A pioglitazone hydrochloride and metformin compound tablet and preparation method thereof

Abstract

The present invention relates to the field of pharmaceutical technology, and in particular to a pioglitazone hydrochloride and metformin compound tablet and a preparation method thereof. The pharmaceutical preparation utilizes ultrasonic technology in combination with a solubility regulator to improve the solubility of pioglitazone hydrochloride, thereby preparing an excellent pioglitazone hydrochloride solid dispersion. The suspension is further prepared and coated around a metformin tablet core by a suspension-loading method. In the present invention, the preparation of the pioglitazone hydrochloride solid dispersion and the loading method are key factors affecting the solubility and uniformity of pioglitazone hydrochloride and metformin. By further optimizing the formulation, controlling the granulation process conditions, and coordinating the solubility of metformin and pioglitazone hydrochloride, a compound tablet with good compounding effect is obtained. The prepared compound tablet has good uniformity, thereby achieving uniform drug dispersion and controlled release.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a pioglitazone hydrochloride and metformin compound tablet and a preparation method thereof. Background Art

[0002] Pioglitazone hydrochloride metformin tablets are a combination tablet that combines the thiazolidinedione drug pioglitazone with the biguanide drug metformin. In 2005, Takeda's pioglitazone metformin tablets (Actoplus Met) received FDA approval in two strengths: 15mg / 500mg and 15mg / 850mg. This became the world's first dual-action combination hypoglycemic drug, offering more effective blood sugar control and reducing the incidence of hypoglycemia. This combination tablet leverages the synergistic effects of the two drugs while minimizing adverse drug reactions, enabling better blood sugar control and preventing and delaying the onset of chronic diabetic complications.

[0003] When preparing compound tablets, it is necessary to consider the effect of multiple active ingredients on the absorption rate and degree of a single drug in the body. If the drug dissolves too slowly in vitro, it will lead to incomplete absorption of the drug in the body, thereby affecting the efficacy of the compounded drug. Therefore, it is necessary to ensure that the drugs in the compound tablets have a high solubility and ensure that they can achieve the same bioavailability when acting in the body.

[0004] However, there are the following difficulties in the preparation of pioglitazone metformin tablets:

[0005] (1) Pioglitazone hydrochloride is poorly soluble in water, while metformin is highly water soluble. There is a large difference in the dissolution rate between the two, which seriously affects the efficacy of the drug after compounding;

[0006] (2) The proportion of metformin in the compound tablet is over 70%, while the content of pioglitazone hydrochloride is relatively low. The disparity between the two can easily lead to uneven mixing.

[0007] (3) Metformin has strong crystallinity and poor compressibility, and has high requirements for tableting technology.

[0008] In the existing technology, there are mainly three ways to solve the above problems:

[0009] (1) Tablet compression: The two drug components are pre-mixed and then compressed into tablets

[0010] The original patent CN200380104419.1 places metformin hydrochloride, pioglitazone hydrochloride, and corn starch in a fluidized bed granulator, using a fluidized bed granulation process that requires three steps: boiling mixing, spray granulation, and airflow drying (see Examples 1-6 in the specification). This process requires numerous control parameters, particularly during the boiling mixing process. Pioglitazone hydrochloride, which is present in a low-content formulation and has a fine particle size, is easily blown away in the fluidized bed or adheres to the equipment surface, resulting in losses. Furthermore, the loss of low-content pioglitazone hydrochloride particles during the mixing process can easily lead to uneven mixing and poor batch stability, further compromising drug dissolution. During the stirring process, due to the low content of pioglitazone hydrochloride, segregation is prone to occur, with the lower-density pioglitazone particles floating while the denser excipients sink, easily causing uneven mixing and ultimately affecting the synergistic efficacy of the drugs.

[0011] (2) Particle size control method: Control the particle size and particle size ratio of the raw material

[0012] Patent CN101721414B discloses a composition containing pioglitazone hydrochloride and metformin hydrochloride and its preparation method. By controlling the particle size distribution of the pioglitazone hydrochloride raw material powder, wherein the particle size is <75μm and the 50-75μm particle size accounts for approximately 80%, the initial dissolution rate of pioglitazone is improved. However, it does not mention or solve the problem of uneven mixing caused by the disparity in the ratio of the two components. Patent CN115804770B discloses a pharmaceutical preparation containing metformin hydrochloride and pioglitazone hydrochloride and its preparation method. By controlling the ratio of the particle sizes of metformin hydrochloride and pioglitazone hydrochloride, further changing the addition method of the binder and the filler, and controlling the ratio of the co-grinding of metformin hydrochloride and the lubricant or flow aid, the compressibility of the prepared granules is significantly improved, and the granulation effect is better than the complex fluidized bed granulation. However, the particle size and particle size ratio of pioglitazone hydrochloride and metformin need to be strictly and accurately controlled to regulate the dissolution rate and content uniformity. The control range is small, and poor control may easily affect the dissolution effect of the drug.

[0013] (3) Layered controlled release method: preparation of metformin sustained-release layer and pioglitazone hydrochloride immediate-release layer

[0014] Patent CN102525991A discloses a compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and its preparation method, wherein the easily soluble metformin hydrochloride is used as the tablet core, and the outer side is wrapped with a controlled release coating film with drug release holes, and the poorly soluble pioglitazone hydrochloride and a surfactant are further made into a coating solution, which is wrapped outside the controlled release coating film to improve the solubility of pioglitazone hydrochloride. By making the easily soluble and poorly soluble drugs into a controlled release layer and a sustained release layer respectively, the purpose of controlling the release of the two drug components is achieved. However, the increase of surfactants may lead to the problem of incompatibility of the coating film. The quality of the coating has a greater impact on pioglitazone hydrochloride. Too thick affects the disintegration and release of the drug. Too thin or improper operation can easily lead to uneven coating or cracking, further affecting the dissolution effect of pioglitazone hydrochloride. Moreover, due to the poor water solubility of pioglitazone hydrochloride, it is unevenly dispersed in the coating layer, and particles are prone to agglomeration, resulting in large differences in release between tablets, and the consistency of drug quality cannot be guaranteed. The dissolution effect of the two drug components can be controlled by controlling the two tablet layers, namely the sustained-release layer and the immediate-release layer. However, the above operation is complicated and poor control of one tablet layer may ultimately affect the dissolution effect of the drug components.

[0015] The above three solutions all have limitations. In traditional tableting, the two drug components are easily mixed unevenly, affecting the synergistic therapeutic effect. Although the particle size control method can improve the solubility of pioglitazone hydrochloride, the particle size and particle size ratio need to be precisely controlled, which is demanding and has a narrow control range. Although the layered controlled release method including a controlled-release layer and a sustained-release layer can adjust the release rate, surfactants can easily cause incompatibility of the coating membrane, and pioglitazone hydrochloride is difficult to disperse, the coating quality is difficult to control, and the process operation is complicated. Summary of the Invention

[0016] In response to the technical problems of disparate proportions of active ingredients in pioglitazone and metformin tablets, large differences in solubility, and uneven mixing, poor dissolution effect, and poor batch stability caused by traditional tableting, the present invention provides a pioglitazone and metformin compound tablet and a preparation method thereof; the present invention overcomes the problems existing in traditional tableting, does not adopt a tableting method, avoids the problem of uneven mixing, and simultaneously overcomes the defect of complex layer control of multiple drug components, thereby achieving uniform mixing of drug components and achieving a dissolution effect consistent with that of the original drug.

[0017] The present invention unexpectedly discovered that the preparation of the solid dispersion and suspension system of pioglitazone hydrochloride and the method of drug application are key factors affecting the uniform mixing of pioglitazone hydrochloride and metformin compound tablets. The above steps are coordinated as a whole, combined with the optimization of the preparation prescription and the control of the granulation process conditions, to obtain compound tablets with good compounding effect. The prepared compound tablets have high uniformity, achieve uniform drug dispersion and controlled release, and achieve a dissolution effect consistent with that of the original drug.

[0018] In order to achieve the purpose of the present invention, the technical solution of the present invention is as follows:

[0019] A pioglitazone hydrochloride and metformin compound tablet, characterized in that it comprises the following components in parts by weight:

[0020] 1) Active ingredient

[0021] Pioglitazone hydrochloride (calculated as pioglitazone), 1.0-2.5 parts;

[0022] Metformin hydrochloride, 50-60 parts;

[0023] 2) Solubility regulator: 1-5 parts;

[0024] 3) Suspension system

[0025] Suspending agent: 0.01-0.1 parts;

[0026] Wetting agent: 0.05-0.2 parts;

[0027] Stabilizer: 0.1-0.5 parts;

[0028] Solvent: 20-30 parts;

[0029] 4) Chip system

[0030] Diluent: 0.12-0.4 parts;

[0031] Adhesive: 0.012-0.06 parts;

[0032] Disintegrant: 0.024-0.1 parts;

[0033] Lubricant: 0.006-0.02 parts;

[0034] The preparation method of the compound tablet is as follows:

[0035] (1) Preparation of pioglitazone hydrochloride solid dispersion: dissolve 1.0-2.5 parts of pioglitazone hydrochloride API and 1-5 parts of solubility modifier in pure water, sonicate, and freeze-dry to obtain pioglitazone hydrochloride solid dispersion;

[0036] (2) Preparation of pioglitazone hydrochloride suspension: 0.01-0.1 parts of a suspending agent, 0.05-0.2 parts of a wetting agent, 0.1-0.5 parts of a stabilizer, and 20-30 parts of a solvent are added to the pioglitazone hydrochloride solid dispersion obtained in step (1) to prepare a uniform suspension;

[0037] (3) Preparation of metformin tablet core: Metformin hydrochloride and the compounds in the tablet core system are mixed and granulated by wet method to obtain metformin tablet core;

[0038] (4) Preparation of a complex of pioglitazone hydrochloride and metformin: The pioglitazone hydrochloride suspension prepared in step (2) is coated on the outside of the metformin tablet core prepared in step (3) by a suspension coating technique, and the suspension is evenly sprayed on the surface of the metformin tablet core using a bottom spray fluidized bed, and a sustained-release coating is applied to the complex of pioglitazone hydrochloride and metformin.

[0039] The preparation method of the present invention comprises the following steps: on the one hand, an ultrasonic method is used to miniaturize drug particles and increase the specific surface area; on the other hand, a pioglitazone hydrochloride raw material drug is mixed with a solubility regulator to reduce the dependence of the solubility of the pioglitazone hydrochloride raw material drug on pH and improve the solubility of pioglitazone hydrochloride, thereby preparing a pioglitazone hydrochloride solid dispersion; and further preparing a suspension, which is then coated on the outside of a metformin tablet core in a drug suspension coating manner. The above steps are coordinated as a whole, combined with optimized preparation prescription and controlled granulation process conditions, to obtain a compound tablet with good compounding effect. The prepared compound tablet has good uniformity and realizes uniform drug dispersion and controlled release.

[0040] In the present invention, one of the key factors in the preparation of pioglitazone hydrochloride solid dispersion is the addition of a solubility regulator, which increases the solubility of pioglitazone hydrochloride in water, inhibits the formation and growth of drug crystal nuclei, and greatly improves the solubility of pioglitazone hydrochloride; the high-frequency mechanical vibration generated by ultrasound can form a cavitation effect and mechanical shear force, so that the raw material drug is dispersed in the solvent in a more uniform fine particle form; at the same time, ultrasound can accelerate the contact between the solubility regulator and the drug particles, and improve the dissolution rate of pioglitazone hydrochloride without adding an organic solvent. The solubility of pioglitazone hydrochloride is increased to obtain an excellent pioglitazone hydrochloride solid dispersion; on this basis, the pioglitazone hydrochloride solid dispersion obtained in step (1) is mixed with 0.01-0.1 parts of a suspending agent, 0.05-0.2 parts of a wetting agent, 0.1-0.5 parts of a stabilizer, and 20-30 parts of a solvent to obtain a uniform suspension. The suspension solution is coated on the metformin tablet core obtained by the traditional method using a suspension drug coating technology, and the inlet air temperature and the material temperature are controlled to make the spraying more uniform.

[0041] Further, the diluent is a combination of one or more of microcrystalline cellulose, lactose, and starch; and / or the binder is a combination of one or more of hypromellose, hydroxypropyl cellulose, and povidone;

[0042] And / or, the disintegrant is a combination of one or more of cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, and corn starch;

[0043] And / or, the lubricant is magnesium stearate.

[0044] Preferably, the suspending agent is 0.08 parts;

[0045] Preferably, the wetting agent is 0.12 parts;

[0046] Preferably, the stabilizer is 0.4 parts;

[0047] Preferably, the solubility regulator is 1.5 parts;

[0048] Preferably, the solvent is 20-30 parts, and more preferably the solvent is 30 parts.

[0049] Furthermore, the suspending agent is one or more of xanthan gum, gum arabic, methyl cellulose, and povidone.

[0050] Furthermore, the wetting agent is one or more of polysorbate 80, poloxamer, and phospholipid.

[0051] Furthermore, the stabilizer is a compound of sodium benzoate and potassium sorbate.

[0052] Furthermore, the solubility regulator is a hydrophilic carrier. Preferably, the hydrophilic carrier is one or more of organic acid, cyclodextrin, and hydrophilic chitosan.

[0053] Furthermore, the solvent is a 30%-70% ethanol / water solution, preferably, the solvent is a 70% ethanol / water solution.

[0054] In the present invention, one of the key factors is the preparation of the suspension. The precise control of the weight of the API and the solubility regulator, suspending agent, wetting agent, stabilizer, and solvent enhances the solubility, stability, uniformity, and rheological properties of the suspension, thus ensuring the uniformity of the subsequent suspension.

[0055] Furthermore, the preparation of the pioglitazone hydrochloride solid dispersion (1) is as follows:

[0056] 1.0-2.5 parts of pioglitazone hydrochloride API and 1-5 parts of a solubility regulator are added to pure water, followed by ultrasonication, filtration, and freeze-drying to obtain a solid powder, which is then sieved to obtain a pioglitazone hydrochloride solid dispersion with a D90 of ≤10 μm;

[0057] Preferably, the ultrasonic temperature is 25-50°C; more preferably, the ultrasonic temperature is 30°C;

[0058] Preferably, the ultrasonic time is 10-30 min, more preferably, the ultrasonic time is 15 min;

[0059] Preferably, the ultrasonic frequency is 10 to 100 kHz, more preferably, the ultrasonic frequency is 100 Hz;

[0060] Preferably, the screen is 80 mesh;

[0061] Furthermore, the preparation of the pioglitazone hydrochloride suspension (2) is as follows: 0.01-0.1 parts of a suspending agent, 0.05-0.2 parts of a wetting agent, 0.1-0.5 parts of a stabilizer, and 20-30 parts of a solvent are added and mixed to obtain a uniform suspension;

[0062] Preferably, the dispersion time is 40-110 minutes, more preferably, the dispersion time is 80 minutes;

[0063] Preferably, the dispersion speed is 1500-4000 r / min, more preferably, the dispersion speed is 2500 r / min.

[0064] Furthermore, the preparation method of the (4) pioglitazone hydrochloride and metformin complex is:

[0065] Pioglitazone hydrochloride is coated on the outside of the metformin tablet core using a suspension coating technique. The suspension is evenly sprayed on the surface of the metformin tablet core using a bottom spray fluidized bed. The inlet air temperature and material temperature are controlled. A sustained-release coating is applied to the pioglitazone hydrochloride and metformin complex to increase the weight by 2%-5%.

[0066] Preferably, the inlet air temperature is 30-45°C, more preferably, the inlet air temperature is 40°C;

[0067] Preferably, the material temperature is 20-50°C, more preferably, the material temperature is 30°C;

[0068] Preferably, the sustained release coating is ethylcellulose.

[0069] Compared with the prior art, the present invention has the following beneficial effects:

[0070] In the present invention, the preparation of the solid dispersion, the preparation of the suspension system, and the method of suspending the drug play a synergistic role as a whole. In conjunction with the optimization of the coating and tableting process parameters, the uniformity of the compound tablets is significantly improved. At the same time, pioglitazone hydrochloride unexpectedly obtains a higher dissolution rate, thereby achieving uniform controlled release of the drug compound preparation. Specifically, the method is as follows: first, an ultrasonic method is used to mix the pioglitazone hydrochloride raw material with water and a solubility regulator, and freeze-drying is performed to obtain a pioglitazone hydrochloride dispersion, thereby overcoming the limitation that pioglitazone hydrochloride only dissolves in an organic solvent. Without introducing an organic solvent, an excellent pioglitazone hydrochloride dispersion is obtained, thereby improving its solubility; further, a suspension is prepared and wrapped around the metformin tablet core in the form of a suspended drug, thereby overcoming the conventional tableting process of tablets and the need to strictly control the particle size and ratio of pioglitazone hydrochloride and metformin to obtain a technical defect of a compound tablet with high uniformity. DETAILED DESCRIPTION

[0071] 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; 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.

[0072] The detection method of the present invention is as follows:

[0073] Dissolution test: According to the dissolution test method in Appendix ⅩC of the 2005 edition (Part II) of the Chinese Pharmacopoeia, the paddle method was used to take the pioglitazone hydrochloride and metformin tablets prepared under different prescriptions and 900 ml of 10.1 mol·L -1 The hydrochloric acid solution was used as solvent and the rotation speed was 50 r·min -1 , the temperature was (37±0.5)℃, 10ml of the medium was taken out at 3, 5, 7, 10, 15, 20, 30 and 45min respectively, filtered through a 0.8μm microporous membrane, the primary filtrate was discarded, and 10ml of the dissolution medium was added at the same time, and the subsequent filtrate was taken with 0.1mol·L -1 Using hydrochloric acid as blank, the absorbance of pioglitazone hydrochloride was measured at a wavelength of 269 nm by UV spectrophotometry, and the dissolution rate was calculated by substituting the standard curve.

[0074] The angle of repose test mainly refers to the national standard GB / T 11986-98 "Determination of the angle of repose of surfactant powders and particles", and at the same time combines the pharmacopoeia specifications (Chinese Pharmacopoeia 2020 edition) to supplement the test methods and judgment criteria.

[0075] Particle bulk density test: Take about 100g of the powder sample to be tested, pass it through a 1.0mm sieve to disperse the lumps, slowly pour it into a dry glass graduated cylinder, scrape the top to avoid compaction, and read the apparent volume (V0).

[0076] Calculate bulk density r B =M / V0 (M is mass, V0 is volume), measure three times in parallel and take the average value.

[0077] Content uniformity test:

[0078] Take 10 samples of the test product and determine the relative content X of each unit with the labeled amount as 100 according to the following method i .

[0079] Calculation parameters:

[0080] mean

[0081] Standard deviation

[0082] Deviation

[0083] A+2.2S≤L (L=15.0) is qualified

[0084] Example 1

[0085] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0086] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1g xanthan gum, 2g polysorbate 80, 2.5g sodium benzoate, and 2.5g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300g as the solvent, add the mixed solid powder to the solution, and disperse at 2500r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension;

[0087] (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform. 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder. Metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator. The stirring speed was set to 200rpm and the cutting speed was set to 1000rpm. Mix for 5 minutes until uniform. Then the speed was increased to 300rpm and the cutting speed was increased to 2000rpm. The hydropropyl methyl cellulose aqueous solution was slowly added to form a soft material with moderate viscosity (moisture content was controlled at 10%). The soft material was granulated through a 20-mesh sieve and sent to a fluidized bed for drying. The inlet air temperature was set to 50℃, the material temperature was ≤40℃, and the final moisture content was ≤3%. Then, magnesium stearate was added to the mixture and the mixture was fed into a rotary tablet press after 5 minutes. The pressure was set to 30 kN and the tablet weight deviation was within ±3%.

[0088] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

[0089] Example 2

[0090] (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of HP-β-cyclodextrin was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency set to 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 8.12 μm.

[0091] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1g xanthan gum, 2g polysorbate 80, 2.5g sodium benzoate, and 2.5g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300g as the solvent, add the mixed solid powder to the solution, and disperse at 2500r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension;

[0092] (3) Preparation of metformin tablet core, refer to Example 1;

[0093] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0094] Example 3

[0095] (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of lecithin was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 9.93 μm.

[0096] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1g xanthan gum, 2g polysorbate 80, 2.5g sodium benzoate, and 2.5g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0097] (3) Preparation of metformin tablet core, refer to Example 1;

[0098] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0099] Example 4

[0100] (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of hydrophilic chitosan was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 10.58 μm.

[0101] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1g xanthan gum, 2g polysorbate 80, 2.5g sodium benzoate, and 2.5g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0102] (3) Preparation of metformin tablet core, refer to Example 1;

[0103] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0104] Example 5

[0105] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0106] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0107] (3) Preparation of metformin tablet core, refer to Example 1;

[0108] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0109] Example 6

[0110] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0111] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.5 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0112] (3) Preparation of metformin tablet core, refer to Example 1;

[0113] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0114] Example 7

[0115] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0116] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.6 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0117] (3) Preparation of metformin tablet core, refer to Example 1;

[0118] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0119] Example 8

[0120] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0121] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0122] (3) Preparation of metformin tablet core, refer to Example 1;

[0123] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0124] Example 9

[0125] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0126] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 0.5 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0127] (3) Preparation of metformin tablet core, refer to Example 1;

[0128] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0129] Example 10

[0130] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the above solution. The resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was removed to obtain a pioglitazone solid dispersion with a D90 of 6.88 μm.

[0131] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion. Prepare a 30% ethanol / water solution, take 300 g of the solution as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0132] (3) Preparation of metformin tablet core, refer to Example 1;

[0133] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0134] Comparative Example 1

[0135] (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution. 10 g of pioglitazone hydrochloride API was weighed and added to the aqueous solution. The resulting mixed solution was stirred in a 30°C oil bath for 30 min. After stirring, the precipitated solid was collected by filtration and then freeze-dried at a controlled temperature of -50°C and a pressure of 0.2 mbar. After freeze-drying for 10 hours, the solid powder was removed to obtain a pioglitazone hydrochloride solid dispersion with a D90 of 20.62 μm.

[0136] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone hydrochloride solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of it as the solvent, add the mixed solid powder to the solution, and disperse it at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0137] (3) Preparation of metformin tablet core, refer to Example 1;

[0138] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0139] Comparative Example 2

[0140] (1) Preparation of pioglitazone hydrochloride solid dispersion: 10 g of pioglitazone hydrochloride API was weighed and added to 100 g of pure water. The resulting mixture was ultrasonically cleaned in an ultrasonic bath at 30°C for 15 min at a frequency of 100 Hz. After the ultrasonication, the precipitated solid was collected by filtration and then freeze-dried at a temperature of -50°C and a pressure of 0.2 mbar. After freeze-drying for 10 hours, the solid powder was removed to obtain a pioglitazone hydrochloride solid dispersion with a D90 of 61.37 μm.

[0141] (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone hydrochloride solid dispersion. Prepare a 70% ethanol / water solution, take 300 g of it as the solvent, add the mixed solid powder to the solution, and disperse it at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0142] (3) Preparation of metformin tablet core, refer to Example 1;

[0143] (4) Preparation of pioglitazone hydrochloride and metformin compound tablets, refer to Example 1.

[0144] Comparative Example 3

[0145] Preparation of pioglitazone hydrochloride solid dispersion: Dissolve 50g of citric acid in 100g of pure water to form an aqueous solution. Add 10g of pioglitazone hydrochloride API to the solution and stir to dissolve. After stirring, remove the solvent by rotary evaporation. Filter the resulting solid and spray dry it at an inlet air temperature of 110°C and an atomizer speed of 25,000 rpm. After spray drying, the powder is dried under reduced pressure (50°C for 10 hours) and then removed to obtain a pioglitazone hydrochloride solid dispersion with a D90 of 126.88μm.

[0146] Preparation of pioglitazone hydrochloride suspension: Weigh 0.8g xanthan gum, 1.2g polysorbate 80, 2.5g sodium benzoate, and 2.5g potassium sorbate, sieve through an 80-mesh sieve, and premix with the pioglitazone hydrochloride solid dispersion. Prepare a 70% ethanol / water solution, take 300g of the mixed solid powder as the solvent, add the solution, and disperse at 2500 rpm for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0147] Preparation of metformin tablet core, refer to Example 1;

[0148] The preparation of pioglitazone hydrochloride and metformin compound tablets is as follows:

[0149] Comparative Example 4

[0150] Preparation of a pioglitazone hydrochloride solid dispersion: Dissolve 50g of citric acid in 100g of pure water to form an aqueous solution. Add 10g of the pioglitazone hydrochloride API to the aqueous solution. Ultrasonicate the resulting mixture in an ultrasonic bath at 30°C for 15 minutes at a frequency of 100Hz. After ultrasonication, collect the precipitated solid by filtration and then freeze-dry at -50°C and 0.2mbar. After 10 hours of freeze-drying, remove the solid powder to obtain a pioglitazone solid dispersion with a D90 value of 6.88μm.

[0151] Preparation of pioglitazone hydrochloride coating solution: Use 95% ethanol as solvent to add the above-mentioned pioglitazone hydrochloride solid dispersion and propylene glycol, mix, then add cellulose acetate, polyvinyl pyrrolidone and polyethylene glycol 6000, heat and stir until completely dissolved to obtain coating slurry.

[0152] Preparation of metformin tablet core, refer to Example 1;

[0153] Preparation of pioglitazone hydrochloride and metformin compound tablets: pioglitazone hydrochloride coating slurry is coated on the outside of metformin tablet core by a coating machine to prepare pioglitazone metformin compound tablets.

[0154] Comparative Example 5

[0155] Preparation of pioglitazone hydrochloride suspension: Dissolve 50g of citric acid in 300g of a 70% ethanol / water solution. Weigh 10g of pioglitazone hydrochloride API, 0.8g of xanthan gum, 1.2g of polysorbate 80, 2.5g of sodium benzoate, and 2.5g of potassium sorbate. Sieve through an 80-mesh sieve and pre-mix the mixture. Then, disperse the mixture at 2500 rpm for 80 minutes to form a uniform pioglitazone hydrochloride suspension.

[0156] Preparation of metformin tablet core, refer to Example 1;

[0157] The preparation of pioglitazone hydrochloride and metformin compound tablets is as follows:

[0158] Table 1 Effect of pioglitazone hydrochloride suspension composition on the preparation of final compound tablets

[0159]

[0160] 1. Result analysis:

[0161] The data results in Table 1 show that the compound tablets obtained by the preparation method of the present invention in Examples 1-10 have high content uniformity, qualified appearance and friability, and meet the requirements of tablet production. The angle of repose in the examples is in the range of 32.0-33.4, while in Comparative Examples 1-5, the angle of repose is in the range of 35.9-42.1. The angle of repose in the comparative examples is close to or exceeds the threshold value of 40, indicating that the particles on the surface of the drug are coarser; while the angle of repose in the examples is smaller, making it easier to distribute evenly during tableting, granulation, etc., reducing problems such as fragmentation and sticking, and improving the formability of the tablets. The bulk density of the particles in Examples 1-10 ranges from 0.4578-0.5486, while the bulk density of the particles in Comparative Examples 1-5 ranges from 0.6112-0.8534. The bulk density of the particles in the examples is lower, has better fluidity, and can be more evenly distributed in the tablet, thereby improving the uniformity of the compound tablets. Content uniformity reflects the degree of consistency of the content of active ingredients in a unit preparation. The pharmacopoeia stipulates that if A+2.2S>15.0, it is judged to be non-compliant with the regulations. The content uniformity A+2.2S of pioglitazone hydrochloride in Examples 1-10 ranges from 4.93 to 10.36, all less than the threshold of 15, which meets the regulations; while the A+2.2S of Comparative Examples 1-5 ranges from 15.11 to 25.73, all exceeding the threshold of 15. The content uniformity of pioglitazone hydrochloride in the comparative examples does not meet the regulations and cannot meet the preparation requirements. The compound tablets finally prepared in Comparative Examples 1-5 are partially unqualified in appearance and their friability is unqualified. Tablets with high friability may cause uneven drug distribution due to fragmentation during storage, affecting the content uniformity of the drug components.

[0162] 2. Cause Analysis:

[0163] (1) Differences in the preparation of pioglitazone hydrochloride solid dispersions

[0164] In the embodiment, a solubility regulator and ultrasound are added, and the two have a synergistic effect. The mass transfer of pioglitazone hydrochloride is enhanced by ultrasound, so that the particles are miniaturized and the specific surface area is significantly increased. The synergistic effect is exerted with the hydrophilic carrier, and the solubility of pioglitazone hydrochloride in water is significantly improved. An excellent pioglitazone hydrochloride solid dispersion is obtained, and the solubility of pioglitazone hydrochloride in water is increased without adding an organic solvent. Further freeze-drying is performed to obtain an excellent pioglitazone hydrochloride solid dispersion, without introducing an organic solvent, reducing the hydrolysis effect of the organic solvent residue on the pioglitazone hydrochloride solid dispersion and reducing the introduction of impurities.

[0165] In Comparative Example 1, only a solubility regulator was added, while in Comparative Example 2, no solubility regulator was added. There was a lack of synergistic effect, and its dispersing force was weakened. The ability to increase the solubility of pioglitazone hydrochloride in water was limited, resulting in a decrease in the solubility of pioglitazone hydrochloride. The resulting pioglitazone hydrochloride solid dispersion was poor. The particle size of the pioglitazone hydrochloride solid dispersion was large, unable to meet the demand. The content uniformity of pioglitazone hydrochloride in the resulting compound tablets did not meet the requirements and exceeded the theoretical threshold. Comparative Example 3 lacked ultrasonic means, resulting in a reduced mixing effect and a reduced solubility of pioglitazone hydrochloride. Conventional spray drying was used, and the temperature was high, which, compared to freeze drying, posed a risk of drug decomposition or oxidation.

[0166] (2) Differences in the preparation of pioglitazone hydrochloride suspension

[0167] In the embodiment, the prepared pioglitazone hydrochloride solid dispersion is added with 0.01-0.1 parts of a suspending agent, 0.05-0.2 parts of a wetting agent, 0.1-0.5 parts of a stabilizer, and 20-30 parts of a solvent, and the mixture is mixed to prepare a uniform suspension. The suspending agent binds the drug and the excipient particles through a viscous effect, adjusts the tightness of the particles, and reduces the risk of fragmentation. The wetting agent enhances the wettability of the drug particles by reducing the solid-liquid interfacial tension. When the prepared suspension is further sprayed onto the surface of the metformin tablet, the wetting agent can improve the synergistic dissolution performance of the two. Pioglitazone hydrochloride contains a thiazolidinedione structure and is easily oxidized under high temperature and high humidity conditions. The stabilizer in the suspension system can inhibit the degradation of pioglitazone hydrochloride, further enhancing the stability of the drug. The solvent is both polar and fat-soluble, effectively promoting the dissolution of various compounds in the suspension system, allowing them to be better dispersed and form a uniform solution. The above components work synergistically to produce a pioglitazone hydrochloride suspension with excellent performance. The final compound tablets have more uniform spraying, improving the content uniformity of pioglitazone hydrochloride A+2.2S.

[0168] In Comparative Example 4, a hydrochloric acid solid dispersion was mixed with a conventional solubilizer, stabilizer, film-forming agent, pore-forming agent, and 95% ethanol as a solvent to prepare a coating slurry, which was then wrapped around the metformin tablet core to prepare a pioglitazone-metformin composite tablet. Due to the poor water solubility of pioglitazone hydrochloride, the various groups could not play a good synergistic role, resulting in uneven mixing of the components in the coating slurry, resulting in increased bulk density and angle of repose of the particles in the composite tablets, unqualified friability, reduced content uniformity, A+2.2S>15, and non-compliance with regulations.

[0169] (3) Combination of pioglitazone hydrochloride solid dispersion and suspension drug delivery

[0170] In the examples, the preparation method of the present invention is used to obtain compound tablets with high content uniformity, qualified appearance and friability, and meet the requirements for tablet production; while in Comparative Example 5, the pioglitazone hydrochloride raw material, solubility regulator, and each component compound of the suspension system are directly added to prepare a suspension. Although the solubility of pioglitazone hydrochloride is increased, the particles obtained after the drug suspension are large in particle size, poor in uniformity, and have a large angle of repose and bulk density, making them difficult to tablet, and unqualified in friability. The pioglitazone hydrochloride content uniformity A+2.2S>15 does not meet the requirements, and the problem of uniformity of the metformin and pioglitazone compound tablets cannot be solved.

[0171] Therefore, in the present application, an innovative solvent system and solubility adjustment means are used to effectively increase the solubility of pioglitazone hydrochloride in water without adding an organic solvent, thereby obtaining an excellent pioglitazone hydrochloride solid dispersion; the obtained pioglitazone hydrochloride solid dispersion is further mixed with the components in the suspension system to obtain a suspension; and the suspension is then applied to further improve the uniformity and quality of the compound tablets, thereby greatly improving production efficiency and reducing production costs.

[0172] Table 2 20min dissolution results of pioglitazone hydrochloride and metformin

[0173]

[0174] The data results in Table 2 show that the 20-min dissolution range of pioglitazone hydrochloride in Examples 1-10 is 87.14-96.18%, all above 85%, which is slightly different from the dissolution of metformin and similar to the original research effect; while the solubility range of pioglitazone hydrochloride in the comparative example is 79.93-82.59%, all below 85%, with a low solubility, which is inconsistent with the dissolution effect of the original research drug; in the embodiment of the present invention, the addition of a solubility regulator and ultrasound produces a synergistic effect, and due to the addition of a hydrophilic carrier in the solubility regulator, the system absorbs moisture. The pioglitazone hydrochloride solid dispersion is prepared, and the drug dispersion in the aqueous medium is effectively promoted to prepare pioglitazone hydrochloride with stronger solubility, reduce the dependence of the solubility of the pioglitazone hydrochloride raw material on pH, narrow the difference in water solubility with metformin, and avoid the problem that the compound tablets cannot work together due to different dissolution rates and absorption rates during medication. After the pioglitazone solid dispersion is prepared, a specific proportion of suspending agent, wetting agent, stabilizer, and solvent are added to form a uniform suspension system, and the drug is suspended to make the drug mixing more uniform, the tablets are more stable, and the dissolution rate is consistent with the original research. In comparative example 2, pioglitazone hydrochloride is directly added to water for suspension. Due to the solubility and component differences of pioglitazone hydrochloride and metformin, the resulting tablets are fragile and the dissolution rate is significantly reduced in the same time. In comparative example 1, the pioglitazone hydrochloride solid dispersion prepared by only using traditional stirring and heating has a larger particle size, and the further obtained tablet dissolution rate is poor, which cannot meet production needs.

[0175] In the present invention, the preparation of the pioglitazone hydrochloride solid dispersion-suspension system-drug application method and the above steps are coordinated as a whole, combined with the optimization of the preparation prescription and the control of the granulation process conditions to obtain a compound tablet with good compounding effect. The prepared compound tablet has high uniformity, realizes uniform dispersion and controlled release of the drug, and the dissolution effect reaches the same effect as the original drug.

[0176] 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;

[0177] 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.

[0178] 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 pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

2. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of HP-β-cyclodextrin was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency set to 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with a D90 of 8.12 μm. (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

3. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of lecithin was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency set to 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with a D90 of 9.93 μm. (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

4. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 30 g of hydrophilic chitosan was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min with a frequency set to 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying at a controlled freezing temperature of -50°C and a pressure of 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with a D90 of 10.58 μm. (2) Preparation of pioglitazone hydrochloride suspension: Weigh 1 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

5. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

6. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.5 g xanthan gum, 2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse it at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

7. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.6 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse it at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

8. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse it at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

9. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 0.5 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 70% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

10. A pioglitazone hydrochloride and metformin compound tablet, characterized in that: Prepared by the following preparation method: (1) Preparation of pioglitazone hydrochloride solid dispersion: 50 g of citric acid was dissolved in 100 g of pure water to form an aqueous solution, and 10 g of pioglitazone hydrochloride raw material was weighed and added to the above solution; the resulting mixed solution was ultrasonicated in an ultrasonic cleaner at 30°C for 15 min, with the frequency set at 100 Hz; after the ultrasonication, the precipitated solid was collected by filtration and then dried by freeze drying, controlling the freezing temperature to -50°C and the pressure to 0.2 mbar. After freeze drying for 10 hours, the solid powder was taken out to obtain a pioglitazone solid dispersion with D90 = 6.88 μm; (2) Preparation of pioglitazone hydrochloride suspension: Weigh 0.8 g xanthan gum, 1.2 g polysorbate 80, 2.5 g sodium benzoate, and 2.5 g potassium sorbate, sieve through an 80-mesh sieve, and pre-mix with the pioglitazone solid dispersion; prepare a 30% ethanol / water solution, take 300 g as the solvent, add the mixed solid powder to the solution, and disperse at 2500 r / min for 80 minutes to form a uniform pioglitazone hydrochloride suspension; (3) Preparation of metformin tablet core: According to the traditional tableting method, 500g of metformin hydrochloride, 150g of microcrystalline cellulose, and 30g of cross-linked carboxymethyl cellulose sodium were pre-mixed through an 80-mesh sieve for 15 minutes until uniform; 20g of hydropropyl methylcellulose was dissolved in water to prepare a 6% aqueous solution as a binder; metformin hydrochloride, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium were weighed according to the prescription and added to a wet mixing granulator, and the stirring speed was set to 200rpm and the cutting speed was set to 1000r. pm, mix for 5 minutes until uniform; then increase the speed to 300 rpm for stirring and 2000 rpm for cutting, slowly add the hydropropyl methylcellulose aqueous solution to form a soft material with moderate viscosity, and control the moisture content at 10%; the soft material is sieved through a 20-mesh sieve for granulation, and sent to a fluidized bed for drying, with the air inlet temperature set at 50°C, the material temperature ≤40°C, and the final moisture content ≤3%; then add magnesium stearate and mix for 5 minutes before sending to a rotary tablet press for tableting, with the pressure set at 30kN, and the tablet weight deviation within ±3%; (4) Preparation of pioglitazone hydrochloride and metformin compound tablets: Pioglitazone hydrochloride suspension was coated on the outside of metformin tablet core by suspension coating technology, and the suspension was evenly sprayed on the surface of metformin tablet core by bottom spray fluidized bed. The fan frequency was controlled at 1000 kW, the inlet air temperature was 40°C, and the material temperature was 30°C. The obtained metformin tablet core containing pioglitazone hydrochloride was coated with ethyl cellulose for sustained release, and the weight was increased by 3% to prepare pioglitazone-metformin compound tablets.

Images