Metformin hydrochloride and fenofibrate double-drug-loading particle and preparation method thereof

Abstract

The invention belongs to the technical field of drug crystallization, and provides metformin hydrochloride and fenofibrate double-drug-loading particles and a preparation method thereof.The preparation method comprises the following steps that polysaccharide, a solvent I and metformin hydrochloride are mixed and heated, and a homogeneous solution is obtained; mixing the homogeneous solution, fenofibrate and triglyceride to obtain a suspension; a cross-linking agent, a solvent II and the suspension are mixed and placed in a crystallizer to be subjected to a crystallization reaction, and a crystallization solution is obtained; and carrying out solid-liquid separation on the crystallization liquid, washing, and drying to obtain the double-drug-loading particles. The obtained particles are in a solid state and have good stability compared with a micelle drug loading system, meanwhile, the operation unit is simplified by adopting an in-situ crystallization means in the carrier, operation such as mixing, grinding and spray drying is not needed, needed equipment is simple, operation is easy and convenient, and good technical economy and high application value are achieved.

Description

Technical Field

[0001] This invention relates to the field of drug crystallization technology, and in particular to a metformin hydrochloride and fenofibrate dual-loaded drug particles and its preparation method. Background Technology

[0002] Metformin hydrochloride, also known as 1,1-dimethylbiguanide hydrochloride, etc. Molecular formula: C4H 12 ClN5, molecular weight: 165.625, structural formula: It is readily soluble in water, soluble in methanol, and slightly soluble in ethanol.

[0003] Fenofibrate, also known as isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropionic acid, etc. Molecular formula: C 20 H 21 ClO4, molecular weight: 360.83, structural formula: It is sparingly soluble in water, but soluble in ethanol, methanol, ethyl acetate, acetone, etc.

[0004] Metformin hydrochloride is a biguanide derivative with good water solubility and is a common treatment for type 2 diabetes. Fenofibrate is a broad-spectrum lipid-lowering drug with hydrophobic properties. Its combination with metformin hydrochloride is primarily used to treat glucose metabolism disorders and lipid disorders, especially in the treatment of type 2 diabetes. This combination therapy can effectively improve blood glucose levels and achieve better clinical efficacy compared to using metformin hydrochloride alone.

[0005] Given the above background, it is necessary to develop a drug delivery system that can simultaneously load both drugs to enhance patient compliance. However, the co-loading of hydrophilic and hydrophobic drugs remains a challenge. Furthermore, metformin hydrochloride and fenofibrate are absorbed at different sites; metformin hydrochloride is primarily absorbed in the stomach and upper small intestine, while fenofibrate is mainly absorbed through the intestines, further complicating effective loading. Spatiotemporal release is a controlled drug release method that controls the spatiotemporal sequence of release of two or more drugs in combination therapy, ensuring drug stability, selectively transporting drugs, and improving the efficacy of combination therapy.

[0006] Currently, the preparation of metformin hydrochloride combination formulations in patents typically requires multiple operational units. Patent publication number CN103735544A discloses a preparation process for a vidagliptin / metformin hydrochloride combination formulation, in which vidagliptin, metformin hydrochloride, magnesium aluminum silicate, and hydroxypropyl cellulose are added to an organic solution to form a dispersion, which is then spray-dried to obtain spherical powder containing the active substances. Patent publication number CN103494816A discloses a pharmaceutical composition for treating diabetes, in which repaglinide is micronized to 3-10 μm, then dissolved in an ethanol solution of ophiopogon japonicus, and coated onto the periphery of metformin tablets. Patent publication number CN103768062A discloses a method for preparing a compound preparation of repaglinide and metformin hydrochloride. Specifically, repaglinide is dissolved in ethanol, and an alkaline agent and a solubilizer are dissolved in water. These are then added to a mixture of metformin hydrochloride and other excipient powders, and finally compressed into tablets.

[0007] Analysis of the aforementioned patents reveals that co-loading metformin hydrochloride with other drugs typically involves mixing, grinding, and spray drying. Batch-to-batch discontinuities and high-energy inputs may lead to drug contamination or crystallization during preparation, while also failing to achieve the spatiotemporal release of different drugs. Compared to the aforementioned methods, in-situ crystallization of the active pharmaceutical ingredient within a carrier allows for the synergistic execution of the drug crystallization process and the preparation of the drug-loaded particles, thus achieving process integration. Therefore, there is an urgent need to develop an in-situ crystallization method for co-loading drugs, simplifying the operational process while achieving the spatiotemporal release of different drugs. Summary of the Invention

[0008] The purpose of this invention is to provide a dual-drug-loaded particle simultaneously loaded with metformin hydrochloride and fenofibrate, and a method for preparing the same. Both the hydrophilic drug metformin hydrochloride and the hydrophobic drug fenofibrate are crystallized in situ within a carrier matrix, simplifying the operational unit. Simultaneously, it enables spatiotemporal release of the components, with the majority of metformin hydrochloride released in the gastric fluid stage, while fenofibrate is released in the intestinal fluid stage.

[0009] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing metformin hydrochloride and fenofibrate dual-drug-loaded particles, comprising the following steps: (1) Mix the polysaccharide, solvent I and metformin hydrochloride and heat to obtain a homogeneous solution; (2) Mix the homogeneous solution, fenofibrate and triglycerides to obtain a suspension; (3) The crosslinking agent, solvent II and suspension are mixed and placed in a crystallizer to carry out a crystallization reaction to obtain a crystallized liquid; (4) The crystallization liquid is separated into solid and liquid and washed and dried to obtain the dual-loaded drug particles.

[0010] Preferably, the polysaccharide in step (1) is one or more of cellulose, chitosan and sodium alginate; In step (1), solvent I is one or more of formic acid, acetic acid, ionic liquid, water and glycerol, wherein the ionic liquid is a choline-based ionic liquid or a combination of the ionic liquid and an organic acid; the mass concentration of the ionic liquid is 20-40%.

[0011] Preferably, in step (1), the mass ratio of metformin hydrochloride to solvent I is 1:2~15; In step (1), the mass ratio of metformin hydrochloride to polysaccharide is 10~50:1.

[0012] Preferably, the heating temperature in step (1) is 50~80℃ and the heating time is 0.5~5h.

[0013] Preferably, the mass ratio of fenofibrate in step (2) to metformin hydrochloride in step (1) is 1:1~10; In step (2), the mass ratio of fenofibrate to triglycerides is 1:2~5.

[0014] Preferably, the crosslinking agent in step (3) is one or more of glutaraldehyde, genipin, calcium chloride, barium chloride, zinc chloride, montmorillonite nanosheets, AgNCs(NH4)9[Ag9(C7H4SO2)9] and sodium tripolyphosphate; In step (3), solvent II is one or more of isopropanol, ethanol, water, acetone, isopropyl acetate, ethyl acetate, and dimethylformamide.

[0015] Preferably, in step (3), the mass ratio of crosslinking agent to solvent II is 1:30~100, and the mass ratio of suspension to solvent II is 1:10~50.

[0016] Preferably, the temperature of the crystallization reaction in step (3) is 5~30℃, the time of the crystallization reaction is 30~60min, and the stirring rate of the crystallization reaction is 100~500rpm.

[0017] Preferably, the drying temperature in step (4) is 20~40℃ and the drying time is 4~10h.

[0018] The present invention also provides a method for preparing metformin hydrochloride and fenofibrate dual-drug-loaded particles.

[0019] The present invention has the following beneficial effects: 1. This invention discloses a method for preparing dual-loaded drug particles simultaneously loaded with hydrophilic and hydrophobic drugs. Metformin hydrochloride and fenofibrate are used as the active pharmaceutical ingredients, and biocompatible polysaccharides and triglycerides are used as dual carriers. By using in-situ crystallization in the dual carriers, dual-loaded drug particles with good sphericity, uniform particle size, high crystallinity, good stability, and spatiotemporal release into the gastrointestinal environment can be obtained. The in-situ crystallization method of this invention simplifies the operation unit, eliminating the need for mixing, grinding, and spray drying. The required equipment is simple, the operation is convenient, the process is stable, and the energy consumption is low, which has good technical and economic benefits and high application value. 2. The product prepared by this invention is in solid form and has good stability, uniform particle size, good sphericity, and can quickly filter intestinal fluid compared to micellar drug delivery systems. 3. The active pharmaceutical ingredients in the products prepared by this invention are all in stable crystal form; 4. The solvents selected in this invention are green and environmentally friendly; 5. The product prepared by this invention can achieve the release of different drugs in gastric and intestinal fluid environments respectively. Attached Figure Description

[0020] Figure 1 Microscopic image of the dual-drug-loaded particles prepared in Example 1 of this invention; Figure 2 The image shows the XRD pattern of the dual-drug-loaded particles prepared in Example 1 of this invention. Figure 3 The in vitro release curve of the dual-drug-loaded particles prepared in Example 1 of the present invention; Figure 4 This is a microscope image of the dual-drug-loaded particles prepared in Comparative Example 1 of the present invention. Figure 5 This is a microscope image of the dual-drug-loaded particles prepared in Comparative Example 2 of this invention. Detailed Implementation

[0021] This invention provides a method for preparing metformin hydrochloride and fenofibrate dual-drug-loaded particles, comprising the following steps: (1) Mix the polysaccharide, solvent I and metformin hydrochloride and heat to obtain a homogeneous solution; (2) Mix the homogeneous solution, fenofibrate and triglycerides to obtain a suspension; (3) The crosslinking agent, solvent II and suspension are mixed and placed in a crystallizer to carry out a crystallization reaction to obtain a crystallized liquid; (4) The crystallization liquid is separated into solid and liquid and washed and dried to obtain the dual-loaded drug particles.

[0022] In this invention, in step (1), the polysaccharide is first dissolved in solvent I and then mixed with metformin hydrochloride and heated. After stirring, a homogeneous solution is obtained.

[0023] In this invention, the polysaccharide in step (1) is preferably one or more of cellulose, chitosan and sodium alginate.

[0024] In this invention, solvent I in step (1) is preferably one or more of formic acid, acetic acid, ionic liquid, water and glycerol, wherein the ionic liquid is a choline-based ionic liquid or a combination of the ionic liquid and an organic acid; the mass concentration of the ionic liquid is preferably 20-40%.

[0025] In this invention, the mass ratio of metformin hydrochloride to solvent I in step (1) is preferably 1:2 to 15, more preferably 1:2 to 12, and even more preferably 1:2 to 10.

[0026] In this invention, the mass ratio of metformin hydrochloride to polysaccharide in step (1) is preferably 10~50:1, more preferably 15~45:1, and even more preferably 20~40:1.

[0027] In this invention, the heating temperature in step (1) is preferably 50~80℃, more preferably 55~75℃, and even more preferably 60~70℃.

[0028] In this invention, the heating time is preferably 0.5 to 5 hours, more preferably 0.7 to 4 hours, and even more preferably 1 to 3 hours.

[0029] In this invention, the mass ratio of fenofibrate in step (2) to metformin hydrochloride in step (1) is preferably 1:1 to 10, more preferably 1:1 to 5, and even more preferably 1:2 to 4.

[0030] In this invention, the mass ratio of fenofibrate to triglycerides in step (2) is preferably 1:2~5, more preferably 1:2.5~4, and even more preferably 1:2.5~3.

[0031] In this invention, in step (3), the crosslinking agent and solvent II are first mixed, and then the suspension is added to carry out the crystallization reaction.

[0032] In this invention, the crosslinking agent in step (3) is preferably one or more of glutaraldehyde, genipin, calcium chloride, barium chloride, zinc chloride, montmorillonite nanosheets, AgNCs(NH4)9[Ag9(C7H4SO2)9] and sodium tripolyphosphate.

[0033] In this invention, solvent II in step (3) is preferably one or more of isopropanol, ethanol, water, acetone, isopropyl acetate, ethyl acetate and dimethylformamide.

[0034] In this invention, the mass ratio of crosslinking agent to solvent II in step (3) is preferably 1:30~100, more preferably 1:40~90, and even more preferably 1:50~70; In this invention, the mass ratio of suspension to solvent II in step (3) is preferably 1:10~50, more preferably 1:15~45, and even more preferably 1:20~40.

[0035] In this invention, the temperature of the crystallization reaction in step (3) is preferably 5~30℃, more preferably 5~25℃, and even more preferably 5~20℃.

[0036] In this invention, the crystallization reaction time is preferably 30-60 min, more preferably 30-50 min, and even more preferably 30-40 min.

[0037] In this invention, the stirring rate of the crystallization reaction is preferably 100-500 rpm, more preferably 150-450 rpm, and even more preferably 200-400 rpm.

[0038] In this invention, the washing method in step (4) is to use a rinsing solution for rinsing.

[0039] In this invention, the rinsing solution is preferably solvent II.

[0040] In this invention, the rinsing temperature is preferably 5~20℃, more preferably 5~15℃, and even more preferably 5~10℃.

[0041] In this invention, the drying temperature in step (4) is preferably 20~40℃, more preferably 22~38℃, and even more preferably 25~35℃.

[0042] In this invention, the drying time is preferably 4 to 10 hours, more preferably 5 to 9 hours, and even more preferably 5 to 8 hours.

[0043] The present invention also provides a method for preparing metformin hydrochloride and fenofibrate dual-drug-loaded particles.

[0044] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention. Example 1

[0045] Metformin hydrochloride was added to water containing dissolved sodium alginate, heated to 60°C, and stirred for 1 hour to obtain a homogeneous solution. The mass ratio of metformin hydrochloride to water was 1:2, and the mass ratio of metformin hydrochloride to sodium alginate was 23:1. Fenofibrate and triglycerides were added to the above homogeneous solution. The mass ratio of fenofibrate to triglycerides was 1:2.5, and the mass ratio of fenofibrate to metformin hydrochloride was 1:5, resulting in a suspension for later use. The suspension was added to an ethanol solution containing calcium chloride (the mass ratio of calcium chloride to ethanol solution was 1:50) using a syringe, and then placed in a crystallizer for crystallization. The temperature in the crystallizer was adjusted to 5°C, the stirring speed was 300 rpm, and the suspension was allowed to stand for 30 minutes to obtain a crystallized solution with a mass ratio of suspension to ethanol solution of 1:20. The crystallized solution was then subjected to solid-liquid separation, washed with ethanol at 5°C, and vacuum dried at 30°C for 5 hours to obtain dual-loaded drug particles.

[0046] The final product obtained in this embodiment consists of white spherical particles, as shown in the microscope image. Figure 1 As shown, the X-ray powder diffraction pattern is as follows: Figure 2 As shown.

[0047] from Figure 1 and Figure 2 As can be seen from the data, the active pharmaceutical ingredients in the dual-drug-loaded particles of this embodiment are all in stable crystalline form, the particle size of the product is 1800 μm, the drug loading of metformin hydrochloride is 30.6%, and the drug loading of fenofibrate is 11.2%.

[0048] An in vitro release simulation test was conducted on the dual-drug-loaded particles of this embodiment, and the in vitro release curve is shown in the figure below. Figure 3 As shown.

[0049] from Figure 3 As can be seen from the results, in the in vitro simulated release experiment, over 80% of metformin hydrochloride was released in gastric fluid, while fenofibrate was released entirely in intestinal fluid. Example 2

[0050] Metformin hydrochloride was added to water containing dissolved sodium alginate, heated to 50°C, and stirred for 2 hours to obtain a homogeneous solution. The mass ratio of metformin hydrochloride to water was 1:5, and the mass ratio of metformin hydrochloride to sodium alginate was 10:1. Fenofibrate and triglycerides were added to the above homogeneous solution. The mass ratio of fenofibrate to triglycerides was 1:2.5, and the mass ratio of fenofibrate to metformin hydrochloride was 1:5, resulting in a suspension for later use. The suspension was added to an ethanol solution containing calcium chloride (the mass ratio of calcium chloride to ethanol solution was 1:50) using a syringe, and then placed in a crystallizer for crystallization. The temperature in the crystallizer was adjusted to 5°C, the stirring speed was 500 rpm, and the suspension was allowed to stand for 30 minutes to obtain a crystallized solution with a mass ratio of suspension to ethanol solution of 1:20. The crystallized solution was then subjected to solid-liquid separation, washed with ethanol at 5°C, and vacuum dried at 30°C for 5 hours to obtain dual-loaded drug particles.

[0051] The dual-drug-loaded particles in this embodiment are white spherical particles with a particle size of 1000 μm. The drug loading of metformin hydrochloride is 3.3%, and the drug loading of fenofibrate is 19.6%. Example 3

[0052] Metformin hydrochloride was added to water containing dissolved sodium alginate, heated to 65°C, and stirred for 0.5 h to obtain a homogeneous solution. The mass ratio of metformin hydrochloride to water was 1:3, and the mass ratio of metformin hydrochloride to sodium alginate was 17:1. Fenofibrate and triglycerides were added to the above homogeneous solution. The mass ratio of fenofibrate to triglycerides was 1:2.5, and the mass ratio of fenofibrate to metformin hydrochloride was 1:5, resulting in a suspension for later use. The suspension was added to an ethanol solution containing calcium chloride (the mass ratio of calcium chloride to ethanol solution was 1:40) using a syringe, and then placed in a crystallizer for crystallization. The temperature in the crystallizer was adjusted to 5°C, the stirring speed was 200 rpm, and the suspension was allowed to stand for 50 min to obtain a crystallized solution with a mass ratio of suspension to ethanol solution of 1:10. The crystallized solution was then subjected to solid-liquid separation, washed with ethanol at 5°C, and vacuum dried at 30°C for 5 h to obtain dual-loaded drug particles.

[0053] The dual-drug-loaded particles in this embodiment are white spherical particles. The active pharmaceutical ingredients are all in stable crystalline form. The product particle size is 1400 μm, the metformin hydrochloride loading is 19.6%, and the fenofibrate loading is 13.4%. Comparative Example 1

[0054] Metformin hydrochloride was added to water containing dissolved sodium alginate, heated to 60°C, and stirred for 1 hour to obtain a homogeneous solution. The mass ratio of metformin hydrochloride to water was 1:3.5, and the mass ratio of metformin hydrochloride to sodium alginate was 14:1. Fenofibrate and triglycerides were added to the above homogeneous solution. The mass ratio of fenofibrate to triglycerides was 1:2.5, and the mass ratio of fenofibrate to metformin hydrochloride was 1:5, resulting in a suspension for later use. The suspension was added to a methanol solution containing calcium chloride (the mass ratio of calcium chloride to methanol solution was 1:50) using a syringe, and then placed in a crystallizer for crystallization. The temperature in the crystallizer was adjusted to 5°C, the stirring rate was 300 rpm, and the suspension was allowed to stand for 30 minutes to obtain a crystallized solution with a mass ratio of suspension to methanol solution of 1:20. The crystallized solution was then subjected to solid-liquid separation, washed with methanol at 5°C, and vacuum dried at 30°C for 5 hours to obtain dual-loaded drug particles.

[0055] Figure 4 This is a microscope image of the comparative product, from... Figure 4 As can be seen from the comparison, the dual-drug-loaded particle product in this study has poor sphericity and is irregular in shape. Comparative Example 2

[0056] Metformin hydrochloride was added to water containing dissolved sodium alginate, heated to 85°C, and stirred for 1 hour to obtain a homogeneous solution. The mass ratio of metformin hydrochloride to water was 1:5, and the mass ratio of metformin hydrochloride to sodium alginate was 10:1. Fenofibrate and triglycerides were added to the above homogeneous solution. The mass ratio of fenofibrate to triglycerides was 1:2.5, and the mass ratio of fenofibrate to metformin hydrochloride was 1:5, resulting in a suspension for later use. The suspension was added to a methanol solution containing calcium chloride (with a mass ratio of calcium chloride to methanol of 1:50) using a syringe, and then placed in a crystallizer for crystallization. The temperature in the crystallizer was adjusted to 5°C, the stirring rate was 300 rpm, and the suspension was allowed to stand for 50 min to obtain a crystallized solution with a mass ratio of suspension to methanol of 1:20. The crystallized solution was then subjected to solid-liquid separation, washed with methanol at 5°C, and vacuum dried at 30°C for 5 h to obtain dual-loaded drug particles.

[0057] Figure 5 This is a microscope image of the comparative product, from... Figure 5 As can be seen from the comparison, the dual-drug-loaded particle product in this study has poor sphericity and is irregular in shape.

[0058] As can be seen from the above embodiments, the present invention provides a method for preparing metformin hydrochloride and fenofibrate dual-drug-loaded particles, comprising the following steps: mixing polysaccharide, solvent I and metformin hydrochloride and heating to obtain a homogeneous solution; mixing the homogeneous solution, fenofibrate and triglycerides to obtain a suspension; mixing a crosslinking agent, solvent II and the suspension and placing them in a crystallizer for crystallization reaction to obtain a crystalline liquid; performing solid-liquid separation and washing of the crystalline liquid, and drying to obtain the dual-drug-loaded particles. This invention discloses a method for preparing dual-loaded drug particles simultaneously loaded with hydrophilic and hydrophobic drugs. Metformin hydrochloride and fenofibrate are used as the active pharmaceutical ingredients, and biocompatible polysaccharides and triglycerides are used as dual carriers. By employing in-situ crystallization within the dual carriers, dual-loaded drug particles with good sphericity, uniform particle size, high crystallinity, and good stability can be obtained, enabling spatiotemporal release into the gastrointestinal environment. The in-situ crystallization method of this invention simplifies the operation unit, eliminating the need for mixing, grinding, and spray drying. The required equipment is simple, the operation is convenient, the process is stable, and energy consumption is low, resulting in good technical and economic benefits and high application value. The product prepared by this invention is in solid form, exhibiting better stability, uniform particle size, and good sphericity compared to micellar drug-loaded systems, and can rapidly filter intestinal fluid. The solvent selected in this invention is environmentally friendly, and the active pharmaceutical ingredients in the prepared product are all in stable crystalline forms, enabling the release of different drugs into gastric and intestinal fluid environments respectively.

[0059] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing metformin hydrochloride and fenofibrate dual-loaded drug particles, characterized in that, Includes the following steps: (1) Mix the polysaccharide, solvent I and metformin hydrochloride and heat to obtain a homogeneous solution; (2) Mix the homogeneous solution, fenofibrate and triglycerides to obtain a suspension; (3) The crosslinking agent, solvent II and suspension are mixed and placed in a crystallizer to carry out a crystallization reaction to obtain a crystallized liquid; (4) The crystallization liquid is separated into solid and liquid and washed and dried to obtain the dual-loaded drug particles.

2. The preparation method according to claim 1, characterized in that, In step (1), the polysaccharide is one or more of cellulose, chitosan and sodium alginate; In step (1), solvent I is one or more of formic acid, acetic acid, ionic liquid, water and glycerol, wherein the ionic liquid is a choline-based ionic liquid or a combination of the ionic liquid and an organic acid; the mass concentration of the ionic liquid is 20-40%.

3. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of metformin hydrochloride to solvent I is 1:2~15; In step (1), the mass ratio of metformin hydrochloride to polysaccharide is 10~50:

1.

4. The preparation method according to claim 1, characterized in that, The heating temperature in step (1) is 50~80℃, and the heating time is 0.5~5h.

5. The preparation method according to claim 1, characterized in that, The mass ratio of fenofibrate in step (2) to metformin hydrochloride in step (1) is 1:1~10; In step (2), the mass ratio of fenofibrate to triglycerides is 1:2~5.

6. The preparation method according to claim 1, characterized in that, In step (3), the crosslinking agent is one or more of glutaraldehyde, genipin, calcium chloride, barium chloride, zinc chloride, montmorillonite nanosheets, AgNCs(NH4)9[Ag9(C7H4SO2)9] and sodium tripolyphosphate; In step (3), solvent II is one or more of isopropanol, ethanol, water, acetone, isopropyl acetate, ethyl acetate, and dimethylformamide.

7. The preparation method according to claim 1, characterized in that, In step (3), the mass ratio of crosslinking agent to solvent II is 1:30~100, and the mass ratio of suspension to solvent II is 1:10~50.

8. The preparation method according to claim 1, characterized in that, In step (3), the temperature of the crystallization reaction is 5~30℃, the time of the crystallization reaction is 30~60min, and the stirring rate of the crystallization reaction is 100~500rpm.

9. The preparation method according to claim 1, characterized in that, The drying temperature in step (4) is 20~40℃ and the drying time is 4~10h.

10. Metformin hydrochloride and fenofibrate dual-loaded drug particles prepared by the method described in claims 1-9.

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