyl cellulose and citric acid is dissolved in water. The two obtained solutions are uniformly mixed, the solvent is removed, granulated, and dried to obtain a pioglitazone hydrochloride solid dispersion. Subsequently, it is made into a pioglitazone hydrochloride sustained-release tablet with a prescribed amount of water-soluble skeleton material and excipients, improving the dissolution rate and bioavailability of pioglitazone hydrochloride.

[0007] Thus, mixing the pioglitazone hydrochloride raw material drug with the carrier, on the one hand, uses the carrier to avoid the situation where the pioglitazone hydrochloride sample changes from an amorphous state to an ordered crystal form during the crushing process, thereby reducing the solubility of pioglitazone hydrochloride. On the other hand, the formed pioglitazone hydrochloride solid dispersion is more easily mixed with the hydrophilic skeleton material and excipients, improving the sample uniformity and the bioavailability of the pioglitazone hydrochloride tablet. Summary of the Invention

[0008] This application for invention provides a method for improving the dissolution rate of pioglitazone hydrochloride tablets, aiming to partially or fully solve technical problems such as poor solubility of the raw material drug during the preparation of pioglitazone hydrochloride tablets, resulting in the dissolution curve of the obtained tablets being difficult to be consistent with the reference product and low bioavailability. Based on the prior art, this application for invention discovers that the type of hydrophilic carrier, its ratio to the pioglitazone hydrochloride raw material drug, and the mixing method are the key factors affecting the dissolution curve of the obtained pioglitazone hydrochloride tablets. By further changing the addition amount of the binder, sample particles, stirring speed of wet granulation, tableting process, etc., the prepared granules are uniform, have good compressibility, and the dissolution curve is consistent with the reference product. To achieve the purpose of this application for invention, the technical solution of this application for invention is as follows: A method for improving the dissolution rate of pioglitazone hydrochloride tablets, comprising: Preparing through wet granulation with pioglitazone hydrochloride solid dispersion, binder, and a pharmaceutically acceptable carrier; The preparation method of the pioglitazone hydrochloride solid dispersion is: adding the pioglitazone hydrochloride raw material drug to an aqueous solution of a hydrophilic carrier at 20 - 40 °C, and fully mixing through stirring or mechanical grinding or ultrasonic method, then precipitating, filtering, and drying to obtain; Wherein the hydrophilic carrier is one or several of lecithin, cyclodextrin, hydrophilic chitosan; the mass ratio of water to the hydrophilic carrier is 1 - 5:1, and the mass ratio of the pioglitazone hydrochloride raw material drug to the hydrophilic carrier is 1:0.5 - 10; The binder includes a 2% - 10% aqueous solution of polyvinylpyrrolidone K30.

[0009] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, freeze-drying is used for drying; the freezing temperature is -60 to -45 °C, the freezing pressure is 0.15 - 0.25 mbar, and the freezing time is 12 hours.

[0010] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, the conditions for ultrasonic treatment are: the ultrasonic temperature is 20 - 40 °C; the frequency is 30 - 100 Hz; the ultrasonic time is 5 - 30 min.

[0011] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, Stirring includes: stirring the mixture of pioglitazone hydrochloride raw material and hydrophilic carrier in a water bath at 30 °C for 40 min; Or, mechanical grinding includes: placing the aqueous solution of the hydrophilic carrier in a mortar, then adding the pioglitazone hydrochloride raw material, and grinding at 30 °C for 30 min; Or, the ultrasonic method includes: ultrasonicating the mixture of pioglitazone hydrochloride raw material and hydrophilic carrier at 30 °C and 100 Hz for 15 min.

[0012] Optionally, the D90 of the particle size of the pioglitazone hydrochloride solid dispersion is 1 - 80 μm, preferably 5 - 60 μm; and / or, in the method for preparing the pioglitazone hydrochloride solid dispersion, the powder obtained after drying passes through a 40 - 80 mesh sieve, preferably an 80 - mesh sieve.

[0013] Optionally, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a lubricant, and a glidant.

[0014] Optionally, the pharmaceutically acceptable carrier includes a filler, a disintegrant, and a lubricant; The filler includes one or more of lactose, powdered sugar, dextrin, crystalline cellulose, and silica; The disintegrant includes one or more of corn starch, potato starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium, effervescent disintegrant, hydroxypropyl starch, and hydroxypropyl starch spheres; The lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate.

[0015] Optionally, the wet granulation includes: Adding the pioglitazone hydrochloride solid dispersion and the pharmaceutically acceptable carrier into a wet granulator, setting the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mixing for 5 minutes until uniform; then increasing the speed to stirring at 100 rpm and the cutter at 1000 rpm, and slowly adding the binder to form a soft material with a moderate viscosity and a moisture content of 2% - 5%; Extrude the soft material through a 18-mesh sieve to form wet granules; Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60 - 65 °C, and dry until the moisture content of the granules ≤ 5%; After drying, size the granules through a 20-mesh sieve to remove fine powder and lumps; Mix the dried granules evenly with the lubricant, use a high-speed rotary tablet press, adjust the tablet weight to the target specification, and control the hardness within the range of 2.5 - 3.1 kg.

[0016] Optionally, the pharmaceutically acceptable carriers include: lactose, starch, hydroxypropyl methylcellulose, and magnesium stearate. The weight ratios of the components of the pioglitazone hydrochloride tablets are as follows: Pioglitazone hydrochloride solid dispersion: lactose: starch: hydroxypropyl methylcellulose: magnesium stearate is 1: 0.5 - 6.5: 0.6 - 3.0: 0.5 - 2: 0.2 - 0.5. The binder accounts for 15 - 30% of the total weight of the pioglitazone hydrochloride tablets, preferably 25%.

[0017] Optionally, before wet granulation, the pharmaceutically acceptable carriers are sieved to ensure powder uniformity, including: Lactose, starch, and hydroxypropyl methylcellulose are pretreated by sieving through an 80-mesh sieve; Magnesium stearate is pretreated by sieving through a 60-mesh sieve.

[0018] Compared with the prior art, the beneficial effects of the present invention application are: (1) In the present invention application, the selected hydrophilic carriers are all amphiphilic carriers, which have both hydrophilic groups and hydrophobic groups at the same time. When incorporated into water, they can form hydrophobic cavities to accommodate hydrophobic pioglitazone hydrochloride. Therefore, even though pioglitazone hydrochloride has extremely poor solubility in water, under the action of the carriers in the present invention application, pioglitazone hydrochloride API can still be highly dispersed under ultrasonic or mechanical force through van der Waals forces, rather than simple physical mixing in the prior art. Under the action of the hydrophilic carrier, the solubility of pioglitazone hydrochloride is greatly improved, and by controlling the amount of the binder, the dissolution of pioglitazone hydrochloride is made consistent with the original research.

[0019] (2) In the present invention application, by adding hydrophilic carriers and cooperating with preparation means such as rapid stirring, high-frequency grinding, and ultrasonic dispersion, the uniformity of pioglitazone hydrochloride raw materials is synergistically improved, and further its dissolution rate is improved; For pioglitazone hydrochloride tablets, the preparation process is optimized by using the control variable orthogonal test method, including items such as prescription composition, the addition amount of the binder, stirring speed, shear speed, and main pressure of the tablet press. The preparation process is evaluated through the dissolution data of the obtained products. The results show that the addition amount of the binder has an important influence on the dissolution rate of pioglitazone tablets. Detailed implementation mode

[0020] Next, in combination with the embodiments of the present invention application, the technical solutions in the embodiments of the present invention application will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention application, rather than all the embodiments. The numerical range can be understood to include at least the endpoint values, and can also be reasonably understood according to the actual situation; based on the embodiments in the present invention application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope protected by the present invention application.

[0021] A method for improving the dissolution rate of pioglitazone hydrochloride tablets A method for improving the dissolution rate of pioglitazone hydrochloride tablets, comprising: Preparing pioglitazone hydrochloride solid dispersion, binder, and pharmaceutically acceptable carrier by wet granulation; The preparation method of the pioglitazone hydrochloride solid dispersion is as follows: under the condition of 20 - 40 °C, adding pioglitazone hydrochloride raw material drug into the aqueous solution of the hydrophilic carrier, and after fully mixing by stirring or mechanical grinding or ultrasonic method, precipitating, filtering, and drying to obtain; Wherein the hydrophilic carrier is one or several of lecithin, cyclodextrin, and hydrophilic chitosan; the mass ratio of water to the hydrophilic carrier is 1 - 5:1, and the mass ratio of pioglitazone hydrochloride raw material drug to the hydrophilic carrier is 1:0.5 - 10; The binder includes 2% - 10% aqueous solution of polyvinylpyrrolidone K30.

[0022] In the present invention application, the temperature range (20 - 40 °C): The temperature range avoids the destruction of the chemical stability of pioglitazone hydrochloride by high temperature, and at the same time ensures the solubility and activity of the hydrophilic carrier in the aqueous solution, facilitating the formation of a uniform dispersion system; hydrophilic carrier: Lecithin, cyclodextrin, and hydrophilic chitosan have excellent water solubility and inclusion ability, and include or disperse pioglitazone hydrochloride in the carrier through intermolecular interactions (such as hydrogen bonds and hydrophobic interactions) to form a molecular-level or microscopic dispersion state. This dispersion state significantly increases the contact area between the drug and the dissolution medium, reduces the crystal energy barrier of the raw material drug, and improves the dissolution kinetics; the mass ratio of water to the carrier (1 - 5:1): The appropriate solution concentration ensures the dispersion ability of the hydrophilic carrier, avoiding both low inclusion efficiency caused by too dilute a solution and difficult dissolution or uneven precipitation caused by too concentrated a solution; the mass ratio of pioglitazone hydrochloride to the carrier (1:0.5 - 10): This ratio range enables the carrier to fully include the raw material drug, and at the same time, avoids excessive carrier increasing the preparation volume or cost, and optimizes the dissolution performance.

[0023] In the application of the present invention, the mixing means (one of stirring, mechanical grinding, and ultrasonic method): By inputting physical energy (such as the shear force of stirring, the mechanical crushing of grinding, and the acoustic cavitation effect of ultrasound), the crystal structure of the API is broken, the size and crystallinity of the crystal particles are reduced, and a solid dispersion is obtained by filtration and drying after precipitation. This process further improves the dissolution rate and dissolution kinetics of the API.

[0024] In the application of the present invention, the types of hydrophilic carriers and their ratio to the API (1:0.5 - 10) improve solubility through the inclusion effect: Lecithin coats pioglitazone hydrochloride through its amphiphilic structure (hydrophilic head and hydrophobic tail) to form a micelle-like structure, enhancing the solubility of the drug in the aqueous medium. Cyclodextrin uses its hydrophobic cavity to include pioglitazone hydrochloride molecules, and its hydrophilic outer surface promotes the interaction between the drug and the dissolution medium. Hydrophilic chitosan adsorbs the API through its polysaccharide structure and cationic properties to form a uniformly dispersed system, improving the dissolution efficiency. A mass ratio of 1:0.5 - 10 ensures the balance between the inclusion efficiency and the formulation cost. Too low a ratio may result in incomplete inclusion, while too high a ratio may increase the burden of excipients.

[0025] In the application of the present invention, polyvinylpyrrolidone K30 has good water solubility and viscosity. A concentration range of 2% - 10% ensures an appropriate water content in the soft material, avoiding both overly hard particles or hindered dissolution caused by excessive wetness and loose particles caused by excessive dryness. Its viscous effect promotes the combination of the solid dispersion and the carrier, and a soft material with moderate viscosity can be formed, facilitating subsequent extrusion into wet granules.

[0026] Thus, in a method for improving the dissolution rate of pioglitazone hydrochloride tablets in the application of the present invention, the pioglitazone hydrochloride API is added to an aqueous solution of a hydrophilic carrier, and sufficient mixing is carried out by stirring or mechanical grinding or ultrasonic method. After precipitation, filtration, and drying, a pioglitazone hydrochloride solid dispersion is prepared. Under mild conditions of 20 - 40°C, using stirring, mechanical grinding or ultrasonic method, the water-to-carrier ratio is 1 - 5:1. The process is simple and controllable, suitable for industrial production. Lecithin, cyclodextrin, and hydrophilic chitosan have strong inclusion capabilities. A mass ratio of 1:0.5 - 10 balances the dissolution performance and cost, optimizing drug release. A 2% - 10% aqueous solution of polyvinylpyrrolidone K30 ensures moderate viscosity of the soft material, improves the solubility of the API, the dissolution curve is consistent with the reference product, the bioavailability is significantly improved, the dissolution performance is stable, the dissolution variability is reduced, and comprehensive optimization achieves a high degree of matching with the reference product, meeting the requirements of the consistency evaluation of generic drugs. Parameters (such as temperature, mass ratio, stirring speed) can be flexibly adjusted, and the stability is high, suitable for production of different batches.

[0027] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, freeze-drying is used for drying; the freezing temperature is -60 to -45 °C, the freezing pressure is 0.15 - 0.25 mbar, and the freezing time is 12 hours.

[0028] In the present invention application, the mixed pioglitazone hydrochloride solid dispersion solution (containing a hydrophilic carrier) is frozen at -60 to -45 °C, so that the water in the solution is quickly frozen into ice crystals, while maintaining the molecular-level or microscopic dispersion state of pioglitazone hydrochloride and the hydrophilic carrier (such as lecithin, cyclodextrin), avoiding the risk of drug degradation or carrier structure damage caused by too high temperature, maintaining the chemical structure and biological activity of the active pharmaceutical ingredient, and at the same time protecting the functionality of the hydrophilic carrier (such as the inclusion ability of cyclodextrin); at the same time, in a low-pressure environment (0.15 - 0.25 mbar), the ice crystals can be directly converted from a solid state to a gaseous state by sublimation to remove water. The low pressure ensures that the sublimation process occurs at a low temperature, avoiding the damage of the liquid water to the dispersion structure. Time control (12 hours): The freezing time of 12 hours ensures sufficient sublimation of water, while avoiding increased energy consumption caused by too long drying or residual water affecting stability caused by too short drying.

[0029] In the present invention application, freeze-drying is carried out under low temperature and low pressure, avoiding the thermal degradation or crystal form change of pioglitazone hydrochloride that may be caused by high-temperature drying (such as hot air drying), maintaining the chemical stability and biological activity of the active pharmaceutical ingredient, and the low-temperature condition also protects the functionality of the hydrophilic carrier (such as the inclusion cavity structure of cyclodextrin), ensuring its wetting and inclusion effects in the subsequent dissolution process. Freeze-drying fixes the molecular-level dispersion state of pioglitazone hydrochloride and the hydrophilic carrier through the freezing and sublimation processes, avoiding the phenomena of particle aggregation or recrystallization caused by water evaporation in traditional drying methods, thereby maintaining the high dispersibility and solubility of the solid dispersion, with high process stability and repeatability, and being suitable for industrial production.

[0030] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, the conditions for ultrasonic treatment are: the ultrasonic temperature is 20 - 40 °C, preferably 30 °C; the frequency is 30 - 100 Hz, preferably 100 Hz; and the ultrasonic time is 5 - 30 min, preferably 15 min.

[0031] In the present invention application, when ultrasonic waves propagate in a liquid, an acoustic cavitation effect is generated, that is, minute bubbles are formed, grow, and rupture under the action of sound waves. High-frequency vibrations with a frequency of 30 - 100 Hz (preferably 100 Hz) enhance the energy of bubble rupture, and the released shock waves and microjets can effectively break the crystal structure and aggregates of pioglitazone hydrochloride API, promoting its uniform dispersion with hydrophilic carriers (lecithin, cyclodextrin, hydrophilic chitosan); the ultrasonic temperature is controlled at 20 - 40 °C (preferably 30 °C), and the mild conditions avoid thermal degradation of pioglitazone hydrochloride at high temperatures while maintaining the aqueous solution stability of the hydrophilic carrier. 30 °C can be used as the preferred temperature close to room temperature, maximizing the ultrasonic effect; the ultrasonic time is 5 - 30 minutes (preferably 15 minutes), ensuring a sufficient mixing process. Dispersion may not be complete within 5 minutes, and exceeding 30 minutes may cause excessive mechanical stress to damage the drug or carrier structure. 15 minutes is used as the preferred time to balance the dispersion efficiency and drug protection.

[0032] In the present invention application, ultrasound reduces the particle size through physical energy input, increases the contact area between pioglitazone hydrochloride and the hydrophilic carrier, and at the same time promotes the inclusion effect of the carrier (such as the cavity inclusion of cyclodextrin), improving the dispersion and solubility of the API in the aqueous solution, laying a foundation for the formation and dissolution performance of the subsequent solid dispersion.

[0033] Optionally, in the preparation method of the pioglitazone hydrochloride solid dispersion, stirring includes: stirring the mixed solution of pioglitazone hydrochloride and the hydrophilic carrier in a water bath at 30 °C for 40 min; Or, mechanical grinding includes: placing the aqueous solution of the hydrophilic carrier in a mortar, and then adding or a certain amount of pioglitazone hydrochloride, and grinding at 30 °C for 30 min; The ultrasonic method includes: ultrasonically treating the mixed solution of pioglitazone hydrochloride and the hydrophilic carrier at 30 °C and 100 Hz for 15 min.

[0034] In some embodiments, the mixed solution is stirred in a water bath at 30 °C for 40 minutes, and the mild shear force enables the pioglitazone hydrochloride API to fully contact the aqueous solution of the hydrophilic carrier (lecithin, cyclodextrin, hydrophilic chitosan). The temperature of 30 °C maintains the stability of the carrier solution and at the same time promotes the inclusion effect of the hydrophilic carrier (such as the cavity inclusion of cyclodextrin), forming a molecular-level or microscopic dispersion state. The stirring time of 40 minutes ensures uniform mixing, enhancing the dispersion and solubility of the API.

[0035] In some embodiments, an aqueous solution of the hydrophilic carrier is placed in a mortar, and pioglitazone hydrochloride is added. It is ground at 30 °C for 30 minutes. The crystal structure of pioglitazone hydrochloride is broken by the mechanical friction and pressure of the mortar to reduce the particle size. The mild temperature of 30 °C avoids thermal degradation, promotes the physical mixing of the carrier and the active pharmaceutical ingredient, enhances the uniformity of the dispersion, and improves the dissolution kinetics.

[0036] In some embodiments, the mixture is sonicated at 30 °C and 100 Hz for 15 minutes. The high-frequency sound waves generate acoustic cavitation effects. The tiny bubbles burst and release shock waves to break the pioglitazone hydrochloride crystals and aggregates, while enhancing the inclusion effect of the hydrophilic carrier. The temperature of 30 °C protects the stability of the drug and the carrier. The 100 Hz frequency optimizes the energy of bubble rupture. The 15-minute sonication time ensures sufficient dispersion without excessive damage.

[0037] In the present invention application, stirring for 40 minutes, grinding for 30 minutes, or sonication for 15 minutes respectively achieve uniform mixing through shear force, frictional force, or acoustic cavitation effects, significantly enhancing the dispersibility of pioglitazone hydrochloride and the hydrophilic carrier, reducing local concentration deviation. The mild condition of 30 °C avoids the degradation of pioglitazone hydrochloride caused by high temperature or the structural damage of the hydrophilic carrier (such as cyclodextrin), ensuring the chemical and physical stability of the drug and the carrier; stirring for 40 minutes, grinding for 30 minutes, and sonication for 15 minutes are all preferred times, balancing the dispersion effect and energy consumption, avoiding drug damage or carrier denaturation caused by excessive processing, and improving the preparation efficiency; the stirring, grinding, or sonication method can be flexibly selected according to the raw material characteristics. The 30 °C temperature and specific time (40 minutes, 30 minutes, 15 minutes) parameters are optimized, the process is simple and easy to control, with high repeatability, and is suitable for industrial production.

[0038] Optionally, the D90 of the particle size of the pioglitazone hydrochloride solid dispersion is controlled to be 1 - 80 μm, preferably 5 - 60 μm; and / or, in the preparation method of the pioglitazone hydrochloride solid dispersion, the powder obtained after drying is passed through a 40 - 80 mesh sieve, preferably an 80 mesh sieve.

[0039] In the present invention application, the pioglitazone hydrochloride solid dispersion is obtained after the dried powder is sieved through a 40 - 80 mesh sieve (preferably 80 mesh). The 80 mesh sieve is preferred, which refines the particle distribution, ensures that the D90 particle size is controlled within the target range (1 - 80 μm, preferably 5 - 60 μm), reduces the particle size difference, and the screening process removes oversized particles (lumps) or undersized particles (fine powder) through physical screening, improving the uniformity and fluidity of the powder, providing a stable raw material basis for subsequent wet granulation and tableting processes, and reducing the dissolution variability caused by uneven particles during storage or processing.

[0040] In the application of the present invention, the particle size D90 of the pioglitazone hydrochloride solid dispersion is controlled within the range of 1 - 80 μm, preferably 5 - 60 μm. After achieving particle refinement and uniform distribution through mixing means (such as stirring, grinding, ultrasonic waves) and sieving, the smaller particle size increases the contact area between the drug and the hydrophilic carriers (lecithin, cyclodextrin, hydrophilic chitosan), enhances the inclusion effect and wetting effect of the carriers, and significantly improves the dissolution rate and dissolution degree of pioglitazone hydrochloride in aqueous media. As the preferred range, 5 - 60 μm balances the particle fineness and the operability of the preparation, avoiding dust flying or decreased flowability caused by too small particle size (<5 μm), and the limitation of dissolution rate caused by too large particle size (>60 μm).

[0041] Optionally, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a lubricant, and a glidant.

[0042] In some embodiments, the filler includes one or more of lactose, powdered sugar, dextrin, crystalline cellulose, and silicon dioxide. Fillers (such as lactose and microcrystalline cellulose) improve the fluidity of the powder by increasing the tablet volume and mass, facilitating the wet granulation and tableting processes. Fillers can also dilute the pioglitazone hydrochloride solid dispersion, reduce the local drug concentration deviation, and enhance the uniformity of the particles. Lactose and crystalline cellulose also have good compressibility and water solubility, contributing to tablet formation and dissolution. In some embodiments, the disintegrant includes one or more of (dry) corn starch, potato starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, effervescent disintegrant, hydroxypropyl starch, and hydroxypropyl starch spherules. The disintegrant has the functions of water absorption and swelling or capillary action. After absorbing water, it rapidly swells or promotes water penetration, causing the tablet to quickly break up, accelerating the release of pioglitazone hydrochloride, and improving the dissolution rate and bioavailability. Cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose swell in volume after absorbing water, quickly breaking up the tablet; (dry) corn starch and potato starch promote water penetration through capillary action; the effervescent disintegrant (such as the combination of sodium bicarbonate and an acid) generates gas when encountering water, accelerating the disintegration process. These mechanisms jointly promote the release of pioglitazone hydrochloride and improve the dissolution rate.

[0043] In some embodiments, the lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate. The preferred lubricant is magnesium stearate (such as magnesium stearate). The lubricant can reduce the friction between powder particles, improve the particle fluidity and the mold release property during the tableting process, prevent sticking to the punch, ensure the smooth surface and uniform hardness of the tablet, and at the same time do not affect the dissolution performance.

[0044] In some embodiments, the glidants include one or more of silica, magnesium stearate, calcium stearate, sodium stearyl fumarate, and microcrystalline cellulose. These glidants may be used at different stages of the pharmaceutical process, including but not limited to direct compression, wet granulation, and dry granulation processes. The glidants can adsorb on the surface of the particles, enhancing the powder flowability and ensuring uniform filling and tableting consistency of the particles in the tablet press after wet granulation.

[0045] In the application of the present invention, the fillers, disintegrants, lubricants, and glidants are all pharmaceutically acceptable carriers recognized by the pharmacopoeia, and the types and proportions can be flexibly adjusted according to the characteristics of the preparation to meet the production requirements of different batches of active pharmaceutical ingredients; the fillers, disintegrants, lubricants, and glidants can act together. The fillers and lubricants act together to reduce the friction between particles and the concentration deviation. The disintegrants ensure the uniform internal structure of the tablets, reduce the variability during the dissolution process, optimize the particle characteristics (compressibility, flowability, uniformity), improve the disintegration and dissolution performance of the tablets, and ensure that the dissolution curve of pioglitazone hydrochloride is consistent with that of the reference product.

[0046] Optionally, the wet granulation includes: The solid dispersion of pioglitazone hydrochloride and the pharmaceutically acceptable carrier are added to a wet granulator. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform; then increase the speed to 100 rpm for stirring and 1000 rpm for the cutter, and slowly add the binder to form a soft paste with a moderate viscosity and a moisture content of 2% - 5%. Extrude the soft paste through a 18-mesh sieve to form wet granules. Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60 - 65 °C, and dry until the moisture content of the granules ≤ 5%; after drying, screen the granules through a 20-mesh sieve to remove fine powder and lumps. Mix the dried granules with the lubricant evenly, use a high-speed rotary tablet press, adjust the tablet weight to the target specification, and control the hardness within the range of 2.5 - 3.1 kg.

[0047] In the present invention application, initial mixing (stirring speed 80 rpm, cutter speed 800 rpm, for 5 minutes): Pioglitazone Hydrochloride solid dispersion is mixed with pharmaceutically acceptable carriers (such as fillers, disintegrants, lubricants, etc.) at low speed in a wet granulator. Stirring at 80 rpm provides gentle shear force, and the cutter at 800 rpm breaks up agglomerates. The 5-minute time ensures preliminary uniformity and reduces local concentration deviation; High-speed granulation (stirring 100 rpm, cutter 1000 rpm, adding binder): Increase the speed to 100 rpm and 1000 rpm to enhance shear force and particle collision. Slowly add the binder (such as 2%-10% aqueous solution of polyvinylpyrrolidone K30). Through the viscous action of the binder, the powder is aggregated into a soft material with moderate viscosity and a moisture content of 2%-5%. Controlling the moisture content at 2%-5% avoids over-wetting (affecting drying) or over-drying (loose particles).

[0048] In the present invention application, the soft material is extruded through an 18-mesh sieve into wet granules. The screening process divides the soft material into uniform granules, controls the particle size distribution, reduces the particle size difference, and provides a consistent basis for subsequent drying and sizing; The wet granules are dried in a hot air circulation oven at 60-65 °C. The moderate temperature avoids thermal degradation of Pioglitazone Hydrochloride. Controlling the moisture content ≤5% ensures the stability of the granules, reduces subsequent dissolution variability. After drying, the granules are screened through a 20-mesh sieve to remove fine powder (which may affect fluidity) and caking (which may cause uneven dissolution), optimizing the granule uniformity and fluidity.

[0049] In the present invention application, the dried granules are mixed with a lubricant (such as magnesium stearate). The lubricant reduces friction and improves the fluidity of the granules. Using a high-speed rotary tablet press, adjust the tablet weight to the target specification, and control the hardness at 2.5-3.1 kg to balance the mechanical strength (to avoid breakage) and disintegration performance (to ensure dissolution) of the tablets. The wet granulation process ensures a stable dissolution rate of Pioglitazone Hydrochloride tablets through uniform mixing, particle control, and tablet pressing optimization. The dissolution curve is consistent with the reference product. The process parameters (speed, moisture, temperature, sieve mesh number) can be optimized in real time to adapt to different batches of raw materials, with high repeatability and suitability for industrial production.

[0050] Optionally, pharmaceutically acceptable carriers include: lactose, starch, hydroxypropyl methylcellulose, and magnesium stearate. The weight ratio of each component of the Pioglitazone Hydrochloride tablets is as follows: Pioglitazone Hydrochloride solid dispersion: lactose: starch: hydroxypropyl methylcellulose: magnesium stearate is 1:0.5-6.5:0.6-3.0:0.5-2:0.2-0.5, and the binder accounts for 15-30% of the total weight of the Pioglitazone Hydrochloride tablets.

[0051] In some embodiments, lactose can be used as a filler, starch can be used as a disintegrant, and hydroxypropyl methylcellulose can be used as a binder and / or disintegrant.

[0052] In some embodiments, lactose can be used as a filler (in an amount of 0.5 - 6.5 parts by weight) to increase the tablet volume, improve the powder flowability, dilute the pioglitazone hydrochloride solid dispersion, and reduce the local concentration deviation. Its good compressibility and water solubility contribute to tablet formation and dissolution.

[0053] In some embodiments, starch can be used as a disintegrant (in an amount of 0.6 - 3.0 parts by weight). Starch can be (dry) corn starch, which promotes water penetration through capillary action, enhances the disintegration performance of the tablet during wet granulation and dissolution processes, and accelerates the release of pioglitazone hydrochloride.

[0054] In some embodiments, hydroxypropyl methylcellulose (HPMC) can be used as a binder and / or disintegrant. Hydroxypropyl methylcellulose HPMC (in an amount of 0.5 - 2 parts by weight) can have both binder and disintegrant functions. In wet granulation, the viscosity of HPMC promotes the formation of soft material (with a moisture content of 2% - 5%), enhances the particle binding force; after absorbing water, it swells and accelerates the disintegration of the tablet, optimizing the dissolution rate.

[0055] In some embodiments, magnesium stearate can be used as a lubricant (in an amount of 0.2 - 0.5 parts by weight) to reduce the friction between particles and between particles and the mold, improve the powder flowability and tableting performance, prevent sticking to the punch, ensure the stability of the tablet hardness (2.5 - 3.1 kg), and at the same time, a low dosage does not affect dissolution.

[0056] In some embodiments, the binder (such as a 2% - 10% aqueous solution of polyvinylpyrrolidone K30) accounts for 15 - 30% of the total weight. By controlling the viscosity of the soft material and the particle binding force, it ensures the uniformity of the particles (RSD < 2%) during the wet granulation process, and synergistically optimizes the disintegration and dissolution performance of the tablet with the carrier.

[0057] In the present invention application, first, lactose (0.5 - 6.5 parts) and starch (0.6 - 3.0 parts) increase the volume and improve the flowability. After wet granulation, the particles are uniform (RSD < 2%) and have good compressibility; and / or, hydroxypropyl methylcellulose HPMC can also accelerate the disintegration of the tablet through water absorption expansion and capillary action with starch, improve the dissolution rate of pioglitazone hydrochloride, make the dissolution curve close to the original research, and enhance the bioavailability; in addition, all carriers are safe excipients recognized by the pharmacopoeia, and the proportion ranges of each component (lactose 0.5 - 6.5 parts, starch 0.6 - 3.0 parts, HPMC 0.5 - 2 parts, magnesium stearate 0.2 - 0.5 parts) match the proportion of the pioglitazone hydrochloride solid dispersion component (1 part), balancing the filling, disintegration, lubrication, and binding effects, and ensuring the stability of the dissolution rate of the pioglitazone hydrochloride tablet and the consistency of the dissolution curve with the original research.

[0058] Optionally, before wet granulation, the pharmaceutically acceptable carrier is sieved to ensure the powder uniformity, including: Lactose, starch, and hypromellose were pretreated by passing through a 80-mesh sieve; Magnesium stearate was pretreated by passing through a 60-mesh sieve.

[0059] In the present invention application, before wet granulation, sieving was used to remove fine powder and lumps in lactose, starch, and HPMC through physical screening to ensure a consistent particle size distribution. The refinement of these three excipients by an 80-mesh sieve improved the powder uniformity and provided a stable raw material basis for subsequent wet granulation; magnesium stearate passed through a 60-mesh sieve. Considering its lubricant properties, the larger pore size removed coarser particles and retained an appropriate particle size to optimize its dispersion during mixing and tableting.

[0060] In the present invention application, the sieved powder had a consistent particle size, reducing adhesion and agglomeration between particles, improving the fluidity of lactose, starch, and HPMC, and the dispersion of magnesium stearate. When the uniform powder was mixed in a wet granulator (stirring at 80 - 100 rpm, chopper at 800 - 1000 rpm), local concentration deviation was reduced, ensuring the uniform distribution of pioglitazone hydrochloride solid dispersion and the carrier. The primary mixing (80 rpm / 800 rpm) and granulation (100 rpm / 1000 rpm) were more efficient.

[0061] In the present invention application, the particle size of the carrier after sieving matched the formation of soft material (moisture 2% - 5%) in wet granulation and the extrusion process through an 18-mesh sieve, reducing uneven granulation caused by oversize or undersize particles. The moderate particle size of magnesium stearate enhanced the lubrication effect during subsequent mixing with dry granules, reduced the friction during tableting, and ensured a stable hardness (2.5 - 3.1 kg).

[0062] In the present invention application, after the uniform carrier powder was mixed with pioglitazone hydrochloride solid dispersion, the particle characteristics during wet granulation and tableting were consistent, reducing variability during the dissolution process, making the dissolution curve of pioglitazone hydrochloride close to the reference product, and improving bioavailability.

[0063] Examples, test examples and comparative examples It should be noted that the raw materials used in the present invention application are all ordinary commercially available products, and no specific limitation is imposed on their sources.

[0064] Example 1 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 20 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 9.66 μm.

[0065] Example 2 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 20 g of water. Place it in a water bath at 30 °C. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material to the above aqueous solution, set the stirring speed to 200 rpm, and stir for 40 min to precipitate a white solid. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 32.15 μm.

[0066] Example 3 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 20 g of water. Pour the solution into a mortar. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material to the mortar. Grind it at 30 °C for 30 min to obtain a white powder, and place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 13.73 μm.

[0067] Example 4 Weigh 10 g of lecithin and dissolve it in 20 g of water. According to the ratio of lecithin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 31.14 μm.

[0068] Example 5 Weigh 10 g of hydrophilic chitosan and dissolve it in 20 g of water. According to the ratio of hydrophilic chitosan to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 28.97 μm.

[0069] Example 6 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 20 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:0.5, add 5 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 11.65 μm.

[0070] Example 7 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 30 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 13.73 μm.

[0071] Example 8 Weigh 10 g of hydroxypropyl-β-cyclodextrin and dissolve it in 20 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 40 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion, D90 = 13.28 μm.

[0072] Test Example: Solubility Experiment First, prepare a buffer solution with a pH of 1 - 7. Add an appropriate amount of pioglitazone hydrochloride raw material and the pioglitazone hydrochloride solid dispersions prepared in Examples 1 - 5 to the buffer solution with the corresponding pH, place them in a constant-temperature shaking water bath, shake at 35°C, and take samples for detection after 6 hours. The results are shown in the following table: It can be seen that after the formation of pioglitazone solid dispersions by adding hydrophilic carriers, the solubility of pioglitazone hydrochloride in the aqueous solutions of the tested pH values has been greatly improved. Among them, hydroxypropyl-β-cyclodextrin has the greatest promoting effect on the solubility of pioglitazone hydrochloride under the same conditions. Under the condition of the optimal hydrophilic carrier, the solid dispersion prepared by the ultrasonic method has the highest solubility finally because of the good dispersion effect of pioglitazone hydrochloride and its better mixing with the hydrophilic carrier.

[0073] (1)Solubility results The solubility of pioglitazone hydrochloride raw material is relatively low (0.0000986 - 6.12 mg / mL) within the pH range of 1 - 7. As the pH increases, the solubility of the raw material gradually decreases. The solubilities of the solid dispersions of Example 1 (hydroxypropyl-β-cyclodextrin, ultrasonic method, D90 = 9.66μm), Example 2 (hydroxypropyl-β-cyclodextrin, stirring method, D90 = 32.15μm), Example 3 (hydroxypropyl-β-cyclodextrin, mechanical grinding method, D90 = 13.73μm), Example 4 (lecithin, ultrasonic method, D90 = 31.14μm), and Example 5 (hydrophilic chitosan, ultrasonic method, D90 = 28.97μm) are significantly higher than those of the control examples. Among them, the solubility of Example 1 (ultrasonic method, D90 = 9.66μm) is the highest, reaching 13.88 mg / mL at pH 1 and 8.82 mg / mL at pH 7.

[0074] The solubilities of Examples 1 - 5 at pH 6 - 7 (small intestine environment) are significantly higher than those of the control examples, which is beneficial to small intestine absorption and is expected to improve the bioavailability and the consistency of the dissolution curve.

[0075] (2)Solubility analysis 1) Pioglitazone hydrochloride is a weakly basic drug (pKa is about 5.5 - 6.0). It exists in a partially ionized form in an acidic environment (pH 1 - 3) and has a relatively high solubility. As the pH increases (pH 4 - 7), the drug gradually turns into a non-ionized form, with enhanced hydrophobicity and a significant decrease in solubility. In addition, the crystal structure and high crystallinity of the raw material limit the dissolution rate.

[0076] 2) Influence of hydrophilic carriers Examples 1-5 used hydrophilic carriers (hydroxypropyl-β-cyclodextrin, lecithin, hydrophilic chitosan) to prepare solid dispersions with pioglitazone hydrochloride. The carriers dispersed pioglitazone hydrochloride into a molecular or microscopic state through inclusion (inclusion in the cyclodextrin cavity), wetting (micelle action of lecithin), or adsorption (dispersion of chitosan), reducing the crystal energy barrier and significantly increasing solubility, indicating that the wetting and / or inclusion effects of hydrophilic carriers effectively improved solubility within the physiological pH range.

[0077] 3) Influence of mixing means Examples 1 and 4-5 used the ultrasonic method (30°C, 100 Hz, 15 minutes). The acoustic cavitation effect efficiently crushed the crystals, resulting in fine particles (D90 = 9.66 μm, 31.14 μm, 28.97 μm) and relatively high solubility (13.88, 8.03, 8.77 mg / mL at pH 1, respectively).

[0078] Example 2 used the stirring method (30°C, 200 rpm, 40 minutes). The shear force was relatively mild, the particles were larger (D90 = 32.15 μm), and the solubility was the lowest (7.02 mg / mL at pH 1). Example 3 used the mechanical grinding method (30°C, 30 minutes). The particle size was moderate (D90 = 13.73 μm), and the solubility was in the middle (10.24 mg / mL at pH 1).

[0079] Due to the acoustic cavitation effect, the ultrasonic method produced finer particles, a larger contact area, and the most significant increase in solubility; the stirring method produced larger particles, weaker dispersion effect, and limited increase in solubility.

[0080] 4) Influence of carrier type Examples 1-3 used hydroxypropyl-β-cyclodextrin, which had a strong cavity inclusion effect and a significant increase in solubility, especially under the ultrasonic method (Example 1).

[0081] Example 4 used lecithin. The micelle action enhanced the wettability, but the inclusion ability was weaker than that of cyclodextrin, and the solubility was slightly lower.

[0082] Example 5 used hydrophilic chitosan, which had good adsorption and dispersion effects. The solubility was lower than or close to that of cyclodextrin, but slightly inferior to Example 1 under the ultrasonic method.

[0083] The inclusion effect of cyclodextrin was stronger than that of lecithin and hydrophilic chitosan; 5) Influence of D90 Example 1 had the smallest D90 (9.66 μm) and the highest solubility, indicating that fine particles increased the contact area with the buffer solution; Example 2 had the largest D90 (32.15 μm) and the lowest solubility, and the larger particles limited the dissolution rate.

[0084] Thus, based on the above solubility results and solubility analysis, solid dispersions were prepared using hydrophilic carriers in Examples 1-5, significantly improving the solubility of pioglitazone hydrochloride in pH 1-7 buffer solutions. The improvement effect was remarkable compared to the comparative examples, and Example 1 showed the best performance. The experimental results indicate that the solid dispersion technology effectively solves the problem of poor solubility of the active pharmaceutical ingredient, providing a reliable basis for optimizing the dissolution curve and bioavailability of tablets.

[0085] Example 9 The pioglitazone hydrochloride solid dispersion prepared in Example 1 and magnesium stearate were passed through 80-mesh and 60-mesh sieves respectively. Other excipients such as lactose filler, corn starch disintegrant, and hypromellose were passed through 80-mesh sieves to remove lumps and ensure powder uniformity. Polyvinylpyrrolidone K30 (polyvinylpyrrolidone) was added to purified water and stirred until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hypromethylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Then increase the speed to stirring at 100 rpm and cutter at 1000 rpm, and slowly add 15% of the polyvinylpyrrolidone K30 aqueous solution based on the total prescription amount to form a soft material with moderate viscosity. Extrude the soft material through a 18-mesh sieve to form wet granules. Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60-65 °C, and dry until the moisture content of the granules is ≤5%. After drying, the granules are sized through a 20-mesh sieve to remove fine powder and lumps. Mix the dried granules evenly with 3 g of magnesium stearate (lubricant), and use a high-speed rotary tablet press. Set the main pressure of the tablet press at 8.0 kN and control the hardness at about 2.5 kg.

[0086] Example 10 The pioglitazone hydrochloride solid dispersion prepared in Example 1 and magnesium stearate were respectively passed through a 80-mesh sieve and a 60-mesh sieve. Other excipients such as lactose filler, corn starch disintegrant, and hydroxypropyl methylcellulose were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Polyvinylpyrrolidone K30 (polyvinylpyrrolidone) was added to purified water and stirred until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hydroxypropyl methylcellulose according to the prescription and add them to a wet granulator. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and cutter at 1000 rpm, and slowly add 20% of the total amount of the polyvinylpyrrolidone K30 aqueous solution in the prescription to form a soft material with moderate viscosity. Extrude the soft material through an 18-mesh sieve to form wet granules. The wet granules were placed in a hot air circulation oven, and the inlet air temperature was controlled at 60 - 65 °C and dried until the moisture content of the granules was ≤ 5%. After drying, the granules were sized through a 20-mesh sieve to remove fines and lumps. The dried granules were mixed evenly with 3 g of magnesium stearate (lubricant), and a high-speed rotary tablet press was used. The main pressure of the tablet press was set at 8.0 kN, and the hardness was controlled at about 2.5 kg.

[0087] Example 11 The pioglitazone hydrochloride solid dispersion prepared in Example 1 and magnesium stearate were respectively passed through a 80-mesh sieve and a 60-mesh sieve. Other excipients such as lactose filler, corn starch disintegrant, and hydroxypropyl methylcellulose were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Polyvinylpyrrolidone K30 (polyvinylpyrrolidone) was added to purified water and stirred until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hydroxypropyl methylcellulose according to the prescription and add them to a wet granulator. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and cutter at 1000 rpm, and slowly add 25% of the total amount of the polyvinylpyrrolidone K30 aqueous solution in the prescription to form a soft material with moderate viscosity. Extrude the soft material through an 18-mesh sieve to form wet granules. The wet granules were placed in a hot air circulation oven, and the inlet air temperature was controlled at 60 - 65 °C and dried until the moisture content of the granules was ≤ 5%. After drying, the granules were sized through a 20-mesh sieve to remove fines and lumps. The dried granules were mixed evenly with 3 g of magnesium stearate (lubricant), and a high-speed rotary tablet press was used. The main pressure of the tablet press was set at 8.0 kN, and the hardness was controlled at about 2.5 kg.

[0088] Example 12 The pioglitazone hydrochloride solid dispersion prepared in Example 1 and magnesium stearate were respectively passed through a 80-mesh sieve and a 60-mesh sieve. Other excipients such as lactose filler, corn starch disintegrant, and hydroxypropyl methylcellulose were passed through an 80-mesh sieve to remove lumps and ensure the uniformity of the powder. Polyvinylpyrrolidone K30 (polyvinylpyrrolidone) was added to purified water and stirred until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hydroxypropyl methylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and the cutter at 1000 rpm, and slowly add 30% of the total amount of the polyvinylpyrrolidone K30 aqueous solution in the prescription to form a soft material with moderate viscosity. The soft material was extruded through an 18-mesh sieve to form wet granules. The wet granules were placed in a hot air circulation oven, and the inlet air temperature was controlled at 60 - 65 °C and dried until the moisture content of the granules was ≤ 5%. After drying, the granules were sized through a 20-mesh sieve to remove fine powder and lumps. The dried granules were mixed evenly with 3 g of magnesium stearate (lubricant), and a high-speed rotary tablet press was used. The main pressure of the tablet press was set at 8.0 kN, and the hardness was controlled at about 2.5 kg.

[0089] Comparative Example 1 The pioglitazone hydrochloride raw material and magnesium stearate were respectively passed through a 80-mesh sieve and a 60-mesh sieve. Other excipients such as lactose filler, corn starch disintegrant, and hydroxypropyl methylcellulose were passed through an 80-mesh sieve to remove lumps and ensure the uniformity of the powder. Polyvinylpyrrolidone K30 (polyvinylpyrrolidone) was added to purified water and stirred until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride raw material, 80 g of lactose, 20 g of corn starch, and 30 g of hydroxypropyl methylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and the cutter at 1000 rpm, and slowly add 25% of the total amount of the polyvinylpyrrolidone K30 aqueous solution in the prescription to form a soft material with moderate viscosity. The soft material was extruded through an 18-mesh sieve to form wet granules. The wet granules were placed in a hot air circulation oven, and the inlet air temperature was controlled at 60 - 65 °C and dried until the moisture content of the granules was ≤ 5%. After drying, the granules were sized through a 20-mesh sieve to remove fine powder and lumps. The dried granules were mixed evenly with 3 g of magnesium stearate (lubricant), and a high-speed rotary tablet press was used. The main pressure of the tablet press was set at 8.0 kN, and the hardness was controlled at about 2.5 kg.

[0090] Comparative Example 2 Weigh 10 g of citric acid and dissolve it in 20 g of water. According to the ratio of citric acid to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride raw material. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz and ultrasonicate for 15 min. After filtering the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, pass it through an 80-mesh sieve to obtain the pioglitazone solid dispersion, D90 = 17.66 μm.

[0091] Pass the prepared pioglitazone hydrochloride solid dispersion and magnesium stearate through an 80-mesh sieve and a 60-mesh sieve respectively. Other excipients such as lactose filler, corn starch disintegrant, and hypromellose are passed through an 80-mesh sieve to remove lumps and ensure the uniformity of the powder. Add polyvinylpyrrolidone K30 (polyvinylpyrrolidone) to purified water and stir until completely dissolved to prepare a 5% polyvinylpyrrolidone K30 aqueous solution as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hypromethylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed to 80 rpm and the cutter speed to 800 rpm, and mix for 5 minutes until uniform. Then increase the speed to stirring 100 rpm and cutter 1000 rpm, and slowly add 25% of the polyvinylpyrrolidone K30 aqueous solution based on the total amount of the prescription to form a soft material with moderate viscosity. Extrude the soft material through an 18-mesh sieve to form wet granules. Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60 - 65 °C, and dry until the moisture content of the granules is ≤5%. After drying, screen the granules through a 20-mesh sieve to size them and remove fine powder and lumps. Mix the dried granules evenly with 3 g of magnesium stearate (lubricant), and use a high-speed rotary tablet press. Set the main pressure of the tablet press to 8.0 kN and control the hardness at about 2.5 kg.

[0092] Comparative Example 3 Pass the pioglitazone hydrochloride bulk drug and magnesium stearate through 80-mesh and 60-mesh sieves respectively. Screen other excipients such as lactose filler, corn starch disintegrant, and hypromellose through 80-mesh sieve to remove caking and ensure the uniformity of the powder. Add polyvinylpyrrolidone K30 (polyvinylpyrrolidone) to purified water and stir until completely dissolved to prepare a 5% aqueous solution of polyvinylpyrrolidone K30 as the binder for wet granulation. Weigh 15 g of pioglitazone hydrochloride bulk drug and dissolve it in a 450 g mixture of methanol and water with a methanol-to-water ratio of 4:1. Subsequently, weigh 15 g of hydroxypropyl-β-cyclodextrin and dissolve it in 30 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 465 g of the pioglitazone hydrochloride solution to make a mixture. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz, and ultrasonicate for 15 min. Remove the solvent by rotary evaporation, set the temperature to 70 °C, the vacuum pressure to 200 mbar, and the rotation speed to 130 rpm. Freeze-dry the wet solid further to obtain the pioglitazone hydrochloride solid dispersion.

[0093] Weigh the obtained solid powder, 80 g of lactose, 20 g of corn starch, and 30 g of hypromethylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed to 80 rpm and the cutter speed to 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and the cutter at 1000 rpm, and slowly add 25% of the total amount of the polyvinylpyrrolidone K30 aqueous solution in the prescription to form a soft material with moderate viscosity. Extrude the soft material through a 18-mesh sieve to form wet granules. Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60 - 65 °C, and dry until the moisture content of the granules is ≤5%. Screen the dried granules through a 20-mesh sieve to size them and remove fine powder and caking. Mix the dried granules evenly with 3 g of magnesium stearate (lubricant), and use a high-speed rotary tablet press. Set the main pressure of the tablet press to 8.0 kN and control the hardness at about 2.5 kg.

[0094] Comparative Example 4 Weigh 10 g of polyvinylpyrrolidone K30 and dissolve it in 20 g of water. According to the ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride of 1:1, add 10 g of pioglitazone hydrochloride bulk drug. Place the obtained mixed solution in an ultrasonic cleaner at 30 °C, set the frequency to 100 Hz, and ultrasonicate for 15 min. Filter the precipitated solid under reduced pressure, place it in a freeze dryer for drying, set the freeze-drying pressure to -50 °C, and the freeze-drying time to 10 hours. Take out the solid powder, and pass it through an 80-mesh sieve to obtain the pioglitazone solid dispersion.

[0095] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared by the above method were respectively passed through 80-mesh and 60-mesh sieves. Other excipients such as lactose filler, corn starch disintegrant, and hydroxypropyl methylcellulose were passed through 80-mesh sieves to remove caking and ensure powder uniformity. Weigh 15 g of pioglitazone hydrochloride solid dispersion, 80 g of lactose, 20 g of corn starch, and 30 g of hydroxypropyl methylcellulose according to the prescription and add them to a wet granulation mixer. Set the stirring speed at 80 rpm and the cutter speed at 800 rpm, and mix for 5 minutes until uniform. Subsequently, increase the speed to stirring at 100 rpm and cutter at 1000 rpm, and slowly add an aqueous solution of polyvinylpyrrolidone K30 accounting for 25% of the total prescription amount to form a soft material with moderate viscosity. Extrude the soft material through a 18-mesh sieve to form wet granules. Place the wet granules in a hot air circulation oven, control the inlet air temperature at 60 - 65 °C, and dry until the moisture content of the granules ≤ 5%. Screen the dried granules through a 20-mesh sieve to remove fine powder and caking. Mix the dried granules evenly with 3 g of magnesium stearate (lubricant), and use a high-speed rotary tablet press. Set the main pressure of the tablet press at 8.0 kN and control the hardness at about 2.5 kg.

[0096] Test examples: average hardness, average dissolution rate, disintegration time According to the dissolution determination method, use the degassed hydrochloric acid solution (0.1 mol / L) thermostated at (37 ± 0.5) °C as the dissolution medium, take 900 mL, set the rotation speed at 50 r / min, sample at 30 min, filter, and take the subsequent filtrate as the test solution; take an appropriate amount of pioglitazone hydrochloride reference substance, dilute it with the dissolution medium to a solution with a concentration of 7.6 µg / mL, measure the absorbance at a wavelength of 269 nm, and calculate the dissolution amount of each tablet. The average hardness test method is to place the tablet vertically between two pressing plates, apply pressure along the diameter direction until it breaks, record the pressure value at the time of breaking (expressed in Newton force or kilogram force), repeat the test 6 times, and take the average value as the final hardness value. The disintegration time uses the basket method to simulate the human gastrointestinal environment, equipped with a 37 °C constant temperature water bath and a sieve (pore size 2.0 mm). The dissolution rate, tablet hardness, and average disintegration time of the comparative example and Examples 9 - 12 are shown in the following table: It can be seen that the amount of binder has a great influence on the dissolution of tablets. Within a certain range, as the amount of binder increases, the dissolution of pioglitazone hydrochloride tablets gradually increases accordingly, and the amount of binder of 25% is basically the best. Under the optimal amount of binder, the dissolution of the comparative example obtained by directly mixing pioglitazone hydrochloride raw material with excipients for tableting significantly decreases. When other hydrophilic carriers such as other organic acids are added, the particle size of the obtained pioglitazone hydrochloride significantly increases, the solubility decreases, and the dissolution of the obtained tablets significantly decreases. Modulating the preparation method of the pioglitazone hydrochloride solid dispersion, such as adding organic solvents, not only increases the energy consumption for solvent removal, but also causes the aggregation of pioglitazone hydrochloride, and the dissolution is also greatly affected.

[0097] (1) Amount of binder and average hardness As the amount of povidone K30 increases from 15% to 30%, the average hardness slightly increases from 2.47 to 3.82, and then slightly decreases to 3.63 at 30%. In the range of 15% - 25%, the increase in the amount of binder can effectively fill the gaps between particles and significantly improve the mechanical strength; after exceeding 25%, the excessive binder may cause excessive bonding of particles, reduce the internal pores, and slightly reduce the final hardness.

[0098] (2) Amount of binder and average dissolution As the amount of povidone K30 increases from 15% to 30%, the dissolution shows an upward trend: 87.88% at 15% dosage, 88.25% at 20% dosage, reaching 99.39% at 25% dosage, and slightly rising to 99.47% at 30% dosage, indicating that the dissolution gradually increases, and the dissolution at 25% and 30% dosages is almost complete, ensuring a high dissolution rate.

[0099] (3) Amount of binder and disintegration time As the amount of povidone K30 increases from 15% to 30%, the disintegration time at 15% is 0.8 min, the disintegration time at 20% and 25% is both 1 min, and it extends to 2.0 min at 30%. When the amount of binder is moderate (20%), the particles disintegrate quickly and dissolve sufficiently; too high a dosage (30%) will form a denser mucosal network, delay the penetration of water, and significantly increase the disintegration time to 2.0 min.

[0100] Those skilled in the art can understand that the various operations, methods, steps, measures, and solutions in the present invention application that have been discussed can be alternated, changed, combined, or deleted; further, other steps, measures, and solutions in the various operations, methods, and processes that have been discussed in the present invention application can also be alternated, changed, rearranged, decomposed, combined, or deleted; further, those in the prior art that have steps, measures, and solutions in the various operations, methods, and processes disclosed in the present invention application can also be alternated, changed, rearranged, decomposed, combined, or deleted. The technical features of the above embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the various technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as within the scope described in this specification; The above-described embodiments merely represent several implementation manners of the embodiments of the present disclosure. The description is relatively specific and detailed, but it should not be construed as a limitation on the patent scope of the embodiments of the present disclosure; it should be noted that for those of ordinary skill in the art, without departing from the concept of the embodiments of the present disclosure, several modifications and improvements can be made, and these all belong to the protection scope of the embodiments of the present disclosure; therefore, the protection scope of the embodiments of the present disclosure should be subject to the appended claims. As described above, although the present invention application has been represented and described with reference to specific preferred embodiments, it should not be construed as a limitation on the present invention application itself. Various changes can be made to it in form and details without departing from the spirit and scope of the present invention application defined by the appended claims.

[0101] The above describes the present invention application and its implementation manners, and this description is not restrictive. Generally speaking, if those of ordinary skill in the art are inspired by it and, without departing from the purpose of the creation of the present invention application, design similar structural manners and embodiments to this technical solution without creative efforts, they should all belong to the protection scope of the present invention application.

Claims

1. A method for improving the dissolution rate of pioglitazone hydrochloride tablets, characterized in that, include: The pioglitazone hydrochloride solid dispersion, a binder, and a pharmaceutically acceptable carrier are prepared by wet granulation; The preparation method of the pioglitazone hydrochloride solid dispersion is as follows: under the condition of 20-40° C., the pioglitazone hydrochloride raw material is added into the aqueous solution of the hydrophilic carrier, and after being fully mixed by stirring, mechanical grinding or ultrasonic method, a precipitate is precipitated, filtered and dried to obtain the solid dispersion; The hydrophilic carrier is one or more of lecithin, cyclodextrin, and hydrophilic chitosan; the mass ratio of water to the hydrophilic carrier is 1-5:1, and the mass ratio of pioglitazone hydrochloride raw material to the hydrophilic carrier is 1:0.5-10; The adhesive includes a 2%-10% aqueous solution of povidone K30.

2. The method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, wherein In the preparation method of the pioglitazone hydrochloride solid dispersion, freeze drying is used for drying; the freezing temperature is -60 to -45°C, the freezing pressure is 0.15-0.25 mbar, and the freezing time is 12 hours.

3. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that, In the preparation method of the pioglitazone hydrochloride solid dispersion, the ultrasonic conditions are: ultrasonic temperature is 20-40° C.; frequency is 30-100 Hz; and ultrasonic time is 5-30 min.

4. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that, In the preparation method of the pioglitazone hydrochloride solid dispersion, The stirring comprises: stirring the mixture of the pioglitazone hydrochloride raw material and the hydrophilic carrier in a water bath at 30° C. for 40 minutes; Alternatively, mechanical grinding comprises: placing an aqueous solution of a hydrophilic carrier in a mortar, then adding the pioglitazone hydrochloride raw material, and grinding at 30° C. for 30 minutes; Alternatively, the ultrasonic method comprises: subjecting the mixture of the pioglitazone hydrochloride raw material and the hydrophilic carrier to ultrasonic treatment at 30° C. and 100 Hz for 15 minutes.

5. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that, The particle size D90 of the pioglitazone hydrochloride solid dispersion is controlled to be 1-80 μm; and / or, in the preparation method of the pioglitazone hydrochloride solid dispersion, the powder obtained after drying is passed through a 40-80 mesh sieve.

6. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that, The pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a lubricant, and a glidant.

7. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 6, characterized in that, The pharmaceutically acceptable carrier includes a filler, a disintegrant, and a lubricant; The filler includes one or more of lactose, powdered sugar, dextrin, crystalline cellulose, and silicon dioxide; The disintegrant includes one or more of corn starch, potato starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, effervescent disintegrant, hydroxypropyl starch, and hydroxypropyl starch granules; The lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate.

8. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that, The wet granulation comprises: The pioglitazone hydrochloride solid dispersion and the pharmaceutically acceptable carrier are added to a wet mixing granulator, and the stirring speed is set to 80 rpm and the cutting speed is set to 800 rpm, and the mixture is mixed for 5 minutes until uniform; then the speed is increased to 100 rpm for stirring and 1000 rpm for cutting, and the adhesive is slowly added to form a moderately viscous soft material with a moisture content of 2%-5%; The soft material is squeezed through an 18-mesh screen to form wet granules; The wet granules are placed in a hot air circulation oven, the air inlet temperature is controlled at 60-65°C, and dried until the moisture content of the granules is ≤5%; after drying, the granules are sieved through a 20-mesh screen to remove fine powder and lumps; Mix the dry granules and the lubricant evenly, use a high-speed rotary tablet press, adjust the tablet weight to the target specification, and control the hardness within the range of 2.5 - 3.1 kg.

9. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 8, characterized in that, Pharmaceutically acceptable carriers include: lactose, starch, hydroxypropyl methylcellulose, and magnesium stearate. The weight ratios of the components of the pioglitazone hydrochloride tablets are as follows: Pioglitazone hydrochloride solid dispersion: lactose: starch: hydroxypropyl methylcellulose: magnesium stearate is 1: 0.5 - 6.5: 0.6 - 3.0: 0.5 - 2: 0.2 - 0.5, and the binder accounts for 15 - 30% of the total weight of the pioglitazone hydrochloride tablets.

10. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 9, characterized in that, Before wet granulation, the pharmaceutically acceptable carriers are sieved to ensure powder uniformity, including: Lactose, starch, and hydroxypropyl methylcellulose are pretreated by sieving through a 80-mesh sieve; Magnesium stearate is pretreated by sieving through a 60-mesh sieve.

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