A method for improving the dissolution rate of pioglitazone hydrochloride tablets

Abstract

The present invention provides a method for improving the dissolution rate of pioglitazone hydrochloride tablets, belonging to the field of pharmaceutical technology. The method for improving the dissolution rate of pioglitazone hydrochloride tablets comprises: preparing a pioglitazone hydrochloride solid dispersion, a binder, and a pharmaceutically acceptable carrier by wet granulation. The present invention selects an amphiphilic carrier, which is dissolved in water to form a hydrophobic cavity to accommodate the hydrophobic pioglitazone hydrochloride. The pioglitazone hydrochloride raw material is highly dispersed by van der Waals forces under ultrasonic or mechanical forces, rather than the simple physical mixing used in the prior art. By controlling the amount of binder, the dissolution of pioglitazone hydrochloride is achieved in a manner consistent with the original research.

Description

Technical Field

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

[0002] Pioglitazone hydrochloride (PGH) belongs to the thiazolidinedione (TZD) class of oral antidiabetic drugs. It is a highly selective peroxisome proliferative activated receptor γ (PPARγ) agonist. It controls blood sugar levels by increasing peripheral and hepatic insulin sensitivity, reducing glucose output in the liver, decreasing hepatic gluconeogenesis, and increasing insulin receptor sensitivity. It is clinically suitable for patients with type 2 diabetes mellitus (T2DM).

[0003] Pioglitazone hydrochloride is a white crystal or crystalline powder that is easily soluble in organic solvents such as methanol and N,N-dimethylformamide, but is virtually insoluble in water and phosphate buffer (pH 6.8). The powder is fine and loose in texture, with poor drying and viscosity. Its absorption and bioavailability are relatively low, and it belongs to the BCS Class II drug class, characterized by low solubility and high permeability. Therefore, improving the dissolution rate of pioglitazone tablets is key to the formulation process.

[0004] Due to the extremely poor water solubility of pioglitazone hydrochloride, the prior art requires dissolving it in an organic solvent such as methanol, then mixing it with an aqueous solution of a water-soluble carrier such as povidone, a surfactant, cross-linked povidone, cellulose, or an organic acid to obtain a mixed solution. The solvent is then removed and dried to obtain a pioglitazone hydrochloride solid dispersion. This introduces unnecessary organic solvents, which affects the quality of subsequent preparations and requires an additional impurity removal step. Furthermore, the API and the carrier are physically blended, which limits uniformity. The API particle size is large (40-70 μm), placing high demands on the micronization process.

[0005] Invention patent application CN101269040A discloses a pioglitazone hydrochloride sustained-release dripping pill and its preparation method. Hydrophilic skeleton materials and hydrophobic skeleton materials are used as a matrix, which is mixed with the pioglitazone hydrochloride raw material to form a solid dispersant. The drug is dispersed in the matrix in a molecular, colloidal or microcrystalline state, increasing the total surface area of ​​the drug, achieving high bioavailability and a long-lasting effect.

[0006] Invention patent CN113116837 B discloses a pioglitazone hydrochloride sustained-release tablet and a preparation method thereof. The pioglitazone hydrochloride raw material 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 solutions are uniformly mixed, the solvent is removed, the particles are granulated, and the particles are dried to obtain a pioglitazone hydrochloride solid dispersion. The solid dispersion is then mixed with a prescribed amount of water-soluble skeleton material and excipients to prepare a pioglitazone hydrochloride sustained-release tablet, thereby improving the solubility and bioavailability of pioglitazone hydrochloride.

[0007] It can be seen that by mixing the pioglitazone hydrochloride raw material with the carrier, on the one hand, the carrier is used to prevent the pioglitazone hydrochloride sample from changing from a disordered amorphous state to an ordered crystalline state during the pulverization process, thereby reducing the solubility of pioglitazone hydrochloride. On the other hand, the formed pioglitazone hydrochloride solid dispersion is easier to mix with hydrophilic skeleton materials and excipients, thereby improving the uniformity of the sample and improving the bioavailability of the pioglitazone hydrochloride tablets. Summary of the Invention

[0008] The present invention provides a method for improving the dissolution rate of pioglitazone hydrochloride tablets, which aims to partially or completely solve the technical problems such as poor solubility of the raw material drug during the preparation process of pioglitazone hydrochloride tablets, which makes it difficult for the dissolution curve of the obtained tablets to be consistent with the original research, and low bioavailability. Based on the existing technology, the present invention has found that the type of hydrophilic carrier and its ratio with the pioglitazone hydrochloride raw material drug and the mixing method are key factors affecting the dissolution curve of the obtained pioglitazone hydrochloride tablets. By further changing the amount of binder added, sample particles, wet granulation stirring speed, tableting process, etc., the prepared particles are uniform, have good compressibility, and the dissolution curve is consistent with the original research. In order to achieve the purpose of the present invention, the technical solution of the present invention is as follows:

[0009] A method for improving the dissolution rate of pioglitazone hydrochloride tablets, comprising:

[0010] The pioglitazone hydrochloride solid dispersion, a binder, and a pharmaceutically acceptable carrier are prepared by wet granulation;

[0011] The preparation method of the pioglitazone hydrochloride solid dispersion is as follows: adding the pioglitazone hydrochloride raw material to an aqueous solution of a hydrophilic carrier at 20-40° C., fully mixing by stirring, mechanical grinding or ultrasonic method, precipitating, filtering and drying to obtain the solid dispersion;

[0012] 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;

[0013] The adhesive includes a 2%-10% aqueous solution of povidone K30.

[0014] Optionally, in the preparation method of the pioglitazone hydrochloride solid dispersion, the drying is performed by freeze 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.

[0015] Optionally, 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.

[0016] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion,

[0017] The stirring comprises: stirring a mixture of the pioglitazone hydrochloride drug substance and the hydrophilic carrier in a water bath at 30° C. for 40 minutes;

[0018] Alternatively, mechanical grinding comprises: placing an aqueous solution of a hydrophilic carrier in a mortar, then adding the pioglitazone hydrochloride drug substance, and grinding at 30° C. for 30 minutes;

[0019] Alternatively, the ultrasonic method comprises: ultrasonicating a mixture of the pioglitazone hydrochloride raw material and the hydrophilic carrier at 30° C. and 100 Hz for 15 minutes.

[0020] Optionally, the particle size D90 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.

[0021] Optionally, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a lubricant, and a glidant.

[0022] Optionally, the pharmaceutically acceptable carrier includes a filler, a disintegrant, and a lubricant;

[0023] The filler includes one or more of lactose, powdered sugar, dextrin, crystalline cellulose, and silicon dioxide;

[0024] 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 pellets;

[0025] The lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate.

[0026] Optionally, the wet granulation comprises:

[0027] The pioglitazone hydrochloride solid dispersion and a pharmaceutically acceptable carrier were added to a wet mixing granulator. The stirring speed was set to 80 rpm and the cutting speed was set to 800 rpm. The mixture was mixed for 5 minutes until uniform. The stirring speed was then increased to 100 rpm and the cutting speed to 1000 rpm. The binder was slowly added to form a soft material with moderate viscosity and a moisture content of 2%-5%.

[0028] The soft material was squeezed through an 18-mesh screen to form wet granules;

[0029] The wet granules are placed in a hot air circulation oven with the air inlet temperature 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.

[0030] The dry granules were mixed evenly with the lubricant and a high-speed rotary tablet press was used to adjust the tablet weight to the target specification and control the hardness within the range of 2.5-3.1 kg.

[0031] Optionally, the pharmaceutically acceptable carrier includes: lactose, starch, hydroxypropyl methylcellulose and magnesium stearate, and the weight ratio of the components of the pioglitazone hydrochloride tablets is:

[0032] The ratio of 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 tablet, preferably 25%.

[0033] Optionally, before wet granulation, the pharmaceutically acceptable carrier is sifted to ensure powder uniformity, including:

[0034] Lactose, starch, and hypromellose were pretreated to pass through an 80-mesh sieve;

[0035] Magnesium stearate was pre-treated to pass through a 60-mesh sieve.

[0036] Compared with the prior art, the present invention has the following advantages:

[0037] (1) In the present application, the hydrophilic carriers selected are all amphiphilic carriers, which have both hydrophilic and hydrophobic groups. When dissolved in water, they can form hydrophobic cavities, thereby accommodating the hydrophobic pioglitazone hydrochloride. Therefore, even though pioglitazone hydrochloride has extremely poor solubility in water, under the action of the carriers in the present application, the pioglitazone hydrochloride API can still be highly dispersed by van der Waals forces under ultrasonic or mechanical forces, rather than the simple physical mixing in the prior art. Under the action of the hydrophilic carrier, the solubility of pioglitazone hydrochloride is greatly improved. By controlling the amount of binder, the dissolution of pioglitazone hydrochloride is consistent with that of the original research.

[0038] (2) In the present application, the addition of a hydrophilic carrier, in combination with preparation methods such as rapid stirring, high-frequency grinding and ultrasonic dispersion, synergistically improves the uniformity of the pioglitazone hydrochloride raw material, thereby further improving its solubility; the orthogonal test method of controlled variables is used to optimize the preparation process of pioglitazone hydrochloride tablets, including the prescription composition, the amount of binder added, stirring speed, shear speed, the main pressure of the tablet press, etc. The preparation process is evaluated by the dissolution data of the obtained products. The results show that the amount of binder added has an important influence on the dissolution of pioglitazone tablets. DETAILED DESCRIPTION

[0039] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. The numerical range can at least be understood to include the endpoint values, and can also be reasonably understood based on actual conditions. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0040] A method for improving the dissolution rate of pioglitazone hydrochloride tablets

[0041] A method for improving the dissolution rate of pioglitazone hydrochloride tablets, comprising:

[0042] The pioglitazone hydrochloride solid dispersion, a binder, and a pharmaceutically acceptable carrier are prepared by wet granulation;

[0043] The preparation method of the pioglitazone hydrochloride solid dispersion is as follows: adding the pioglitazone hydrochloride raw material to an aqueous solution of a hydrophilic carrier at 20-40° C., fully mixing by stirring, mechanical grinding or ultrasonic method, precipitating, filtering and drying to obtain the solid dispersion;

[0044] 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;

[0045] The adhesive includes a 2%-10% aqueous solution of povidone K30.

[0046] In the present application, the temperature range (20-40°C) is as follows: the temperature range avoids the destruction of the chemical stability of pioglitazone hydrochloride by high temperature, while ensuring the solubility and activity of the hydrophilic carrier in the aqueous solution, thereby facilitating the formation of a uniform dispersion system; the hydrophilic carrier: lecithin, cyclodextrin and hydrophilic chitosan have excellent water solubility and inclusion capacity, and the pioglitazone hydrochloride is included or dispersed in the carrier through intermolecular interactions (such as hydrogen bonds and hydrophobic interactions), forming a molecular-level or microscopic dispersion state. This dispersed state significantly increases the contact area between the drug and the dissolution medium, reduces the crystal energy barrier of the API, and improves dissolution kinetics. The water-to-carrier mass ratio (1-5:1) ensures the dispersion of the hydrophilic carrier, avoiding both low inclusion efficiency due to overly dilute solutions and difficulty in dissolution or uneven precipitation due to overly concentrated solutions. The pioglitazone hydrochloride-to-carrier mass ratio (1:0.5-10) optimizes dissolution performance by enabling the carrier to fully encapsulate the API while preventing excess carrier from increasing the volume or cost of the preparation.

[0047] In the present application, the mixing method (one of stirring, mechanical grinding, and ultrasonic method) is to break the crystal structure of the API through physical energy input (such as the shear force of stirring, the mechanical crushing of grinding, and the acoustic cavitation effect of ultrasound), reduce the size and crystallinity of the crystal particles, and obtain a solid dispersion by filtering and drying after precipitation. This process further improves the dissolution rate and dissolution kinetics of the API.

[0048] In the present application, the type of hydrophilic carrier and its ratio to the API (1:0.5-10) improve solubility through the inclusion effect: lecithin encapsulates pioglitazone hydrochloride through its amphiphilic structure (hydrophilic head and hydrophobic tail) to form a micelle-like structure, thereby enhancing the solubility of the drug in aqueous media; cyclodextrin utilizes its hydrophobic cavity to encapsulate 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, thereby improving dissolution efficiency; a mass ratio of 1:0.5-10 ensures a balance between inclusion efficiency and formulation cost; a too low ratio may lead to incomplete inclusion, while a too high ratio may increase the burden of excipients.

[0049] In this application, povidone K30 exhibits excellent water solubility and viscosity. A concentration range of 2%-10% ensures a moderate moisture content in the soft material, preventing both hard particles or impeded dissolution caused by overwetting and loose particles caused by overdrying. Its viscosity promotes the bonding of the solid dispersion with the carrier, forming a soft material with moderate viscosity, facilitating subsequent extrusion into wet granules.

[0050] Therefore, in a method for improving the dissolution rate of pioglitazone hydrochloride tablets applied in the present invention, the pioglitazone hydrochloride raw material is added to an aqueous solution of a hydrophilic carrier, and the mixture is fully mixed by stirring, mechanical grinding or ultrasonic method, and the precipitation is precipitated, filtered, and dried to prepare a pioglitazone hydrochloride solid dispersion. The method adopts stirring, mechanical grinding or ultrasonic method under mild conditions of 20-40°C, and the ratio of water to carrier is 1-5:1. The process is simple and controllable and suitable for industrial production. The inclusion capacity of lecithin, cyclodextrin and hydrophilic chitosan is strong. The mass ratio of 1:0.5-10 balances the dissolution performance and cost, optimizes drug release, and the 2%-10% povidone K30 aqueous solution ensures moderate viscosity of the soft material, improves the solubility of the raw material, and the dissolution curve is consistent with the original research. The bioavailability is significantly improved, the dissolution performance is stable, and the dissolution variability is reduced. The comprehensive optimization achieves a high degree of matching with the original research and meets the consistency evaluation requirements of generic drugs. The parameters (such as temperature, mass ratio, stirring speed) can be flexibly adjusted, the stability is high, and it is suitable for different batch production.

[0051] Optionally, in the preparation method of the pioglitazone hydrochloride solid dispersion, the drying is performed by freeze 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.

[0052] In this application, a mixed pioglitazone hydrochloride solid dispersion solution (containing a hydrophilic carrier) is frozen at -60 to -45°C, rapidly freezing the water in the solution into ice crystals while maintaining the molecular or microscopic dispersion of pioglitazone hydrochloride and the hydrophilic carrier (such as lecithin or cyclodextrin). This prevents the risk of drug degradation or carrier structural damage caused by excessive temperatures, preserves the chemical structure and biological activity of the API, and protects the functionality of the hydrophilic carrier (such as the inclusion capacity of cyclodextrin). Furthermore, under low pressure (0.15-0.25 mbar), the ice crystals can be directly converted from solid to gaseous state through sublimation, removing water. The low pressure ensures that the sublimation process occurs at low temperatures, preventing liquid water from damaging the dispersion structure. The 12-hour freezing time ensures sufficient sublimation of the water while avoiding the increased energy consumption caused by excessively long drying times or the impact of residual moisture on stability caused by excessively short drying times.

[0053] In the present application, freeze drying is carried out at low temperature and low pressure, avoiding 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 raw material drug. 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 effect 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 process, avoiding the particle agglomeration or recrystallization caused by water evaporation in traditional drying methods, thereby maintaining the high dispersibility and solubility of the solid dispersion, and the process has high stability and repeatability, which is suitable for industrial production.

[0054] Optionally, in the preparation method of the pioglitazone hydrochloride solid dispersion, the ultrasonic conditions are: ultrasonic temperature is 20-40°C, preferably 30°C; frequency is 30-100 Hz, preferably 100 Hz; and ultrasonic time is 5-30 min, preferably 15 min.

[0055] In this application, ultrasonic waves propagating in liquids produce an acoustic cavitation effect, whereby tiny bubbles form, grow, and collapse under the influence of the sound waves. High-frequency vibrations at a frequency of 30-100 Hz (preferably 100 Hz) enhance the energy required for bubble collapse. The resulting shock waves and microfluidics effectively break up the crystal structure and aggregates of the pioglitazone hydrochloride API, promoting its uniform dispersion with the hydrophilic carrier (lecithin, cyclodextrin, or hydrophilic chitosan). The ultrasonication temperature is controlled between 20-40°C (preferably 30°C). This mild condition avoids thermal degradation of pioglitazone hydrochloride at high temperatures while maintaining the stability of the hydrophilic carrier in aqueous solution. A temperature of 30°C is preferred, close to room temperature, to maximize the ultrasonic effect. A sonication duration of 5-30 minutes (preferably 15 minutes) ensures thorough mixing. Dispersion under 5 minutes may be incomplete, while durations exceeding 30 minutes may result in excessive mechanical stress that damages the drug or carrier structure. A duration of 15 minutes is preferred, balancing dispersion efficiency and drug protection.

[0056] In the present application, ultrasound reduces the particle size through physical energy input, increases the contact area between pioglitazone hydrochloride and the hydrophilic carrier, and promotes carrier inclusion (such as cavity inclusion of cyclodextrin), thereby improving the dispersibility and solubility of the API in aqueous solution, laying the foundation for the subsequent formation of solid dispersions and dissolution performance.

[0057] Optionally, in the method for preparing the pioglitazone hydrochloride solid dispersion, the stirring comprises: stirring the mixture of pioglitazone hydrochloride and the hydrophilic carrier in a water bath at 30° C. for 40 min;

[0058] Alternatively, mechanical grinding comprises: placing an aqueous solution of a hydrophilic carrier in a mortar, then adding or, a certain amount of pioglitazone hydrochloride, and grinding at 30° C. for 30 minutes;

[0059] The ultrasonic method comprises: ultrasonicating a mixture of pioglitazone hydrochloride and a hydrophilic carrier at 30° C. and 100 Hz for 15 minutes.

[0060] In some embodiments, the mixture is stirred in a 30°C water bath for 40 minutes, utilizing gentle shear forces to fully contact the pioglitazone hydrochloride API with the aqueous solution of the hydrophilic carrier (lecithin, cyclodextrin, or hydrophilic chitosan). The 30°C temperature maintains the stability of the carrier solution while promoting inclusion complexation of the hydrophilic carrier (e.g., inclusion complexation of the cyclodextrin cavity), resulting in a molecular or microscopic dispersion. The 40-minute stirring period ensures uniform mixing and enhances the dispersibility and solubility of the API.

[0061] In some embodiments, an aqueous solution of a hydrophilic carrier is placed in a mortar, pioglitazone hydrochloride is added, and the mixture is ground at 30°C for 30 minutes. The mechanical friction and pressure of the mortar break up the crystal structure of pioglitazone hydrochloride and reduce the particle size. The mild temperature of 30°C avoids thermal degradation while promoting physical mixing of the carrier and the drug substance, thereby enhancing the uniformity of the dispersion and improving the dissolution kinetics.

[0062] In some embodiments, the mixture is sonicated at 30°C and 100 Hz for 15 minutes. This high-frequency sound wave generates acoustic cavitation, which causes the collapse of tiny bubbles and releases shock waves, breaking up pioglitazone hydrochloride crystals and aggregates while enhancing the inclusion complex of the hydrophilic carrier. The 30°C temperature protects the stability of the drug and carrier, while the 100 Hz frequency optimizes the energy required for bubble collapse. The 15-minute sonication duration ensures sufficient dispersion without excessive damage.

[0063] In the present invention application, stirring for 40 minutes or grinding for 30 minutes or ultrasonication for 15 minutes respectively achieves uniform mixing through shear force, friction force or acoustic cavitation effect, significantly enhances the dispersibility of pioglitazone hydrochloride and the hydrophilic carrier, reduces local concentration deviation, and the mild condition of 30°C avoids the degradation of pioglitazone hydrochloride or structural destruction of the hydrophilic carrier (such as cyclodextrin) caused by high temperature, thereby ensuring the chemical and physical stability of the drug and the carrier; stirring for 40 minutes, grinding for 30 minutes and ultrasonication for 15 minutes are all preferred times, which balance the dispersion effect and energy consumption, avoid drug damage or carrier denaturation caused by excessive treatment, and improve preparation efficiency; stirring, grinding or ultrasonication can be flexibly selected according to the characteristics of the raw materials, and the parameters of 30°C temperature and specific time (40 minutes, 30 minutes, 15 minutes) are optimized. The process is simple and easy to control, with high repeatability, and is suitable for industrial production.

[0064] Optionally, the particle size D90 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.

[0065] In the present application, the dried powder is sieved through a 40-80 mesh sieve (preferably 80 mesh) to obtain a pioglitazone hydrochloride solid dispersion. The 80 mesh sieve is preferred to refine the particle size distribution, ensuring that the D90 particle size is within the target range (1-80 μm, preferably 5-60 μm), reducing particle size variation. The sieving process physically removes oversized particles (agglomerates) or undersized particles (fines), improving powder uniformity and flowability. This provides a stable raw material base for subsequent wet granulation and tableting processes, and reduces dissolution variability caused by uneven particle size during storage or processing.

[0066] In the present application, the particle size D90 of the pioglitazone hydrochloride solid dispersion is controlled within the range of 1-80 μm, preferably 5-60 μm. After particle refinement and uniform distribution are achieved through mixing means (such as stirring, grinding, ultrasound) and sieving, the smaller particle size increases the contact area between the drug and the hydrophilic carrier (lecithin, cyclodextrin, hydrophilic chitosan), enhances the inclusion complexation and wetting effect of the carrier, and significantly improves the dissolution rate and solubility of pioglitazone hydrochloride in aqueous media. 5-60 μm is the preferred range, which balances the particle fineness and the operability of the preparation, avoids dust flying or decreased flowability caused by too small a particle size (<5 μm), and avoids the limitation of the dissolution rate caused by too large a particle size (>60 μm).

[0067] Optionally, the pharmaceutically acceptable carrier includes one or more of a filler, a disintegrant, a lubricant, and a glidant.

[0068] 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) increase tablet volume and mass, improve powder fluidity, and facilitate wet granulation and tableting processes. Fillers can also dilute the pioglitazone hydrochloride solid dispersion, reduce local drug concentration deviations, and enhance granule uniformity. Lactose and crystalline cellulose also have good compressibility and water solubility, which aids tablet formation and dissolution.

[0069] In some embodiments, the disintegrant includes one or more of (dry) corn starch, potato starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, effervescent disintegrants, hydroxypropyl starch, and hydroxypropyl starch granules. Disintegrants exhibit water-swelling or capillary action, rapidly expanding upon absorption of water or promoting water penetration, resulting in rapid tablet disintegration, accelerated release of pioglitazone hydrochloride, and improved dissolution rate and bioavailability. Crospovidone and crospovidone sodium expand upon absorption of water, rapidly disintegrating the tablet; (dry) corn starch and potato starch promote water penetration through capillary action; and effervescent disintegrants (such as sodium bicarbonate combined with an acid) generate gas upon contact with water, accelerating the disintegration process. These mechanisms collectively promote the release of pioglitazone hydrochloride and improve the dissolution rate.

[0070] In some embodiments, the lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate, with magnesium stearate (e.g., magnesium stearate) being preferred. Lubricants can reduce friction between powder particles, improve particle flowability and mold release during tableting, prevent sticking, and ensure a smooth tablet surface with uniform hardness without affecting dissolution performance.

[0071] In some embodiments, the glidant includes one or more of silicon dioxide, magnesium stearate, calcium stearate, sodium stearyl fumarate, and microcrystalline cellulose. These glidants may be used in different stages of the pharmaceutical process, including but not limited to direct tableting, wet granulation, and dry granulation. The glidant can be adsorbed on the surface of the particles to improve the fluidity of the powder and ensure uniform filling and tableting consistency of the particles in the tablet press after wet granulation.

[0072] In the present application, 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 adapt to the production requirements of different batches of raw materials; fillers, disintegrants, lubricants and glidants can work together. The fillers and lubricants work together to reduce inter-particle friction and concentration deviation. The disintegrant ensures the uniformity of the internal structure of the tablet, reduces the variability in the dissolution process, optimizes the particle characteristics (compressibility, fluidity, uniformity), improves the disintegration and dissolution performance of the tablet, and ensures that the dissolution curve of pioglitazone hydrochloride is consistent with the original research.

[0073] Optionally, the wet granulation comprises:

[0074] The pioglitazone hydrochloride solid dispersion and a pharmaceutically acceptable carrier were added to a wet mixing granulator. The stirring speed was set to 80 rpm and the cutting speed was set to 800 rpm. The mixture was mixed for 5 minutes until uniform. The stirring speed was then increased to 100 rpm and the cutting speed to 1000 rpm. The binder was slowly added to form a soft material with moderate viscosity and a moisture content of 2%-5%.

[0075] The soft material was squeezed through an 18-mesh screen to form wet granules;

[0076] The wet granules are placed in a hot air circulation oven with the air inlet temperature 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.

[0077] The dry granules were mixed evenly with the lubricant and a high-speed rotary tablet press was used to adjust the tablet weight to the target specification and control the hardness within the range of 2.5-3.1 kg.

[0078] In the present application, initial mixing (stirring speed 80 rpm, cutter speed 800 rpm, 5 minutes): pioglitazone hydrochloride solid dispersion and pharmaceutically acceptable carriers (such as fillers, disintegrants, lubricants, etc.) are mixed at low speed in a wet mixing granulator, 80 rpm stirring provides mild shear force, 800 rpm cutter breaks up agglomerates, and 5 minutes is used to ensure initial uniformity and reduce 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, and slowly add binder (such as 2%-10% povidone K30 aqueous solution). The viscosity of the binder causes the powder to aggregate into a moderately viscous soft material with a moisture content of 2%-5%. The moisture content is controlled at 2%-5% to avoid excessive moisture (affecting drying) or excessive dryness (loose particles).

[0079] In the present application, the soft material is extruded into wet granules through an 18-mesh screen. The screening process divides the soft material into uniform granules, controls the particle size distribution, reduces the difference in particle size, and provides a consistency basis for subsequent drying and granulation. The wet granules are dried in a hot air circulation oven at 60-65°C. The moderate temperature avoids thermal degradation of pioglitazone hydrochloride. The moisture content is controlled to ≤5% to ensure granule stability and reduce subsequent dissolution variability. After drying, the granules are screened through a 20-mesh screen to remove fine powder (which may affect fluidity) and lumps (which may cause uneven dissolution), thereby optimizing granule uniformity and fluidity.

[0080] In this application, the dry granules are mixed with a lubricant (such as magnesium stearate) to reduce friction and improve granule flowability. A high-speed rotary tablet press is used to adjust the tablet weight to the target specification, controlling the hardness between 2.5 and 3.1 kg. This balances the tablet's mechanical strength (to avoid breakage) and disintegration performance (to ensure dissolution). The wet granulation process ensures a stable dissolution rate for pioglitazone hydrochloride tablets through uniform mixing, particle control, and tableting optimization. The dissolution profile is consistent with the original research. Process parameters (rotation speed, moisture content, temperature, and mesh size) can be optimized in real time to accommodate different batches of API, resulting in high reproducibility and suitability for industrial production.

[0081] Optionally, the pharmaceutically acceptable carrier includes: lactose, starch, hydroxypropyl methylcellulose and magnesium stearate, and the weight ratio of the components of the pioglitazone hydrochloride tablets is:

[0082] The ratio of the pioglitazone hydrochloride solid dispersion to 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 tablet.

[0083] In some embodiments, lactose can be used as a filler, starch can be used as a disintegrant, and hydroxypropylmethylcellulose can be used as a binder and / or disintegrant.

[0084] In some embodiments, lactose can be used as a filler (0.5-6.5 parts by weight) to increase tablet volume, improve powder flowability, dilute the pioglitazone hydrochloride solid dispersion, and reduce local concentration deviations. Its good compressibility and water solubility facilitate tablet formation and dissolution.

[0085] 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, and accelerates the release of pioglitazone hydrochloride.

[0086] In some embodiments, hydroxypropyl methylcellulose (HPMC) can serve as a binder and / or disintegrant. Hydroxypropyl methylcellulose (HPMC) (0.5-2 parts by weight) can function as both a binder and a disintegrant. During wet granulation, the viscosity of HPMC promotes the formation of a soft material (2%-5% moisture), enhancing granule binding. Upon contact with water, it absorbs and swells, accelerating tablet disintegration and optimizing dissolution rate.

[0087] In some embodiments, magnesium stearate can be used as a lubricant (in an amount of 0.2-0.5 parts by weight) to reduce friction between particles and between particles and the mold, improve powder fluidity and tableting performance, prevent sticking, and ensure stable tablet hardness (2.5-3.1 kg). At the same time, low dosage does not affect dissolution.

[0088] In some embodiments, the binder (e.g., a 2%-10% aqueous solution of povidone K30) accounts for 15-30% of the total weight. By controlling the viscosity of the soft material and the binding force of the particles, the binder ensures uniform particles (RSD < 2%) during the wet granulation process and synergizes with the carrier to optimize the disintegration and dissolution properties of the tablets.

[0089] In the present application, firstly, lactose (0.5-6.5 parts) and starch (0.6-3.0 parts) increase the volume and improve the fluidity, and after wet granulation, the particles are uniform (RSD <2%) and have good compressibility; and / or, hydroxypropyl methylcellulose (HPMC) can also accelerate the disintegration of tablets through water absorption expansion and capillary action with starch, thereby increasing the dissolution rate of pioglitazone hydrochloride, making the dissolution curve close to that of the original research, and improving the bioavailability; in addition, all carriers are safe excipients approved by the pharmacopoeia, and the proportion range 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) matches the proportion of the pioglitazone hydrochloride solid dispersion component (1 part), balancing the filling, disintegration, lubrication and bonding effects, ensuring that the dissolution rate of the pioglitazone hydrochloride tablets is stable and the dissolution curve is consistent with that of the original research.

[0090] Optionally, before wet granulation, the pharmaceutically acceptable carrier is sifted to ensure powder uniformity, including:

[0091] Lactose, starch, and hypromellose were pretreated to pass through an 80-mesh sieve;

[0092] Magnesium stearate was pre-treated to pass through a 60-mesh sieve.

[0093] In this application, prior to wet granulation, physical sieving is used to remove fine powder and agglomerates from lactose, starch, and HPMC, ensuring a consistent particle size distribution. Refining these three excipients through an 80-mesh screen improves powder uniformity, providing a stable raw material base for subsequent wet granulation. Magnesium stearate is screened through a 60-mesh screen. Considering its lubricant properties, the larger pore size removes coarse particles, retaining an appropriate particle size and optimizing its dispersibility during mixing and tableting.

[0094] In this invention, the sieved powder has a uniform particle size, reducing inter-particle adhesion and agglomeration, improving the flowability of lactose, starch, and HPMC, and the dispersibility of magnesium stearate. When the uniform powder is mixed in a wet granulator (stirring at 80-100 rpm and cutting at 800-1000 rpm), local concentration deviations are reduced, ensuring uniform distribution of the pioglitazone hydrochloride solid dispersion and the carrier. This results in higher efficiency during initial mixing (80 rpm / 800 rpm) and granulation (100 rpm / 1000 rpm).

[0095] In this application, the carrier particle size after sieving matches the soft material formed during wet granulation (moisture content 2%-5%) and the 18-mesh screen extrusion process, reducing uneven granulation caused by oversized or undersized particles. The moderate particle size of magnesium stearate enhances lubrication during subsequent mixing with the dry granules, reducing friction during tableting and ensuring a stable hardness (2.5-3.1 kg).

[0096] In the present invention, after the uniform carrier powder is mixed with the pioglitazone hydrochloride solid dispersion, the particle characteristics of the wet granulation and tableting processes are consistent, which reduces the variability in the dissolution process, makes the dissolution curve of the pioglitazone hydrochloride close to that of the original research, and improves the bioavailability.

[0097] Examples, Test Examples and Comparative Examples

[0098] It is worth noting that the raw materials used in the present application are all common commercially available products, and their sources are not specifically limited.

[0099] Example 1

[0100] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and ultrasonicate for 15 minutes. After vacuum filtration of the precipitated solid, place it in a freeze dryer and dry it at a freeze drying pressure of -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 of 9.66μm.

[0101] Example 2

[0102] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 20g of water. Place it in a 30°C water bath. Add 10g of pioglitazone hydrochloride API to the aqueous solution in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Set the stirring speed to 200rpm and stir for 40 minutes to precipitate a white solid. After vacuum filtration, dry the precipitated solid in a freeze dryer at -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 value of 32.15μm.

[0103] Example 3

[0104] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 20g of water. Pour the solution into a mortar. Add 10g of pioglitazone hydrochloride API to the mortar in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Grind the mixture at 30°C for 30 minutes to obtain a white powder. Dry the powder in a freeze dryer at -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 value of 13.73μm.

[0105] Example 4

[0106] Weigh 10g of lecithin and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of lecithin to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and ultrasonicate for 15 minutes. After vacuum filtration of the precipitated solid, dry it in a freeze dryer at a freeze drying pressure of -50°C and a freeze drying time of 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 value of 31.14μm.

[0107] Example 5

[0108] Weigh 10g of hydrophilic chitosan and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of hydrophilic chitosan to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic bath at 30°C, set the frequency to 100Hz, and sonicate for 15 minutes. Filter the precipitated solid under reduced pressure and dry it in a freeze dryer at -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 value of 28.97μm.

[0109] Example 6

[0110] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 20g of water. Add 5g of pioglitazone hydrochloride API in a ratio of 1:0.5 between hydroxypropyl-β-cyclodextrin and pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and ultrasonicate for 15 minutes. After decompression and filtration of the precipitated solid, place it in a freeze dryer and dry it at a freeze drying pressure of -50°C for 10 hours. Take out the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 of 11.65μm.

[0111] Example 7

[0112] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 30g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and ultrasonicate for 15 minutes. After vacuum filtration of the precipitated solid, place it in a freeze dryer and dry it at a freeze drying pressure of -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 of 13.73μm.

[0113] Example 8

[0114] Weigh 10g of hydroxypropyl-β-cyclodextrin and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 40Hz, and ultrasonicate for 15 minutes. After vacuum filtration of the precipitated solid, place it in a freeze dryer and dry it at a freeze drying pressure of -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 of 13.28μm.

[0115] Test example: Solubility experiment

[0116] First, prepare a buffer solution with a pH of 1-7. Add appropriate amounts of pioglitazone hydrochloride API and the pioglitazone hydrochloride solid dispersion prepared in Example 1-5 to the corresponding pH buffer solution. Place the solution in a constant temperature shaking water bath at 35°C and shake. After 6 hours, sample the solution for testing. The results are shown in the following table:

[0117]

[0118] It can be seen that the addition of a hydrophilic carrier to prepare a pioglitazone solid dispersion significantly improves the solubility of pioglitazone hydrochloride in aqueous solutions at all tested pH values. Under the same conditions, hydroxypropyl-β-cyclodextrin has the greatest effect on the solubility of pioglitazone hydrochloride. In the presence of the optimal hydrophilic carrier, the solid dispersion prepared by ultrasound has the highest solubility due to the excellent dispersion of pioglitazone hydrochloride and better mixing with the hydrophilic carrier.

[0119] (1) Solubility results

[0120] The solubility of the pioglitazone hydrochloride raw material is low in the pH range of 1-7 (0.0000986-6.12 mg / mL). As the pH increases, the solubility of the raw material gradually decreases. The solubility of the solid dispersions of Example 1 (hydroxypropyl-β-cyclodextrin, ultrasonic method, D90=9.66 μm), Example 2 (hydroxypropyl-β-cyclodextrin, stirring method, D90=32.15 μm), Example 3 (hydroxypropyl-β-cyclodextrin, mechanical grinding method, D90=13.73 μm), Example 4 (lecithin, ultrasonic method, D90=31.14 μm), and Example 5 (hydrophilic chitosan, ultrasonic method, D90=28.97 μm) is significantly higher than that of the comparative example, among which Example 1 (ultrasonic method, D90=9.66 μm) has the highest solubility, reaching 13.88 mg / mL at pH 1 and 8.82 mg / mL at pH 7.

[0121] The solubility of Examples 1-5 at pH 6-7 (small intestinal environment) is significantly higher than that of the comparative example, which is beneficial for small intestinal absorption and is expected to improve bioavailability and dissolution curve consistency.

[0122] (2) Solubility analysis

[0123] 1) Pioglitazone hydrochloride is a weakly basic drug (pKa approximately 5.5-6.0). In acidic environments (pH 1-3), it partially exists in an ionized form, resulting in high solubility. As the pH increases (pH 4-7), the drug gradually converts to a non-ionized form, becoming more hydrophobic and significantly decreasing its solubility. Furthermore, the API's crystal structure and high crystallinity limit its dissolution rate.

[0124] 2) Influence of hydrophilic carrier

[0125] In Examples 1-5, hydrophilic carriers (hydroxypropyl-β-cyclodextrin, lecithin, and hydrophilic chitosan) were used to prepare solid dispersions with pioglitazone hydrochloride. The carriers dispersed the pioglitazone hydrochloride at the molecular level or microscopic level through inclusion (cyclodextrin cavity inclusion), wetting (lecithin micelle effect), or adsorption (chitosan dispersion), thereby lowering the crystal energy barrier and significantly improving the solubility. This indicates that the wetting and / or inclusion effect of the hydrophilic carrier effectively improves the solubility within the physiological pH range.

[0126] 3) Influence of mixing methods

[0127] Examples 1 and 4-5 used ultrasound (30°C, 100 Hz, 15 minutes), and the acoustic cavitation effect effectively crushed the crystals, resulting in fine particles (D90 = 9.66 μm, 31.14 μm, 28.97 μm) and high solubility (13.88, 8.03, 8.77 mg / mL at pH 1, respectively).

[0128] Example 2 uses a stirring method (30°C, 200 rpm, 40 minutes), which has a mild shear force, large particles (D90 = 32.15 μm), and the lowest solubility (7.02 mg / mL at pH 1).

[0129] Example 3 adopts the mechanical grinding method (30°C, 30 minutes), and the particles are moderate (D90 = 13.73 μm) and the solubility is moderate (10.24 mg / mL at pH 1).

[0130] Due to the acoustic cavitation effect, the ultrasonic method produces finer particles, a larger contact area, and the most significant improvement in solubility; the stirring method produces larger particles, a weaker dispersion effect, and a limited improvement in solubility.

[0131] 4) Influence of carrier type

[0132] Examples 1-3 use hydroxypropyl-β-cyclodextrin, which has a strong cavity inclusion effect and significantly improves solubility, especially under ultrasound (Example 1).

[0133] Example 4 uses lecithin, which enhances wettability through micellar action, but has weaker inclusion capacity than cyclodextrin and slightly lower solubility.

[0134] Example 5 uses hydrophilic chitosan, which has good adsorption and dispersion effects, and its solubility is lower than or close to that of cyclodextrin, but slightly lower than that of Example 1 using the ultrasonic method.

[0135] The inclusion effect of cyclodextrin is stronger than that of lecithin and hydrophilic chitosan;

[0136] 5) D90 Impact

[0137] Example 1 has the smallest D90 (9.66 μm) and the highest solubility, indicating that the small particles increase the contact area with the buffer solution; Example 2 has the largest D90 (32.15 μm) and the lowest solubility, and the larger particles limit the dissolution rate.

[0138] Therefore, based on the above solubility results and solubility analysis, Examples 1-5, using hydrophilic carriers to prepare solid dispersions, significantly improved the solubility of pioglitazone hydrochloride in pH 1-7 buffers. Compared to the comparative example, the improvement was significant, with Example 1 performing best. These experimental results demonstrate that solid dispersion technology effectively improves the poor solubility of the API, providing a reliable foundation for optimizing tablet dissolution profiles and bioavailability.

[0139] Example 9

[0140] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared in Example 1 were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Povidone K30 (polyvinyl pyrrolidone) was added to purified water and stirred until completely dissolved. A 5% povidone K30 aqueous solution was prepared to serve as a binder for wet granulation. 15g of the pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. The speed was then increased to 100 rpm for stirring and 1000 rpm for blade. The povidone K30 aqueous solution, representing 15% of the total amount of the recipe, was slowly added 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0141] Example 10

[0142] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared in Example 1 were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Povidone K30 (polyvinyl pyrrolidone) was added to purified water and stirred until completely dissolved. A 5% povidone K30 aqueous solution was prepared to serve as a binder for wet granulation. 15g of the pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. The speed was then increased to 100 rpm for stirring and 1000 rpm for blade. The povidone K30 aqueous solution, representing 20% ​​of the total amount of the recipe, was slowly added 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0143] Example 11

[0144] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared in Example 1 were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Povidone K30 (polyvinyl pyrrolidone) was added to purified water and stirred until completely dissolved. A 5% povidone K30 aqueous solution was prepared to serve as a binder for wet granulation. 15g of pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. The speed was then increased to 100 rpm for stirring and 1000 rpm for blade. The povidone K30 aqueous solution, representing 25% of the total amount of the recipe, was slowly added 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0145] Example 12

[0146] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared in Example 1 were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Povidone K30 (polyvinyl pyrrolidone) was added to purified water and stirred until completely dissolved. A 5% povidone K30 aqueous solution was prepared to serve as a binder for wet granulation. 15g of pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. The speed was then increased to 100 rpm for stirring and 1000 rpm for blade. 30% of the povidone K30 aqueous solution, representing 30% of the total amount of the recipe, was slowly added 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0147] Comparative Example 1

[0148] Pass the pioglitazone hydrochloride API and magnesium stearate through an 80-mesh sieve and a 60-mesh sieve, respectively. Pass other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, through an 80-mesh sieve to remove lumps and ensure powder uniformity. Add povidone K30 (polyvinyl pyrrolidone) to purified water and stir until completely dissolved. Prepare a 5% povidone K30 aqueous solution as a binder for wet granulation. Weigh 15g of pioglitazone hydrochloride API, 80g of lactose, 20g of corn starch, and 30g of hypromellose according to the recipe and add them to a wet mixer granulator. Set the stirring speed to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. Then increase the stirring speed to 100 rpm and the blade speed to 1000 rpm. Slowly add 25% of the total povidone K30 aqueous solution 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0149] Comparative Example 2

[0150] Weigh 10g of citric acid and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of citric acid to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and sonicate for 15 minutes. After vacuum filtration of the precipitated solid, dry it in a freeze dryer at -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion with a D90 value of 17.66μm.

[0151] The prepared pioglitazone hydrochloride solid dispersion and magnesium stearate were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose (filler), corn starch (disintegrant), and hypromellose (hydroxypropyl methylcellulose), were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. Povidone K30 (polyvinyl pyrrolidone) was added to purified water and stirred until completely dissolved. This was used as a 5% aqueous solution of povidone K30 as a binder for wet granulation. 15g of pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the blade speed to 800 rpm. Mix for 5 minutes until uniform. The speeds were then increased to 100 rpm and 1000 rpm, and 25% of the total povidone K30 aqueous solution was slowly added 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 circulating oven at an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0kN and a hardness of approximately 2.5kg.

[0152] Comparative Example 3

[0153] Pass the pioglitazone hydrochloride API and magnesium stearate through an 80-mesh sieve and a 60-mesh sieve, respectively. Pass other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, through an 80-mesh sieve to remove lumps and ensure powder uniformity. Add povidone K30 (polyvinyl pyrrolidone) to purified water and stir until completely dissolved. Prepare a 5% povidone K30 aqueous solution as a binder for wet granulation. Weigh 15g of pioglitazone hydrochloride API and dissolve it in 450g of a 4:1 methanol-water mixture. Next, weigh 15g of hydroxypropyl-β-cyclodextrin and dissolve it in 30g of water. Add 465g of the pioglitazone hydrochloride solution in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride to form a mixed solution. The resulting mixed solution was placed in an ultrasonic bath at 30°C and ultrasonicated at 100 Hz for 15 minutes. The solvent was removed by rotary evaporation at a temperature of 70°C, a vacuum pressure of 200 mbar, and a rotation speed of 130 rpm. The wet solid was further freeze-dried to obtain a pioglitazone hydrochloride solid dispersion.

[0154] The resulting solid powder, 80g lactose, 20g corn starch, and 30g hydroxypropyl methylcellulose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the cutting speed to 800 rpm. Mix for 5 minutes until uniform. The stirring speed was then increased to 100 rpm and the cutting speed to 1000 rpm. A 25% aqueous solution of povidone K30 was slowly added to form a soft material with moderate viscosity. The soft material was extruded through an 18-mesh screen to form wet granules. The wet granules were placed in a hot air circulating oven with an inlet air temperature controlled at 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh screen to remove fine powder and lumps. The dried granules were then mixed with 3g of magnesium stearate (lubricant) and uniformly mixed. The tablets were then pressed using a high-speed rotary tablet press with a main pressure of 8.0 kN and a hardness of approximately 2.5 kg.

[0155] Comparative Example 4

[0156] Weigh 10g of povidone K30 and dissolve it in 20g of water. Add 10g of pioglitazone hydrochloride API in a 1:1 ratio of hydroxypropyl-β-cyclodextrin to pioglitazone hydrochloride. Place the resulting mixed solution in an ultrasonic cleaner at 30°C, set the frequency to 100Hz, and ultrasonicate for 15 minutes. After vacuum filtration of the precipitated solid, dry it in a freeze dryer at -50°C for 10 hours. Remove the solid powder and pass it through an 80-mesh sieve to obtain a pioglitazone solid dispersion.

[0157] The pioglitazone hydrochloride solid dispersion and magnesium stearate prepared by the above method were passed through an 80-mesh sieve and a 60-mesh sieve, respectively. Other excipients, such as lactose filler, corn starch disintegrant, and hypromellose, were passed through an 80-mesh sieve to remove lumps and ensure powder uniformity. 15g of pioglitazone hydrochloride solid dispersion, 80g of lactose, 20g of corn starch, and 30g of hypromellose were weighed according to the recipe and added to a wet mixer granulator. The stirring speed was set to 80 rpm and the cutting speed to 800 rpm. Mix for 5 minutes until uniform. The speed was then increased to 100 rpm for stirring and 1000 rpm for cutting. A povidone K30 aqueous solution, representing 25% of the total recipe, was slowly added 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 circulating oven with an inlet air temperature of 60-65°C and dried to a moisture content of ≤5%. After drying, the granules were passed through a 20-mesh sieve to remove fine powder and lumps. The dried granules were mixed evenly with 3 g of magnesium stearate (lubricant). A high-speed rotary tablet press was used, with the main pressure of the tablet press set to 8.0 kN and the hardness controlled to about 2.5 kg.

[0158] Test examples: average hardness, average dissolution, disintegration time

[0159] According to the dissolution test method, degassed hydrochloric acid solution (0.1 mol / L) kept at a constant temperature of (37±0.5)°C was used as the dissolution medium. 900 mL was taken, the speed was set to 50 r / min, and a sample was taken at 30 minutes. The sample was filtered and the filtrate was taken as the test solution. Another amount of pioglitazone hydrochloride reference substance was taken and diluted with the dissolution medium to a concentration of 7.6 μg / mL. The absorbance was measured at a wavelength of 269 nm to calculate the dissolution amount of each tablet. The average hardness test method was to place the tablet vertically between two pressing plates, pressurize it in the diameter direction until it broke, 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 used the hanging 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, tablet hardness and average disintegration time of the comparative example and Examples 9-12 are shown in the following table:

[0160]

[0161] It can be seen that the amount of binder has a great influence on the dissolution rate of the tablets. Within a certain range, as the amount of binder added increases, the dissolution rate of the pioglitazone hydrochloride tablets gradually increases accordingly, and the amount of binder used is basically the best. Under the optimal amount of binder, the dissolution rate of the comparative example obtained by directly mixing the pioglitazone hydrochloride raw material with the excipients to prepare tablets has a significant decrease. By adding other hydrophilic carriers such as organic acids, the particle size of the obtained pioglitazone hydrochloride solids increases significantly, the solubility decreases, and the dissolution rate of the obtained tablets decreases significantly. Adjusting the preparation method of the pioglitazone hydrochloride solid dispersion, such as adding an organic solvent, not only increases the energy consumption of solvent removal, but also causes pioglitazone hydrochloride to agglomerate, and the dissolution rate is also greatly affected.

[0162] (1) Adhesive dosage and average hardness

[0163] As the amount of povidone K30 increases from 15% to 30%, the average hardness increases slightly from 2.47 to 3.82, then decreases slightly to 3.63 at 30%. Within the 15%-25% range, the increase in binder effectively fills the gaps between particles, significantly improving mechanical strength. However, above 25%, excessive binder may cause excessive bonding of particles, reducing internal porosity and slightly reducing the final hardness.

[0164] (2) Adhesive dosage and average dissolution rate

[0165] As the dosage of povidone K30 increased from 15% to 30%, the dissolution rate showed an upward trend: 87.88% at 15% dosage, 88.25% at 20% dosage, 99.39% at 25% dosage, and slightly rebounded to 99.47% at 30% dosage, indicating that the dissolution rate gradually increased. The dissolution at the dosages of 25% and 30% was almost complete, ensuring a high dissolution rate.

[0166] (3) Binder dosage and disintegration time

[0167] As the povidone K30 dosage increased from 15% to 30%, the disintegration time increased from 0.8 minutes at 15% to 1 minute at both 20% and 25%, and then to 2.0 minutes at 30%. A moderate binder dosage (20%) resulted in rapid granule disintegration and sufficient dissolution. However, a high dosage (30%) resulted in a denser mucosal network, which delayed water penetration and significantly increased the disintegration time to 2.0 minutes.

[0168] Those skilled in the art can understand that the various operations, methods, steps in the process, measures, and schemes discussed in the present invention application can be interchanged, changed, combined, or deleted; further, the various operations, methods, and other steps, measures, and schemes in the process discussed in the present invention application can also be interchanged, changed, rearranged, decomposed, combined, or deleted; further, the various operations, methods, and steps in the process disclosed in the present invention application in the prior art can also be interchanged, changed, rearranged, decomposed, combined, or deleted. The various technical features of the above embodiments can be arbitrarily combined. To make the description concise, 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, they should be considered to be within the scope of this specification;

[0169] The embodiments described above only express several implementation methods of the embodiments of the present disclosure, and their descriptions are relatively specific and detailed, but they cannot be understood as limiting the patent scope of the embodiments of the present disclosure; it should be pointed out that for ordinary technicians in this field, without departing from the concept of the embodiments of the present disclosure, several variations and improvements can be made, which all fall within the protection scope of the embodiments of the present disclosure; therefore, the protection scope of the embodiments of the present disclosure should be based on the attached claims. As mentioned above, although the present invention application has been expressed and described with reference to specific preferred embodiments, it shall not be interpreted as limiting the present invention application itself. Various changes can be made to it in form and detail without departing from the spirit and scope of the present invention application defined in the attached claims.

[0170] The above description of the present invention and its implementation methods is non-limiting. In short, if a person skilled in the art is inspired by the above description and designs a structure and embodiment similar to the technical solution without inventive means without departing from the inventive purpose of the present invention, such design shall fall within the scope of protection of the present invention.

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: adding the pioglitazone hydrochloride raw material to an aqueous solution of a hydrophilic carrier at 20-40° C., fully mixing by stirring, mechanical grinding or ultrasonic method, precipitating, filtering and drying to obtain the solid dispersion; The hydrophilic carrier is one or more of lecithin, hydroxypropyl-β-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 binder includes a 2% to 10% aqueous solution of povidone K30, and the binder accounts for 15 to 30% of the total weight of the pioglitazone hydrochloride tablet; 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; In the preparation method of the pioglitazone hydrochloride solid dispersion, drying is performed by freeze 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; The pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a lubricant, and a glidant; The stirring comprises: stirring a mixture of the pioglitazone hydrochloride raw material and the hydrophilic carrier in a water bath at 30° C. for 40 minutes; or, the mechanical grinding comprises: placing an aqueous solution of the hydrophilic carrier in a mortar, then adding the pioglitazone hydrochloride raw material, and grinding at 30° C. for 30 minutes; or, the ultrasonic conditions of the ultrasonic method are: ultrasonic temperature of 20-40° C.; frequency of 30-100 Hz; and ultrasonic time of 5-30 minutes.

2. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that: The ultrasonic method comprises: ultrasonicating a mixture of the pioglitazone hydrochloride raw material and the hydrophilic carrier at 30° C. and 100 Hz for 15 minutes.

3. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 1, characterized in that: The filler includes one or more of lactose, powdered sugar, dextrin, 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 pellets; The lubricant includes one or more of magnesium stearate, stearic acid, and calcium stearate.

4. 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 a pharmaceutically acceptable carrier were added to a wet mixing granulator. The stirring speed was set to 80 rpm and the cutting speed was set to 800 rpm. The mixture was mixed for 5 minutes until uniform. The stirring speed was then increased to 100 rpm and the cutting speed to 1000 rpm. The binder was slowly added to form a soft material with moderate viscosity and a moisture content of 2%-5%. The soft material was squeezed through an 18-mesh screen to form wet granules; The wet granules are placed in a hot air circulation oven with the air inlet temperature 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. The dry granules are mixed with lubricant and the tablet weight is adjusted to the target specification using a high-speed rotary tablet press.

5. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 4, characterized in that: The pharmaceutically acceptable carrier includes: lactose, starch, hydroxypropyl methylcellulose and magnesium stearate. The weight ratio of the components of the pioglitazone hydrochloride tablets is: The ratio of 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.

6. A method for improving the dissolution rate of pioglitazone hydrochloride tablets according to claim 5, characterized in that: Before wet granulation, the pharmaceutically acceptable carrier is sieved to ensure powder uniformity, including: Lactose, starch, and hypromellose were pretreated to pass through an 80-mesh sieve; Magnesium stearate was pre-treated to pass through a 60-mesh sieve.

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