Piperine solid dispersion, its preparation method and application

Abstract

This invention discloses a piperine solid dispersion, relating to the field of pharmaceutical technology. The solid dispersion comprises piperine and a low-molecular-weight organic acid carrier, or piperine and an inorganic mesoporous particle carrier; wherein the mass ratio of piperine to the carrier is 1:(0.5-9), and the drug loading is 10%-67%. In this invention, the drug is dispersed in an amorphous form within the carrier material and forms hydrogen bonds with the carrier, breaking the crystal structure of piperine, lowering the energy barrier required for drug dissolution, significantly increasing the solubility and dissolution rate of piperine, maintaining the supersaturation of the formulation, and enhancing the stability of the amorphous formulation. Furthermore, the preparation process uses safe, non-toxic, and volatile anhydrous ethanol as a solvent, eliminating the safety hazards associated with solvent residue.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to a piperine solid dispersion, its preparation method, and its application. Background Technology

[0002] Piperine was first isolated from pepper extract by Hans Christian Stede in 1819. It is the most abundant cinnamic alkaloid in pepper. Piperine is a yellow crystalline compound with a melting point of 128–130 °C, soluble in acetic acid, benzene, ethanol, and chloroform, and slightly soluble in ether. Its structure is piperoylpiperidine, as shown in

[0003] , with the chemical formula C17H19NO3, and the IUPAC name 1-(5-[1,3-benzodioxo5-yl]-1-oxo-2,4-pentadienyl)piperidine. Piperine is a weak base that not only imparts a spicy taste to food and stimulates appetite, but also possesses a wide range of biological activities, such as sedation, hypnosis, anticonvulsant, antidepressant, antioxidant, and antitumor effects. However, piperine's immunotoxicity, poor water solubility, and high first-pass metabolism limit its clinical application.

[0003]

[0004] Currently, researchers have adopted various methods to improve the poor solubility of piperine. For example, invention patent CN103784421 B discloses and authorizes "Solid lipid nanoparticles loaded with curcumin and piperine and their preparation method." This technology utilizes materials such as curcumin, piperine, solid lipid materials, liquid oil phase, emulsifier, and water to prepare solid lipid nanoparticles loaded with curcumin and piperine through thin-film dispersion, microemulsion, or emulsion evaporation-low-temperature curing methods. Although this technology improves the solubility of curcumin and piperine drugs, increases the stability and in vitro release of drugs in nanoparticles, solid lipid nanoparticles generally have low drug loading, increasing the volume of the final formulation, and their ability to reach supersaturation is weaker than that of solid dispersions.

[0005] The development of drug solid dispersions depends on the application and development of carrier materials. Currently, commonly used carrier materials are mostly polymers, such as poloxamer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate. However, because polymers are inherently hygroscopic, solid dispersions prepared from polymers tend to absorb moisture, increasing recrystallization. Furthermore, drugs have limited solubility in polymers, requiring large amounts of polymer to maintain the stability of amorphous drugs.

[0006] Therefore, how to improve the solubility or drug loading of drug solid dispersions is a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0007] In view of this, the present invention provides a piperine solid dispersion, its preparation method and application. The piperine solid dispersion prepared by this method significantly improves the solubility and dissolution rate of the poorly soluble drug piperine, thereby improving its bioavailability. Moreover, the preparation process is simple and easy to promote.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A piperine solid dispersion comprising piperine and a low molecular weight organic acid carrier or piperine and an inorganic mesoporous particle carrier.

[0010] Furthermore, the mass ratio of piperine to the carrier is 1:(0.5-9), and the drug loading is 10% to 67%.

[0011] Preferably, the solid dispersion improves drug dissolution and maintains stable supersaturation within 120 min;

[0012] The piperine organic acid solid dispersion exhibits a dissolution rate 10%–74% higher than that of the active pharmaceutical ingredient in a pH 1.2 medium; and a dissolution rate exceeding 80% within 5 minutes in a pH 6.8 medium, representing a 35%–254% increase compared to the active pharmaceutical ingredient.

[0013] The dissolution rate of the piperine inorganic mesoporous particle solid dispersion is 75% to 165% higher than that of the active pharmaceutical ingredient in a medium with a pH of 1.2, and 40% to 245% higher than that of the active pharmaceutical ingredient in a medium with a pH of 6.8.

[0014] More preferably, the low molecular weight organic acid carrier is selected from one or more of citric acid, tartaric acid, oxalic acid, glycyrrhizic acid, isobutylphenylpropionic acid, and benzoic acid, and more preferably glycyrrhizic acid;

[0015] The inorganic mesoporous particle carrier is selected from one or more of ordered mesoporous silica and disordered mesoporous silica, and more preferably disordered mesoporous silica 244FP.

[0016] Preferably, in a medium of pH 1.2, the dissolution of piperine is inhibited due to the limited dissociation of the carboxylic acid group in glycyrrhizic acid; while in a medium of pH 6.8, the dissolution of glycyrrhizic acid leads to the rapid release of piperine. The glycyrrhizic acid can inhibit drug recrystallization, reduce crystal nucleation and growth rates, increase the activation energy required for desolvation during crystal nucleation and growth, and delay the precipitation of supersaturated solutions.

[0017] Preferably, the solid dispersion prepared from piperine and mesoporous silica, in media with pH 1.2 and pH 6.8, causes the drug molecules to amorphize due to the interaction of water-soluble groups (silanol groups) modified on the surface of the mesoporous particles with the drug to form hydrogen bonds, and the drug adsorbed on the surface is rapidly released; subsequently, the drug encapsulated in its adjustable nanoscale pore size (2-50 nm) is released into the medium with the solvent diffusion, and the dissolution rate continues to increase and maintains supersaturation for more than 120 min.

[0018] Preferably, the precipitates collected after dissolving the solid dispersion in a pH 1.2 medium for 30 min and 120 min contain amorphous drug molecules, and the carrier material can increase the drug activation energy and slow down and inhibit drug recrystallization, maintaining supersaturation for a long time.

[0019] Preferably, the piperine solid dispersion, due to its amorphous state, has a smaller particle size, no lattice structure, and is in a thermodynamic high-energy state. The energy barrier required for dissolution is reduced to supersaturation. The increase and maintenance of supersaturation can enhance the solubility of the drug, thereby increasing bioavailability and improving the oral absorption of poorly soluble drugs.

[0020] Preferably, the piperine solid dispersion is verified by molecular docking and molecular dynamics simulation to have hydrogen bonding forces between piperine and the carboxylic acid groups of organic acids and the silanol groups on the surface of mesoporous particles. These forces have high spatial binding energy, which hinders drug molecule migration, delays drug molecule nucleation and crystallization, and improves its kinetic stability.

[0021] 11. Another object of the present invention is to provide a method for preparing the above-mentioned piperine solid dispersion, which uses a solvent method to dissolve or disperse piperine in an organic solvent with glycyrrhizic acid or inorganic disordered mesoporous silica to prepare the solid dispersion. The specific steps include:

[0022] (1) The glycyrrhizic acid carrier and the active pharmaceutical ingredient are dissolved or dispersed in organic solvents such as ethanol, methanol, acetone, and ethyl acetate at a mass ratio of 1:(0.5-9), sonicated for 0.5-1 h, and vacuum dried at 40°C until the solvent is completely evaporated to obtain a dry, light yellow piperine-glycyrrhizic acid solid dispersion.

[0023] (2) The inorganic disordered mesoporous silica 244FP carrier and the active pharmaceutical ingredient are dissolved or dispersed in organic solvents such as ethanol, methanol, acetone, and ethyl acetate at a mass ratio of 1:(0.5-9). The suspension is obtained by ultrasonication in a water bath, and then magnetically stirred at 25-55°C for 1-5 hours. The organic solvent is removed by rotary evaporation at 30-60°C. The resulting white solid is vacuum dried for 24 hours to obtain a piperine-mesoporous silica solid dispersion.

[0024] Furthermore, the organic solvent is preferably anhydrous ethanol.

[0025] Another object of the present invention is to provide the application of the above-mentioned piperine solid dispersion as a pharmaceutical intermediate in the pharmaceutical field, which can be further formulated into tablets, pills, capsules or other oral solid dosage forms.

[0026] As can be seen from the above technical solution, compared with the prior art, this invention discloses a piperine solid dispersion, its preparation method, and its application. The piperine solid dispersion of this invention has a reduced particle size and exists in an amorphous state. Amorphous solid dispersion technology can transform drugs from a crystalline to an amorphous state, improving thermodynamic activity and significantly improving the solubility and dissolution rate of poorly soluble drugs. It has the following advantages:

[0027] 1. The piperine-glycyrrhizic acid solid dispersion prepared by the solvent method of the present invention has a dissolution rate that is 10% to 74% higher than that of the active pharmaceutical ingredient in a pH 1.2 hydrochloric acid solution within 120 min; and a dissolution rate that is higher than 80% within 5 min and higher than 85% within 30 min in a pH 6.8 phosphate buffer solution, and can maintain a supersaturated state for 120 min, with a dissolution rate that is 35% to 254% higher than that of the active pharmaceutical ingredient.

[0028] Piperine-mesoporous silica solid dispersion exhibits a two-step release curve in the dissolution medium, first from the outer surface and then from within the pore structure. The dissolution rate is above 65% within 120 min, showing a continuous upward trend. The dissolution rate is 75%–165% higher than that of the active pharmaceutical ingredient in pH 1.2 medium and 40%–245% higher than that of the active pharmaceutical ingredient in pH 6.8 medium.

[0029] 2. The piperine solid dispersion of the present invention uses a smaller amount of low molecular weight carrier compared to polymer carrier, resulting in stronger compatibility and interaction with the drug. Glycyrrhizic acid, containing three weak acid groups, exhibits different solubility in different media, leading to varying drug release behaviors and mechanisms; it can also act as a surfactant to inhibit drug nucleation and crystallization, thereby improving the stability of amorphous formulations. Mesoporous silica, with its surface containing silanol groups, can form hydrogen bonds with the drug; its tunable nanoscale pores encapsulate the drug in an amorphous form, improving drug dissolution and formulation stability.

[0030] The dissolution precipitation of the piperine solid dispersion in a pH 1.2 medium at 30 min and 120 min revealed the presence of amorphous piperine drug molecules. The conversion between different solid forms of a drug can affect its bioavailability, and amorphous drug molecules are more conducive to prolonging the supersaturation state and increasing the degree of absorption in vivo.

[0031] 3. Computer simulations have verified that the piperine solid dispersion of this invention exhibits hydrogen bonding between the carboxylic acid groups of piperine and glycyrrhizic acid and the silanol groups on the surface of mesoporous silica. This bonding has a high spatial binding energy, which hinders drug molecule migration, delays drug molecule nucleation and crystallization, and improves the stability of amorphous formulations.

[0032] 4. The piperine solid dispersion prepared by the solvent method in this invention was determined by SEM, DSC, PXRD, FTIR and 1H NMR to be dispersed in the carrier material in an amorphous state with reduced particle size. It has no lattice structure and therefore no lattice energy. The energy barrier that the drug molecule needs to cross is low, which significantly increases the dissolution rate of the drug.

[0033] 5. The method for preparing piperine solid dispersion of the present invention adopts a solvent method, which is simple and easy to promote. Anhydrous ethanol is used as the solvent, which is green and environmentally friendly, and the problem of solvent residue can be ignored. Moreover, after soaking in the solvent, piperine-mesoporous silica is rotary evaporated, which can avoid filtration, thereby reducing the risk of drug crystallization on the carrier surface, fixing the amount of drug loaded, and providing industrial scalability for loading drugs into porous materials. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0035] Figure 1 The images shown are scanning electron microscope (SEM) images of the piperine solid dispersion of the present invention (A is piperine; B is glycyrrhizic acid; C is mesoporous silica; D is piperine-glycyrrhizic acid solid dispersion; E is piperine-mesoporous silica solid dispersion; F and G are the precipitates observed after dissolving the piperine-glycyrrhizic acid solid dispersion in a pH 1.2 medium for 30 min and 120 min, respectively; H and I are the precipitates observed after dissolving the piperine-mesoporous silica solid dispersion in a pH 1.2 medium for 30 min and 120 min, respectively).

[0036] Figure 2 The images show (A) a powder-X-ray diffraction pattern and (B) a crystallinity bar chart of the piperine solid dispersion of the present invention.

[0037] Figure 3 This is a differential scanning calorimetry (DSC) image of the piperine solid dispersion of the present invention.

[0038] Figure 4The Fourier transform infrared spectra of the piperine solid dispersion of the present invention are shown below (A is the raw material, physical mixture, solid dispersion and dissolution precipitation diagram of piperine-glycyrrhizic acid; B is the raw material, physical mixture, solid dispersion and dissolution precipitation diagram of piperine-mesoporous silica).

[0039] Figure 5 The images show (a) a one-dimensional proton NMR spectrum of the piperine solid dispersion of the present invention and (b) and (c) magnified views of the region within the dashed box on the left.

[0040] Figure 6 The dissolution diagrams for the piperine solid dispersion of the present invention are shown below [wherein, (A and B) are dissolution diagrams of piperine-glycyrrhizic acid solid dispersion with different drug loading ratios in media of pH 1.2 and pH 6.8, respectively; (C and D) are dissolution diagrams of piperine-disordered mesoporous silica solid dispersion with different drug loading ratios in media of pH 1.2 and pH 6.8, respectively; (E and F) are dissolution diagrams of piperine solid dispersion with a drug loading ratio of 1:6 in media of pH 1.2 and pH 6.8, respectively].

[0041] Figure 7 Computer simulations of the drug and different carriers (where A represents the molecular docking conformation of piperine and glycyrrhizic acid; B represents the molecular docking conformation of piperine and mesoporous silica; C represents the molecular dynamics simulation of piperine and glycyrrhizic acid; and D represents the molecular dynamics simulation of piperine and mesoporous silica).

[0042] In the above figures, the ratio of piperine to the carrier is 1:6. Detailed Implementation

[0043] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0044] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0045] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0046] Example 1

[0047] Preparation of piperine-glycyrrhizic acid solid dispersion by solvent method (SEM image attached) Figure 1 )

[0048] The raw material usage is shown in Table 1.

[0049] Table 1

[0050]

[0051] Preparation method:

[0052] Weigh piperine and glycyrrhizic acid according to the mass ratio in Table 1 and place them in a beaker. Add an appropriate amount of anhydrous ethanol, sonicate for 1 hour until completely dissolved, and vacuum dry at 40°C under light-protected conditions until the solvent evaporates completely. Grind the mixture in a mortar until it becomes a fine powder to obtain a pale yellow piperine-glycyrrhizic acid solid dispersion with a drug loading of 10%-67%.

[0053] Example 2

[0054] Preparation of piperine-mesoporous silica solid dispersion by solvent method

[0055] The raw material usage is shown in Table 2.

[0056] Table 2

[0057]

[0058] Preparation method:

[0059] Weigh piperine and mesoporous silica carrier according to the mass ratio in Table 2 and place them in a beaker. Add an appropriate amount of anhydrous ethanol, sonicate in a water bath for 1 hour until uniformly dispersed, stir magnetically at 50°C for 1 hour, remove the solvent by rotary evaporation at 50°C, vacuum dry at 60°C for 24 hours, grind in a mortar and pass through an 80-mesh sieve to obtain a white piperine-mesoporous silica solid dispersion with a drug loading of 10%-67%.

[0060] Example 3

[0061] Computer simulations verify intermolecular interaction forces

[0062] Molecular docking using Schrodinger Suite 2018-1 software can predict the optimal binding sites and conformations of drugs and carriers, and verify the existence of intermolecular interactions. Optimized drug molecule structures were obtained through LigPrep processing. The binding sites of carrier molecules were determined using "protein preparation guidance" and "binding site detection," and the optimized drug was docked with the carrier on the molecule, with the docking bond distances marked.

[0063] Furthermore, Materials Studio 2017 software was used to calculate the binding energy of the drug carrier. A solid dispersion system was constructed based on the amorphous cell module, and then the structure was optimized at 298 K using the Forcite module with a time step of 1 fs, ultimately obtaining an equilibrium structure. Finally, the binding energy between the drug and the carrier was calculated using the mixture module. Molecular docking and molecular dynamics simulation conformation diagrams are attached. Figure 7 As shown. Piperine is defined as Base, and the low molecular weight carrier is defined as Screen. The binding energy between the drug and the carrier is calculated using the following formula:

[0064] E bs =E total -E bb -E ss

[0065] E bs E represents the binding energy between the drug and the carrier. bb E represents the binding energy of the drug dimer. ss E represents the binding energy between carriers. total It represents the total energy of the system.

[0066] The binding energies of piperine with different carriers are shown in Table 3.

[0067] Table 3

[0068]

[0069] As can be seen from the binding energies generated by molecular docking in Table 3, both low molecular weight carriers and piperine drugs have high spatial binding energies.

[0070] Example 4

[0071] Mechanism of piperine solid dispersion

[0072] 1. Scanning electron micrograph of piperine solid dispersion

[0073] 1.1 Experimental Groups: Piperine raw material, glycyrrhizic acid, disordered mesoporous silica, piperine-glycyrrhizic acid solid dispersion (1:6), piperine-disordered mesoporous silica solid dispersion (1:6)

[0074] 1.2 Results Analysis

[0075] Piperine is an aggregate with different particle sizes and smooth surfaces (see appendix). Figure 1 A); Glycyrrhizic acid spherical particles have a smooth surface (attached). Figure 1 B). Disordered mesoporous silica is subspherical, loose, and irregular in shape, exhibiting good dispersibility (see appendix). Figure 1C). In contrast, no piperine crystals were observed in the piperine-glycyrrhizic acid solid dispersion (see appendix). Figure 1 D) The reduced particle size indicates that piperine is dispersed in the support in an amorphous or molecular state, and that piperine is well encapsulated or adsorbed by disordered mesoporous silica (see appendix). Figure 1 E).

[0076] 2. Powder X-ray diffraction and differential scanning calorimetry of piperine solid dispersions (Piperine, PIP; glycyrrhizic acid, GA; mesoporous silica, MSN; PIP-GA-ASD is an amorphous solid dispersion of piperine and glycyrrhizic acid; PIP-MSN-ASD is an amorphous solid dispersion of piperine and mesoporous silica; PIP-GA-PM is a physical mixture of piperine and glycyrrhizic acid; PIP-MSN-PM is a physical mixture of piperine and mesoporous silica).

[0077] 2.1 Experimental Groups: Piperine raw material, glycyrrhizic acid, disordered mesoporous silica, piperine-glycyrrhizic acid solid dispersion (1:6), piperine-disordered mesoporous silica solid dispersion (1:6), piperine-glycyrrhizic acid physical mixture (1:6), piperine-disordered mesoporous silica physical mixture (1:6).

[0078] The crystallinity of PXRD diffraction peaks was analyzed using Origin 2019 software, which is an indicator of the material's crystallinity.

[0079] 2.2 Results Analysis

[0080] Crystallinity=Ic / (Ic+Ia) (1)

[0081] Appendix Figure 2 In A, the characteristic peaks of the piperine solid dispersion almost disappear compared to the piperine raw material and physical mixture, indicating that piperine exists amorphously in both carriers. Furthermore, the crystallinity histogram also illustrates this phenomenon (Equation 1 and Appendix). Figure 2 B). Differential scanning calorimetry (with appendix) Figure 3 In the piperine solid dispersion, the melting peak of piperine disappeared and a wider peak band was observed, further indicating that piperine in the formulation exists in an amorphous form in the carrier.

[0082] 3. Infrared spectrum, one-dimensional 1H NMR spectrum, and schematic diagram of interactions between components of the piperine solid dispersion (1:6) (Piperine, PIP; glycyrrhizic acid, GA; mesoporous silica, MSN). Results are attached. Figure 4 and attached Figure 5 .

[0083] The results show that the carboxyl groups of glycyrrhizic acid and the surface silanol groups of mesoporous silica form hydrogen bonds with piperine drug molecules, breaking the original crystal lattice structure of piperine, reducing the energy barrier that drug dissolution can overcome, improving drug dissolution, increasing the stability of amorphous formulations, and helping to maintain the supersaturated state of amorphous formulations.

[0084] Example 5

[0085] Comparison of in vitro dissolution rates of piperine raw material and piperine solid dispersion

[0086] Methods: Dissolution and release determination method (Method II) of Part IV of the 2020 edition of the Chinese Pharmacopoeia was used, with 900 mL of pH 1.2 hydrochloric acid solution and pH 6.8 phosphate buffer as the dissolution medium. 900 mL of degassed dissolution medium was added to each dissolution vessel. A paddle method was used at 50 rpm and a temperature of (37±0.5)℃. A solid dispersion equivalent to 10 mg of piperine raw material was added to each dissolution vessel. 10 mL samples were taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, and 10 mL of isothermal fresh medium was added simultaneously. The solution was filtered through a 0.45 μm aqueous filter membrane, and the filtrate was used as the test solution. The absorbance was measured at 343 nm using a UV spectrophotometer. Simultaneously, the solid-state characteristics of the precipitate after dissolution in pH 1.2 medium for 30 min and 120 min were determined.

[0087] From the appendix Figure 6 As shown in E and 6F, the dissolution rate of piperine-glycyrrhizic acid solid dispersion in hydrochloric acid solution at pH 1.2 was 10%–74% higher than that of the active pharmaceutical ingredient within 120 min; in phosphate buffer solution at pH 6.8, the dissolution rate was higher than 80% within 5 min and higher than 85% within 30 min, and it could maintain a supersaturated state for 120 min, with a dissolution rate 35%–254% higher than that of the active pharmaceutical ingredient.

[0088] Piperine-mesoporous silica solid dispersion exhibits a two-step release curve in the dissolution medium, first from the outer surface and then from within the pore structure. The dissolution rate is above 65% within 120 min, showing a continuous upward trend. The dissolution rate is 75%–165% higher than that of the active pharmaceutical ingredient in pH 1.2 medium and 40%–245% higher than that of the active pharmaceutical ingredient in pH 6.8 medium.

[0089] Example 6

[0090] Determination of leached precipitate content and solid-state characterization

[0091] Methods: The precipitates obtained by dissolving piperine solid dispersion in pH 1.2 medium for 30 min and 120 min were dried, dissolved in methanol, and their drug content was determined. The solid phase characteristics were also characterized.

[0092] The results of the piperine drug content determination at 120 min are shown in Table 4.

[0093] Table 4

[0094]

[0095] The content determination results of the precipitate showed that it contained piperine, indicating that piperine was not completely dissolved within 2 hours of the determination.

[0096] Scanning electron micrograph of the precipitate of piperine solid dispersion (see attached image) Figure 1 FI) found that piperine was still in an amorphous form, and the infrared spectrum (attached) Figure 4 This also indicates that the precipitate exhibits similar curve characteristics to the piperine solid dispersion. It is speculated that piperine can be further released over a longer dissolution measurement time, thus increasing the dissolution rate.

[0097] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0098] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A piperine solid dispersion, characterized in that, The solid dispersion comprises piperine and a low molecular weight organic acid carrier or piperine and an inorganic mesoporous particle carrier. Furthermore, the mass ratio of piperine to the carrier is 1:(0.5-9), and the drug loading is 10%~67%. The low molecular weight organic acid carrier is glycyrrhizic acid; the inorganic mesoporous particle carrier is disordered mesoporous silica 244FP.

2. The piperine solid dispersion according to claim 1, characterized in that, The solid dispersion improved drug dissolution and maintained stable supersaturation for 120 min; The piperine organic acid solid dispersion exhibits a dissolution rate 10%–74% higher than that of the active pharmaceutical ingredient in a pH 1.2 medium; and a dissolution rate exceeding 80% within 5 minutes in a pH 6.8 medium, representing an improvement of 35%–254% compared to the active pharmaceutical ingredient. The dissolution rate of the piperine inorganic mesoporous particle solid dispersion is 75% to 165% higher than that of the active pharmaceutical ingredient in a medium with a pH of 1.2, and 40% to 245% higher than that of the active pharmaceutical ingredient in a medium with a pH of 6.

8.

3. The piperine solid dispersion according to claim 1, characterized in that, The solid dispersion prepared from piperine and glycyrrhizic acid exhibits inhibited piperine dissolution in a pH 1.2 medium due to the limited dissociation of the carboxylic acid group in glycyrrhizic acid. However, in a pH 6.8 medium, the dissolution of glycyrrhizic acid leads to the rapid release of piperine. The glycyrrhizic acid can inhibit drug recrystallization, reduce crystal nucleation and growth rates, increase the activation energy required for desolvation during crystal nucleation and growth, and delay the precipitation of supersaturated solutions.

4. The piperine solid dispersion according to claim 1, characterized in that, The solid dispersion prepared from piperine and mesoporous silica, in media with pH 1.2 and pH 6.8, undergoes hydrogen bonding with the drug due to the interaction of water-soluble groups modified on the surface of the mesoporous particles, leading to amorphization of the drug molecules and rapid release of the drug adsorbed on the surface. Subsequently, the drug encapsulated in the adjustable nanoscale pores diffuses and is released into the medium with the solvent, and the dissolution rate continues to increase and maintains supersaturation for more than 120 minutes. The nanoscale pore size is 2-50 nm.

5. The piperine solid dispersion according to claim 1, characterized in that, The precipitates collected after dissolving the solid dispersion in a pH 1.2 medium for 30 min and 120 min contain amorphous drug molecules, and the carrier material can increase the drug activation energy and slow down and inhibit drug recrystallization, maintaining supersaturation for a long time.

6. The piperine solid dispersion according to claim 1, characterized in that, The piperine solid dispersion, due to its amorphous state, has a smaller particle size and no lattice structure, and is in a high thermodynamic energy state. The energy barrier required for dissolution is reduced to supersaturation. The increase and maintenance of supersaturation can enhance the solubility of the drug, thereby increasing bioavailability and improving the oral absorption of poorly soluble drugs.

7. The piperine solid dispersion according to claim 1, characterized in that, The piperine solid dispersion was verified through molecular docking and molecular dynamics simulations to have hydrogen bonding forces between piperine and the carboxylic acid groups of organic acids and the silanol groups on the surface of mesoporous particles. These forces have high spatial binding energy, which hinders drug molecule migration, delays drug molecule nucleation and crystallization, and improves its kinetic stability.

8. A method for preparing a piperine solid dispersion, characterized in that, A solvent method was used to prepare solid dispersions by dissolving or dispersing piperine with glycyrrhizic acid or inorganic disordered mesoporous silica 244FP in organic solvents. Specific steps included: (1) The glycyrrhizic acid carrier and the active pharmaceutical ingredient are dissolved or dispersed in an organic solvent at a mass ratio of 1:(0.5-9), sonicated for 0.5-1 h, and vacuum dried at 40°C until the solvent is completely evaporated to obtain a dry, pale yellow piperine-glycyrrhizic acid solid dispersion; the organic solvent is ethanol, methanol, acetone or ethyl acetate; (2) The inorganic disordered mesoporous silica 244FP carrier and the active pharmaceutical ingredient are dissolved or dispersed in organic solvents such as ethanol, methanol, acetone, and ethyl acetate at a mass ratio of 1: (0.5-9). The suspension is obtained by ultrasonication in a water bath, and the suspension is magnetically stirred at 25-55°C for 1-5 hours. The organic solvent is removed by rotary evaporation at 30-60°C. The obtained white solid is vacuum dried for 24 hours to obtain piperine-mesoporous silica solid dispersion.

9. The method for preparing a piperine solid dispersion according to claim 8, characterized in that, The organic solvent is anhydrous ethanol.

10. The use of the piperine solid dispersion according to any one of claims 1-7 in the preparation of a pharmaceutical product, characterized in that, The drug is in the form of tablets, pills, or capsules.

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