A CURCUMIN SELF-DISPERSING PARTICLE SYSTEM, ITS PREPARATION METHOD, PREPARATION DEVICE, AND APPLICATIONS

Description

TECHNICAL FIELD

The present invention belongs to the field of pharmaceutical technology, and specifically relates to a curcumin self-dispersing particle system, its preparation method, preparation device, and applications.

BACKGROUND ART

The extremely low solubility of compounds in aqueous solutions is one of the main reasons limiting their widespread application in the pharmaceutical field. To improve the solubility of compounds in aqueous solutions and enable them to function better in vivo, different solubilization strategies have been proposed and applied in various studies. These mainly include two approaches: (1) Modifying the chemical structure of the compound itself by introducing hydrophilic groups, such as salt formation or prodrug formation, to increase the compound's solubility; (2) Employing small molecule compounds or polymeric carriers with amphiphilic properties, utilizing their ability to self-assemble into water-soluble nanostructures in water, to encapsulate or load poorly soluble compounds, thereby increasing their solubility in aqueous solutions.

However, hydrophilic modification of the chemical structure of a compound often leads to changes in the original compound's charge distribution, geometric configuration, and even pharmacological activity. For example, the hydrophilic derivatives of camptothecin, irinotecan and topotecan, have less than one-thousandth of the biological activity of camptothecin. The hydrophilic micro/nanostructures formed by amphiphilic materials face stability issues in physiological environments, which also severely limits their clinical application. For instance, the first problem faced by micellar dispersions when injected into the body is blood dilution. When the concentration is diluted to a level insufficient to support the self-assembly of the structure, the micro/nanostructure will rupture. Additionally, when amphiphilic carrier materials are used to enhance the solubility of compounds, the proportion of the compound within the carrier particles is not high, with few reports of compound proportions exceeding 50%, which directly affects the in vivo efficacy of the compound.

Compared to traditional molecular compounds, micronization of compounds has significant advantages. For example, in the diagnosis and treatment of solid tumors, micronized compound systems can deliver the compound to the target site through enhanced permeability and retention effects, increasing the accumulation of the compound at the target site while reducing its distribution in other tissues and organs. This not only increases the therapeutic effect at the target site but also reduces the potential toxicity of the compound to healthy tissues and organs. Furthermore, physical and chemical modifications of the particle surface, such as charge reversal, can further increase cellular uptake efficiency and enhance the therapeutic effect of the compound.

SUMMARY OF THE INVENTION

To overcome the shortcomings of the prior art, the present invention provides a novel curcumin self-dispersing particle system, its preparation method, preparation device, and applications.

The first aspect of the present invention provides a curcumin self-dispersing particle system: The system comprises at least one compound having a chemical structure represented by general formula I, II, or III and at least one compound having a chemical structure represented by general formula IV. Said compounds can be categorically combined based on their ionization capabilities and ionization types, and interact in an aqueous solution with a pH value of 0 to 14 at room temperature and atmospheric pressure to form a crystalline particle system that can be uniformly dispersed in the aqueous solution:

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Wherein, the core ring structure of the compound having the chemical structure represented by general formula I, II, or III is selected from at least one of the following substituted or unsubstituted fused four- to seven-membered rings forming a resonance hybrid, and each resonance hybrid ring itself contains at most two atoms with three or more bonds:

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Preferably, the core ring structure of the compound having the chemical structure represented by general formula I, II or III is selected from at least one of the following resonance hybrids:

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The atoms forming three bonds in the ring in the above resonance hybrids can be replaced by any one of the following bioisosteres:

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The atoms forming two bonds in the ring can be replaced by any one of the following bioisosteres:

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R in the above bioisosteres and R in general formula IV are any atom, ion, or group. Hydrogen atoms in the bioisosteres form two bonds in the form of single bonds and hydrogen bonds.

More specifically, the compounds having the chemical structure represented by general formula I, II, III or IV are selected from at least one of the following numbered compounds and/or their derivatives, salts, hydrates, and/or bioisosteres.

The compound numbering corresponds to the compound numbering in Table 3. Among them, the compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of two six-membered rings and one five-membered ring are selected from at least one of the following numbered compounds:

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Compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of three six-membered rings are selected from at least one of the following numbered compounds:

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Compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of two six-membered rings and one seven-membered ring are selected from at least one of the following numbered compounds:

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Compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of two five-membered rings and one other ring are selected from at least one of the following numbered compounds:

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Compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of other combinations are selected from at least one of the following numbered compounds:

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Compounds having the chemical structure represented by general formula I, II, or III containing a fused ring system of one five-membered ring, one six-membered ring, and one seven-membered ring are selected from at least one of the following numbered compounds:

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The compound having the chemical structure represented by general formula IV is selected from at least one curcuminoid compound. Preferably, the compound having the chemical structure represented by general formula IV is selected from at least one of the following numbered compounds:

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In the compounds having the chemical structure represented by general formula I, II or III and the compounds having the chemical structure represented by general formula IV, the conjugated structures (π-π conjugation, p-π conjugation, cross-conjugation, or σ-π hyperconjugation) formed by parallel p electron cloud orbitals between atoms result in an uneven distribution of the overall electron cloud of the compound, forming electron-rich and electron-deficient regions within the compound, and further forming a relative difference in electrical properties between different regions of the compound. The relative differences in electrical properties between different regions of the compound allow the compound to spontaneously aggregate through electrical attraction. Such compounds with differentiated electrical properties in different regions can naturally aggregate through π interactions. Under normal circumstances, to reduce interfacial tension, the size of the particles formed by such natural aggregation can tend towards arbitrarily large. The core of the present invention is to construct a curcumin self-dispersing mode, which provides a dispersing effect when the combined compounds aggregate, balancing the aggregation of the compounds through this dispersing effect, making the aggregation controllable, and thereby controllably adjusting the size of the particles formed during compound aggregation. This dispersing effect is achieved by constructing an ionized layer on the particle surface. This ionized layer can provide electrostatic repulsion of the same electrical property to the particles. When the electrostatic repulsion of the same electrical property provided by the ionized layer is sufficient to counteract the further aggregation caused by the attraction of the compound due to the differentiated electrical properties, it can prevent the particles from becoming larger due to the continued aggregation of the compound. Moreover, by changing the intensity of the electrostatic repulsion provided by the ionized layer, the size of the particles formed by the aggregation of the compound can be controllably adjusted.

Bioisosteres are atoms, ions or molecules with the same number of valence electrons. Since bioisosteres have the same number of valence electrons, similar bioisosteres often have similar geometric configurations and electronic properties. Compounds having the chemical structure represented by general formula I, II, or III and compounds having the chemical structure represented by general formula IV can form various compounds with differentiated electrical property regions through the combination of different bioisosteres. Such compounds generally exhibit hydrophobicity due to their spontaneous aggregation caused by electrical attraction. Moreover, such compounds are mostly sparingly soluble or even insoluble (solubility less than 1 mg/mL) in aqueous solutions. By constructing this curcumin self-dispersing particle system, the controlled aggregation of such compounds with differentiated electrical property regions can be achieved, not only enabling controllable adjustment of the size of the particles formed by the compounds, but also significantly improving the dispersion of the formed particles in aqueous solutions and increasing the solubility of the compounds in aqueous solutions, thus forming a particle system that can self-disperse in aqueous solutions.

The construction of the ionized layer on the surface of the curcumin self-dispersing particles is achieved by categorically combining the ionization capabilities and ionization types of the compounds. Specifically, based on the ionization capability, compounds can be classified into compounds with ionization capability and their conjugate salts, compounds without ionization capability, and permanently ionized compounds. Among them, compounds with ionization capability refer to compounds containing groups with ionization capability. Based on their ionization type, compounds with ionization capability are further divided into acidic compounds and basic compounds. Acidic compounds include compounds containing only acidic groups with ionization capability and compounds containing both acidic and basic groups with ionization capability but with an isoelectric point less than 7, while basic compounds include compounds containing only basic groups with ionization capability and compounds containing both acidic and basic groups with ionization capability but with an isoelectric point greater than 7. The conjugate base salt of an acidic compound refers to the salt formed by the acidic compound with a pharmaceutically acceptable base, and the conjugate acid salt of a basic compound refers to the salt formed by the basic compound with a pharmaceutically acceptable acid. Permanently ionized compounds refer to compounds containing permanently ionized groups. Compounds without ionization capability refer to compounds that contain neither groups with ionization capability nor permanently ionized groups.

Acidic groups with ionization capability include at least one of hydroxyl, thiol, hydroseleno, hydrotelluro, carboxyl, thiocarboxyl, sulfo, sulfinic acid, sulfenic acid, selenic acid, selenous acid, selenenic acid, telluric acid, tellurous acid, tellurenic acid, phosphoric acid, phosphorous acid, peroxy acid, imide, sulfonamide, phosphoramide, or boronic acid groups. Preferably, the acidic groups with ionization capability are selected from at least one of the following groups:

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Basic groups with ionization capability include amino groups. Preferably, the basic groups with ionization capability are selected from at least one of the following groups:

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Permanently ionized groups include groups in which the nitrogen, phosphorus, arsenic, oxygen, sulfur, selenium, or tellurium atom uses the lone pair of electrons in its p orbital to bond with a non-hydrogen atom, resulting in permanent ionization, or groups in which the carbon atom loses the electrons in its p orbital to form an empty orbital, resulting in permanent ionization. Preferably, the permanently ionized groups are selected from the following groups, where R is any atom or ion:

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pK_ais the dissociation equilibrium constant of a compound. The acidity or basicity of a compound is determined by itself, and the pK_avalue only reflects the strength of the compound's acidity or basicity. For acidic compounds, the smaller the pK_avalue, the stronger the acidity. For basic compounds, the larger the pK_avalue, the stronger the basicity. The pK_avalues of different compounds with ionization capability and their conjugate salts are denoted as pK_a_n, n≥1, where the smallest pK_avalue of one or more compounds or their conjugate salts is denoted as pK_a_min, the largest pK_avalue of one or more compounds or their conjugate salts is denoted as pK_a_max, the smallest pK_avalue of one or more acidic compounds or their conjugate base salts is denoted as pK_a_min-Acid, and the largest pK_avalue of one or more basic compounds or their conjugate acid salts is denoted as pK_a_max-Base. The combination of compounds satisfies the following combination conditions:

- When the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: The combination condition includes that the smallest pK_avalue of one or more compounds and/or one or more conjugate salts of compounds, i.e., pK_a_min, should be at least two units smaller than all other pK_avalues in the combination, i.e., pK_a_n≥pK_a_min+2;
- When the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: The combination condition includes that the largest pK_avalue of one or more compounds and/or one or more conjugate salts of compounds, i.e., pK_a_max, should be at least two units larger than all other pK_avalues in the combination, i.e., pK_a_n≤pK_a_max−2;
- When the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: The combination condition has no requirement for the magnitude relationship of the pK_avalues of the combined compounds;
- When the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: The combination condition has no requirement for the magnitude relationship of the pK_avalues of the combined compounds;
- When the combined compounds are one or more acidic compounds and one or more basic compounds: The combination condition has no requirement for the magnitude relationship of the pK_avalues of the combined compounds;
- When the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: The combination condition has no requirement for the magnitude relationship of the pK_avalues of the combined compounds;
- When the combined compounds are one or more permanently ionized compounds and one or more basic compounds: The combination condition has no requirement for the magnitude relationship of the pK_avalues of the combined compounds;
- When the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: The combination condition includes that the pK_avalue of one or more acidic compounds with the smallest pK_avalue, i.e., pK_a_min-Acid, should be at least four units larger than the pK_avalue of one or more basic compounds with the largest pK_avalue, i.e., pK_a_max-Base, i.e., pK_a_min-Acid−pK_a_max-Base≥4; min-Acid
- If a permanently ionized compound contains an acidic group with ionization capability, it is also considered as an acidic compound when comparing pK_avalues;
- One or more compounds without ionization capability can be added to each of the above combinations to form a corresponding new combination. In the new combination, compounds without ionization capability do not participate in the comparison of the magnitude relationship of the compound pK_avalues in the combination condition.

In some embodiments of this application, the different constructed curcumin self-dispersing particle systems and their corresponding compound combinations are shown in Table 4. Wherein, the number of each compound in each combination corresponds to the number of the compound in Table 3.

The second aspect of the present invention provides a method for preparing a curcumin self-dispersing particle system. The preparation steps include: (1) mixing the compounds with an organic solvent to obtain an organic mixture; (2) mixing the obtained organic mixture with an aqueous solution to obtain a dispersion of the curcumin self-dispersing particles containing the combination of said compounds; (3) removing the organic solvent from the dispersion of curcumin self-dispersing particles to obtain an aqueous dispersion of curcumin self-dispersing particles containing the combination of said compounds, or removing the aqueous phase from the aqueous dispersion of curcumin self-dispersing particles to obtain curcumin self-dispersing particles containing the combination of said compounds; (4) formulating the curcumin self-dispersing particles or the aqueous dispersion of curcumin self-dispersing particles containing the combination of said compounds into a curcumin self-dispersing particle system, said system including pharmaceutically acceptable different dosage forms, including injections, capsules, tablets, patches, or sprays. Wherein, the molar ratio of the compounds satisfies the following conditions:

- When the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: The molar ratio of one or more compounds and/or one or more conjugate salts of compounds with the smallest pK_avalue to all other compounds in the combination is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of all other compounds in the combination, i.e., the added compounds without ionization capability can partially or completely replace all other compounds in the original combination;
- When the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: The molar ratio of one or more compounds and/or one or more conjugate salts of compounds with the largest pK_avalue to all other compounds in the combination is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of all other compounds in the combination, i.e., the added compounds without ionization capability can partially or completely replace all other compounds in the original combination;
- When the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: The molar ratio of one or more acidic compounds to one or more conjugate acid salts of basic compounds is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of acidic compounds, i.e. the added compounds without ionization capability can partially or completely replace the acidic compounds in the original combination;
- When the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: The molar ratio of one or more basic compounds to one or more conjugate base salts of acidic compounds is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of basic compounds, i.e., the added compounds without ionization capability can partially or completely replace the basic compounds in the original combination;
- When the combined compounds are one or more acidic compounds and one or more basic compounds: The molar ratio of one or more acidic compounds to one or more basic compounds is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount may be included in the amount of any compound in the combination depending on the preparation environment, i.e., the added compounds without ionization capability can partially or completely replace the compounds in the original combination whose amounts they are included in;
- When the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: The molar ratio of one or more permanently ionized compounds to one or more acidic compounds is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of the acidic compounds, i.e., the added compounds without ionization capability can partially or completely replace the acidic compounds in the original combination;
- When the combined compounds are one or more permanently ionized compounds and one or more basic compounds: The molar ratio of one or more permanently ionized compounds to one or more basic compounds is 1:50 to 50:1; when one or more compounds without ionization capability are added, their amount is included in the amount of the basic compounds, i.e., the added compounds without ionization capability can partially or completely replace the basic compounds in the original combination;
- When the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: There is no requirement for the molar ratio between the acidic compounds and basic compounds; the molar ratio of one or more permanently ionized compounds to acidic or basic compounds is 1:50 to 50:1; preferably 1:10 to 10:1; more preferably 1:2 to 2:1; when one or more compounds without ionization capability are added, their amount is included in the amount of one or more acidic compounds and/or one or more basic compounds, i.e. the added compounds without ionization capability can partially or completely replace one or more acidic compounds and/or one or more basic compounds in the original combination.

Furthermore, the molar ratio of compounds in the curcumin self-dispersing particle system obtained using the preparation method in this application is the same as the above ratio.

The pH of the aqueous solution is pH_a. Under the premise of ensuring that the compound is not destroyed by acidity or alkalinity, the aqueous solution satisfies the following requirements:

- When the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: The pH of the aqueous solution should be at least two units larger than the smallest pK_avalue of all the compounds in the combination, i.e., pH_a≥pK_a_min+2;
- When the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: The pH of the aqueous solution should be at least two units smaller than the largest pK_avalue of all the compounds in the combination, i.e., pH_a≤pK_a_max−2;
- When the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: The pH of the aqueous solution should be at least two units smaller than the smallest pK_avalue of all the compounds in the combination, i.e., pH_a≤pK_a_min−2;
- When the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: The pH of the aqueous solution should be at least two units larger than the largest pK_avalue of all the compounds in the combination, i.e., pH_a≥pK_a_max+2;
- When the combined compounds are one or more acidic compounds and one or more basic compounds: The pH of the aqueous solution should be at least two units larger than the largest pK_avalue of all the compounds in the combination, or at least two units smaller than the smallest pK_avalue of all the compounds in the combination, i.e., pH_a≥pK_a_max+2 or pH_a≤pK_a_min−2;
- When the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: The pH of the aqueous solution should be at least two units smaller than the smallest pK_avalue of the acidic compounds in the combination, i.e., pH_a≤pK_a_min-Acid−2;
- When the combined compounds are one or more permanently ionized compounds and one or more basic compounds: The pH of the aqueous solution should be at least two units larger than the largest pK_avalue of the basic compounds in the combination, i.e., pH_a≥pK_a_max-Base+2;
- When the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: The pH of the aqueous solution should be at least two units smaller than the smallest pK_avalue of the acidic compounds in the combination, and at the same time, at least two units larger than the largest pK_avalue of the basic compounds in the combination, i.e., pK_a_min-Acid−2≥pK_a≥pK_a_max-Base+2;
- If a permanently ionized compound contains an acidic group with ionization capability, it is also considered as an acidic compound in the comparison of the relationship between pH and/or pK_a;
- When one or more compounds without ionization capability are added to the above combinations to form corresponding new combinations, the aqueous solution used in the preparation process of the new combinations is the same as that of the original combinations, respectively;
- If the new combination contains only one or more permanently ionized compounds and one or more compounds without ionization capability, and the permanently ionized compounds do not contain acidic groups with ionization capability, there is no requirement for the magnitude relationship between the pH of the aqueous solution and the pK_avalue of the compounds.

The organic solvent is selected from pharmaceutically acceptable organic solvents, including formic acid, acetic acid, propionic acid, butyric acid, methanol, ethanol, ethylene glycol, propanol, propylene glycol, glycerol, butylene glycol, pentylene glycol, triethylene glycol, furfuryl alcohol, methyldiethanolamine, methyl isocyanide, methylpyrrolidone, pyridine, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, dimethyl imidazolidinone, hexamethylphosphoramide, ethylamine, diethanolamine, diethylenetriamine, acetaldehyde, ethylene glycol dimethyl ether, ethylene glycol monobutyl ether, dioxane, or any combination thereof.

The curcumin self-dispersing particles constructed using this curcumin self-dispersing particle system have a particle size of 30 nm to 3000 nm, preferably 30 nm to 300 nm. In an aqueous solution with a pH of 0 to 14 at room temperature and atmospheric pressure, the absolute value of the Zeta potential of the curcumin self-dispersing particle system is between 15 mV and 80 mV. The Zeta potential is denoted as ζ:

- When the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than −15 mV, i.e., ζ≤−15 mV;
- When the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;
- When the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;
- When the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than-15 mV, i.e., ζ≤−15 mV;
- When the combined compounds are one or more acidic compounds and one or more basic compounds: Depending on the preparation conditions, the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than −15 mV or not less than 15 mV, i.e., ζ≤−15 mV or ζ≥15 mV;
- When the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;
- When the combined compounds are one or more permanently ionized compounds and one or more basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;
- When the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;
- when one or more compounds without ionization capability are added to the above combinations to form corresponding new combinations, the Zeta potential of the prepared new combination's curcumin self-dispersing particle dispersion under the preparation conditions remains consistent with the Zeta potential of the original combination's curcumin self-dispersing particle dispersion under the corresponding preparation conditions.

The preparation device for the curcumin self-dispersing particle system comprises: (1) at least one mixing module for mixing the compounds with an organic solvent to obtain an organic mixture, and for mixing the organic mixture with an aqueous solution to obtain a dispersion of the curcumin self-dispersing particles; (2) at least one solvent removal module for removing the solvent from the dispersion of curcumin self-dispersing particles to obtain an aqueous dispersion or particles of curcumin self-dispersing particles containing the combination of said compounds; (3) at least one system preparation module for processing the curcumin self-dispersing particles and/or the aqueous dispersion of curcumin self-dispersing particles to obtain the curcumin self-dispersing particle system.

Thus, the construction of the ionized layer on the surface of the curcumin self-dispersing particles and the construction of the curcumin self-dispersing particle system are completed. Through this curcumin self-dispersing particle system, the categorizeically combined compounds can interact under suitable conditions to form a crystalline particle system with controllable particle size that can self-disperse in aqueous solution. The curcumin self-dispersing particle system is a system containing curcumin self-dispersing particles obtained by the above method. This system can be any solid, liquid, or gaseous system. For example, the aforementioned dispersion of curcumin self-dispersing particles containing a combination of compounds is a liquid system containing organic solvent and water; the aqueous dispersion of curcumin self-dispersing particles containing a combination of compounds is a liquid system without organic solvent; while the curcumin self-dispersing particles containing a combination of compounds obtained by further removing the aqueous phase are themselves a solid system; formulating the obtained curcumin self-dispersing particles containing a combination of compounds into other pharmaceutically acceptable dosage forms, such as capsules, tablets, and patches, results in other solid systems containing curcumin self-dispersing particles with a combination of compounds; formulating the obtained curcumin self-dispersing particles containing a combination of compounds into injections again results in a liquid system containing curcumin self-dispersing particles with a combination of compounds; while formulating the obtained curcumin self-dispersing particles containing a combination of compounds into a spray results in a gaseous system containing curcumin self-dispersing particles with a combination of compounds.

The present invention also provides the use of the above-mentioned curcumin self-dispersing particle system in preparing diagnostic and therapeutic drugs, luminescent micro/nanomaterials, or energy conversion micro/nanomaterials.

The main features of the curcumin self-dispersing particle system constructed from the combination of compounds in the present invention include: (1) Imparting micro/nano characteristics to compounds. Compounds form uniformly distributed micro/nano particles through this curcumin self-dispersing particle system, giving them micro/nano-sized characteristics. In the field of tumor diagnosis and treatment, nanoparticles have natural passive targeting properties, which can make diagnostic and therapeutic drugs accumulate more in the tumor site, significantly improving efficacy and reducing systemic toxicity; (2) Enhancing the solubility of compounds in aqueous solutions. Compounds that are sparingly soluble or insoluble in aqueous solutions form curcumin self-dispersing particles that can be uniformly dispersed in aqueous solutions through this curcumin self-dispersing particle system, significantly enhancing the solubility of sparingly soluble or insoluble compounds in aqueous solutions; (3) Combination of multiple compounds. Through this curcumin self-dispersing particle system, multiple compounds can be combined to construct curcumin self-dispersing particles containing a combination of multiple compounds, which is very beneficial for combination therapy, synergistic enhancement and toxicity reduction, and drug resistance in the pharmaceutical field; (4) Controllable size. The size of curcumin self-dispersing particles constructed through this curcumin self-dispersing particle system can be controllably adjusted by adjusting the formulation process to meet different needs for particle size; (5) Crystalline form. Curcumin self-dispersing particles constructed through this curcumin self-dispersing particle system exist in crystalline form. While overcoming the disadvantages of poor water solubility of conventional bulk crystalline solids, curcumin self-dispersing particles retain the advantages of high stability of crystalline forms; (6) Extremely high compound proportion. Through this curcumin self-dispersing particle system, compounds directly combine and interact to form curcumin self-dispersing particles, with a compound proportion that can reach up to 100%; (7) No additional carrier material. Compounds interact through this curcumin self-dispersing particle system to form particles that can self-disperse in aqueous solutions without the assistance of additional carrier materials; (8) The curcumin self-dispersing particle system constructed in the present invention has a simple process, rapid preparation, wide application range, easy industrial production, and is suitable for clinical translation. It can be used to construct micro/nano particles for different applications such as diagnostic and therapeutic drugs, luminescent materials, and energy conversion materials, achieving water solubility and micronization of compounds for different purposes.

BRIEF DESCRIPTION OF THE DRAWINGS

To illustrate the technical solutions in the embodiments of the present invention or the prior art more clearly, the accompanying drawings needed in the description of the embodiments or prior art will be briefly introduced below. Obviously, the drawings described below are only one embodiment of the present invention, and those skilled in the art can also obtain other embodiments based on these drawings.

FIG. 1 shows the particle size, zeta potential, and surface morphology of different curcumin self-dispersing particles prepared in Working Examples 1-11.

FIG. 2 shows the X-ray powder diffraction patterns of curcumin self-dispersing particles with combination numbers 1, 11, 18, 30, 58, 67, and 73 in Table 4.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention provides the following specific examples, which are intended to illustrate the invention, but the invention is not limited by the following examples.

The aqueous solutions with different pH values used in the examples are shown in Table 1, including deionized water, buffer solutions with different pH buffering capacities, or aqueous solutions without buffering capacity prepared with different acids and bases.

TABLE 1

Aqueous Solutions with Different pH Values

Aqueous Solution
pH
pK_a

H₂O
7.0
14.0

Glycine HCl buffer
2.2-3.6
2.35

Sodium acetate buffer
3.6-5.6
4.76

Cacodylate buffer
5.0-7.4
6.27

Citrate buffer
3.0-6.2
6.4

Sørensen's phosphate buffer
5.8-8.0
7.20

Barbital buffer
6.8-9.2
7.98

Glycine NaOH buffer
8.6-10.6
9.78

Phosphate-citrate buffer
2.2-8.0
7.20, 6.40

H₂SO₄aqueous solution
<7.0
1.92

HCl aqueous solution
<7.0
−6.3, Strong acid

NaoH aqueous solution
>7.0
14.0, Strong base

The organic solvents used in the examples include formic acid, acetic acid, propionic acid, methanol, ethanol, pyridine, tetrahydrofuran, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, diethanolamine, acetaldehyde, ethylene glycol dimethyl ether, or combinations thereof.

The compound numbers and their physicochemical properties used in the examples are shown in Table 3. The physicochemical properties mainly include molecular weight (Mass), ionization capability, hydrophilicity/hydrophobicity, solubility, isoelectric point (pI) for amphoteric substances, and dissociation equilibrium constant (pK_a) of the compounds. According to the aforementioned definitions, the compounds used in the examples can be classified into acidic compounds, basic compounds, conjugate base salts of acidic compounds, conjugate acid salts of basic compounds, compounds without ionization capability, and permanently ionized compounds.

The hydrophilicity/hydrophobicity of a compound can be determined by the oil-water partition coefficient (Log P). The larger the Log P value, the higher the lipophilicity and the lower the hydrophilicity of the compound. Generally, when Log P>0, the compound exhibits hydrophobicity. Conversely, the compound exhibits hydrophilicity. As shown in the table, except for a few compounds that exhibit hydrophilicity, all other compounds involved in the examples are hydrophobic compounds.

The solubility criteria for compounds at room temperature and atmospheric pressure are based on the United States Pharmacopeia (USP) standards, as shown in Table 2. When the solubility of a compound is less than 0.1 mg/mL, the compound is practically insoluble (insoluble) in water; when the solubility is 0.1-1 mg/mL, the compound is very slightly soluble in water; when the solubility is 1-10 mg/mL, the compound is slightly soluble in water; when the solubility is 10-33 mg/mL, the compound is sparingly soluble in water. As shown in Table 3, among the compounds used in the examples, excluding salts, about two-thirds of the compounds are insoluble in water, while the remaining compounds are very slightly soluble in water except for a few that are slightly soluble in water.

TABLE 2

Solubility Definition Standards

Parts of Solvent Required

Solubility
for One Part of Solute
Solubility (mg/mL)

Very soluble
less than 1
>1000

Easily soluble
from 1 to 10
100-1000

Soluble
from 10 to 30
33-100

Sparingly soluble
from 30 to 100
10-33

Slightly soluble
from 100 to 1,000
1-10

Very slightly soluble
from 1,000 to 10,000
0.1-1

Practically insoluble
more than 10,000
<0.1

When a compound contains both acidic and basic functional groups with ionization capability, the compound can exhibit amphoteric properties. The isoelectric point is the environmental pH value at which the statistical average of the charges carried by this type of compound is electrically neutral (net charge is zero). Compounds with pI>7 mainly exhibit basicity and very weak acidity. Conversely, the compounds mainly exhibit acidity. The pK_avalues of the compounds with ionization capability and their conjugate salts in the table are their values as the strongest acid or base. These values are experimental or calculated values in H₂O as the solvent at room temperature and atmospheric pressure.

The preparation steps of the curcumin self-dispersing particle system mainly include: (1) mixing the compounds with an organic solvent to obtain an organic mixture; (2) mixing the organic mixture with an aqueous solution to obtain a dispersion containing the combination of said compounds; (3) removing the organic solvent from the curcumin self-dispersing particle dispersion to obtain an aqueous curcumin self-dispersing particle dispersion containing the combination of said compounds, or removing the aqueous phase from the aqueous curcumin self-dispersing particle dispersion to obtain curcumin self-dispersing particles containing the combination of said compounds; (4) formulating the curcumin self-dispersing particles or aqueous curcumin self-dispersing particle dispersion containing the combination of said compounds into different pharmaceutically acceptable dosage forms, including injections, capsules, tablets, patches, or sprays.

Working Examples 1-11 illustrate the specific operating procedures, as well as the particle size, zeta potential, and scanning electron microscopy (SEM) morphology of the prepared curcumin self-dispersing particles.

Working Example 1 Preparation of curcumin self-dispersing particles using a combination of two acidic compounds (Group 1 in Table 4): Compound 38 (1.9 mg) and Compound 111 (3.0 mg) from Table 3 were mixed with 300 μL of dimethylsulfoxide (DMSO). The resulting organic mixture was mixed with 20 mL of deionized water (pH 7.0) and stirred continuously for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1A.

Working Example 2 Preparation of curcumin self-dispersing particles using a combination of two acidic compounds and one conjugate base salt of an acidic compound (Group 11 in Table 4): Compound 106 (2.4 mg), Compound 111 (1.0 mg), and Compound 112 (0.9 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was sonicated for 3 minutes and then added dropwise to 25 mL of stirred deionized water (pH 7.0). The mixture was stirred for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.5% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1B.

Working Example 3 Preparation of curcumin self-dispersing particles using a combination of one acidic compound and one conjugate acid salt of a basic compound (Group 12 in Table 4): Compound 102 (3.4 mg) and Compound 113 (3.0 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was slowly injected into 20 mL of sodium acetate buffer (pH 4.6) using a syringe and stirred for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1E.

Working Example 4 Preparation of curcumin self-dispersing particles using a combination of one acidic compound and one basic compound (Group 18 in Table 4): Compound 63 (1.0 mg) and Compound 111 (2.0 mg) from Table 3 were mixed with 200 μL of DMSO. The resulting organic mixture was slowly injected into 20 mL of glycine-sodium hydroxide buffer (pH 9.8) using a syringe and stirred for 5 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 2.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1G.

Working Example 5 Preparation of curcumin self-dispersing particles using a combination of one acidic compound and one basic compound (Group 30 in Table 4): Compound 75 (2.3 mg) and Compound 112 (2.0 mg) from Table 3 were mixed with 200 μL of DMSO. The resulting organic mixture was slowly injected into 20 mL of sodium acetate buffer (pH 4.5) using a syringe and stirred for 5 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.5% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1G.

Working Example 6 Preparation of curcumin self-dispersing particles using a combination of one permanently ionized compound and one acidic compound (Group 58 in Table 4): Compound 109 (2.7 mg) and Compound 111 (3.0 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was slowly injected into 25 mL of phosphate-citrate buffer (pH 5.0) using a syringe and stirred for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 2.0% w/w mannitol was added and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1I.

Working Example 7 Preparation of curcumin self-dispersing particles using a combination of one compound without ionization capability and two acidic compounds (Group 67 in Table 4): Compound 58 (2.5 mg), Compound 112 (1.7 mg), and Compound 8 (1.0 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was rapidly injected into 20 mL of glycine-sodium hydroxide buffer (pH 9.8) using a syringe and stirred for 5 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.5% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1K.

Working Example 8 Preparation of curcumin self-dispersing particles using a combination of one compound without ionization capability, one conjugate base salt of an acidic compound, and one acidic compound (Group 70 in Table 4): Compound 106 (4.6 mg), Compound 111 (1.8 mg), and Compound 11 (1.0 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was rapidly injected into 25 mL of deionized water (pH 7.0) using a syringe and stirred for 5 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.5% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1K.

Working Example 9 Preparation of curcumin self-dispersing particles using a combination of one compound without ionization capability, one conjugate acid salt of a basic compound, and one acidic compound (Group 73 in Table 4): Compound 104 (4.6 mg), Compound 113 (1.5 mg), and Compound 14 (0.9 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was rapidly injected into 25 mL of dimethylarsinate buffer (pH 5.8) using a syringe and stirred for 5 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 2.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1K.

Working Example 10 Preparation of curcumin self-dispersing particles using a combination of one compound without ionization capability, one basic compound, and one acidic compound (Group 86 in Table 4): Compound 96 (2.7 mg), Compound 113 (1.5 mg), and Compound 28 (1.5 mg) from Table 3 were mixed with 200 μL of DMSO. The resulting organic mixture was added dropwise to 20 mL of stirred dimethylarsinate buffer (pH 5.8) and stirred continuously for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1L.

Working Example 11 Preparation of curcumin self-dispersing particles using a combination of one permanently ionized compound, one compound without ionization capability, and one acidic compound (Group 94 in Table 4): Compound 110 (5.4 mg), Compound 111 (1.8 mg), and Compound 37 (2.9 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was added dropwise to 25 mL of stirred citrate buffer (pH 5.0) and stirred continuously for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles. The particle size, zeta potential, and morphology of the curcumin self-dispersing particles are shown in FIG. 1L.

The procedures for preparing curcumin self-dispersing particles using other combinations of compounds are generally similar. In specific preparation operations, the mixing method of the compounds and the organic solvent, the mixing method of the organic mixture and the aqueous solution (such as dropwise addition, reverse dropwise addition, injection, etc.), and the treatment after mixing the organic mixture and the aqueous solution (such as stirring time, dialysis, vacuum concentration, etc.) do not significantly affect the particle size and zeta potential of the prepared curcumin self-dispersing particles. In addition, as shown in FIG. 1, the curcumin self-dispersing particles exhibit a spherical and smooth surface morphology under SEM.

Examples 12-18 describe the particle size, zeta potential, and particle size distribution under preparation conditions of curcumin self-dispersing particles prepared in batches using different categories of compound combinations.

Working Example 12 Preparation of curcumin self-dispersing particles using combinations of acidic compounds (Groups 1-10 in Table 4): The pK_avalues of the combined compounds differed by at least two units, and the pH values of the aqueous solutions used in each group and each combination were at least two units greater than the smallest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles ranged from 100 nm to 170 nm. At the same time, the small polydispersity index (PDI≤0.211) indicated that the particle size distribution of the curcumin self-dispersing particles prepared from the combined compounds in each combination was uniform. The ζ potential was between −30 mV and −60 mV. The negative ζ potential indicates that the prepared curcumin self-dispersing particles carried a negative charge under the preparation conditions, while the larger absolute values of the potential mean that the curcumin self-dispersing particles had good stability.

Working Example 13 Preparation of curcumin self-dispersing particles using a combination of acidic compounds and conjugate base salts of acidic compounds (Group 11 in Table 4): The pK_avalues of the combined compounds differed by at least two units, and the pH values of the aqueous solutions used in each group and each combination were at least two units greater than the smallest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles was approximately 60 nm. At the same time, the small polydispersity index (PDI=0.150) indicated that the particle size distribution of the curcumin self-dispersing particles prepared from the combined compounds in each combination was uniform. The ζ potential was −45.0 mV. The negative ζ potential indicates that the prepared curcumin self-dispersing particles carried a negative charge under the preparation conditions. Similarly, the larger absolute value of the potential means that the curcumin self-dispersing particles had good stability.

Working Example 14 Preparation of curcumin self-dispersing particles using combinations of acidic compounds and conjugate acid salts of basic compounds (Groups 12-15 in Table 4): There was no requirement for the pK_avalues of the combined compounds, but the pH values of the aqueous solution used in each combination were at least two units less than the smallest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles ranged from 100 nm to 140 nm, and the polydispersity index was small (PDI≤0.157). The ζ potential ranged from +36.0 mV to +50.0 mV, indicating that the curcumin self-dispersing particles carried a positive charge under the preparation conditions, and the larger absolute value of the potential indicated good stability of the curcumin self-dispersing particles.

Working Example 15 Preparation of curcumin self-dispersing particles using combinations of acidic compounds and basic compounds (Groups 16-28 in Table 4): There was no requirement for the pK_avalues of the combined compounds, and the pH values of the aqueous solution used in each combination were at least two units larger than the largest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles ranged from 100 nm to 200 nm, and the polydispersity index was less than 0.264. The ζ potential ranged from −30.0 mV to −70.0 mV, indicating that the curcumin self-dispersing particles carried a negative charge under the preparation conditions, and the larger absolute value of the potential indicated good stability of the curcumin self-dispersing particles.

Working Example 16 Preparation of curcumin self-dispersing particles using combinations of acidic compounds and basic compounds (Groups 29-56 in Table 4): There was no requirement for the pK_avalues of the combined compounds, and the pH values of the aqueous solution used in each combination were at least two units less than the smallest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles ranged from 50 nm to 170 nm, and the polydispersity index was less than 0.214. The ζ potential ranged from +20.0 mV to +60.0 mV, indicating that the curcumin self-dispersing particles carried a positive charge under the preparation conditions, and the larger absolute value of the potential indicated good stability of the curcumin self-dispersing particles.

Working Example 17 Preparation of curcumin self-dispersing particles using combinations of permanently ionized compounds and acidic compounds (Groups 57-59 in Table 4): There was no requirement for the pK_avalues of the combined compounds, and the pH values of the aqueous solution used in each combination were at least two units less than the smallest pK_avalue of the compounds in each combination. The particle size of the prepared curcumin self-dispersing particles ranged from 50 nm to 200 nm, and the polydispersity index was less than 0.253. The ζ potential ranged from +20.0 mV to +70.0 mV, indicating that the curcumin self-dispersing particles carried a positive charge under the preparation conditions, and the larger absolute value of the potential indicated good stability of the curcumin self-dispersing particles.

Working Example 18 Preparation of curcumin self-dispersing particles by adding one or more compounds without ionization capability to the above combinations of compounds to form corresponding new combinations (Groups 60-94 in Table 4): The compounds without ionization capability in the new combinations were not involved in the comparison of the pK_avalues of the compounds in the combination conditions, i.e., the classification and combination conditions of the compounds remained the same as the original combinations; the aqueous solutions used in the preparation process of the new combinations were also the same as the original combinations, respectively. The particle size of the prepared curcumin self-dispersing particles ranged from 50 nm to 200 nm, and the polydispersity index was less than 0.260. The absolute value of the ζ potential ranged from 20.0 mV to 70.0 mV. The larger absolute value of the potential indicated good stability of the curcumin self-dispersing particles.

It is worth noting that the preparation parameters shown in Table 4 have not been specifically optimized and may not be the optimal conditions for preparing curcumin self-dispersing particles for each group of compounds. They are only used to present a possible way to prepare curcumin self-dispersing particles using combined compounds. The molar ratio of the combined compounds, the pH value of the aqueous solution, and the choice of organic solvent can be further optimized to obtain curcumin self-dispersing particles of different sizes to meet different needs. In addition, the prepared curcumin self-dispersing particles all exist in crystalline form. The X-ray powder diffraction patterns of the curcumin self-dispersing particles with combination numbers 1, 11, 18, 30, 58, 67, and 73 in Table 4 are shown in FIG. 2.

Examples 19-22 demonstrate the controllable adjustment of curcumin self-dispersing particles by changing the relevant parameters of the combined compounds.

Working Example 19 Controllable adjustment of curcumin self-dispersing particles by changing the molar ratio of the combined compounds (Groups 1-7 in Table 5): The combined compounds were Compound 38 and Compound 111 from Table 3, the organic solvent was DMSO, and the aqueous solution was phosphate buffer (pH 7.4). The particle sizes of different groups could differ by several times, but the distribution was uniform (PDI≤0.22), and the ζ potential ranged from −30.0 mV to −50.0 mV. Thus, the particle size and distribution of the prepared curcumin self-dispersing particles can be controllably adjusted by changing the molar ratio of the combined compounds to meet different needs.

Working Example 20 Controllable adjustment of curcumin self-dispersing particles by changing the pH value of the aqueous solution (Groups 8-11 in Table 5): The combined compounds were Compound 39 and Compound 112 from Table 3, the organic solvent was DMSO, and the pH range of the aqueous solution was 4.0 to 8.0. When the pH value of the aqueous solution was 6.0-7.0, the prepared particles were at the nanoscale with a narrow distribution; when the pH of the aqueous solution deviated from this range, the prepared particles reached the micron scale. Thus, the curcumin self-dispersing particles can be controllably adjusted by changing the acidity of the aqueous solution to obtain particles that meet expectations and different needs.

Working Example 21 Investigation of curcumin self-dispersing particles by changing the type of organic solvent (Groups 12-18 in Table 5): The combined compounds were Compound 109 and Compound 111 from Table 3, the aqueous solution was deionized water (pH 7.0), and the organic solvents were tetrahydrofuran, methanol, methanol, methanol-dimethylformamide mixture (volume ratio 1:1), acetonitrile, ethanol, dimethylformamide, and DMSO, respectively. Different organic solvents had a significant impact on the particle size of the curcumin self-dispersing particles. Particles of different sizes could be obtained using different organic solvents.

Working Example 22 Investigation of curcumin self-dispersing particles by changing the composition of the aqueous solution (Groups 19-21 in Table 5): The combined compounds were Compound 38 and Compound 111 from Table 3, the organic solvent was DMSO, and the aqueous solutions were alkaline aqueous solutions with or without buffering capacity (pH 7.4) with different compositions. The particle sizes of the curcumin self-dispersing particles in different groups were around 120 nm, the ζ potential was around −50.0 mV, and the particle size distribution was uniform (PDI≤0.3). It can be seen that aqueous solutions with different compositions at the same pH value did not significantly affect the prepared curcumin self-dispersing particles.

In addition, as shown in Example 23, adding an appropriate amount of amphiphilic materials, such as surfactants or polymers, to the formulation for preparing the curcumin self-dispersing particle system does not affect the preparation of the curcumin self-dispersing particle system.

Working Example 23 Preparation of curcumin self-dispersing particles using a combination of one acidic compound, one conjugate acid salt of a basic compound (Group 95 in Table 4), and an appropriate amount of amphiphilic polymer: Compound 102 (3.4 mg), Compound 113 (3.0 mg), and Poloxamer 188 (0.6 mg) from Table 3 were mixed with 300 μL of DMSO. The resulting organic mixture was slowly injected into 20 mL of sodium acetate buffer (pH 4.6) using a syringe and stirred for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion by dialysis to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added, and the mixture was freeze-dried to obtain curcumin self-dispersing particles.

Examples 24-28 describe different formulation systems prepared using curcumin self-dispersing particles.

Working Example 24 Injection of curcumin self-dispersing particles: Curcumin self-dispersing particles or their concentrated solution from Example 1 were added to a pharmaceutically acceptable solvent, such as water for injection, oil for injection, or other solvents for injection, to prepare an injection suitable for administration into the human body.

Working Example 25 Capsules of curcumin self-dispersing particles: Curcumin self-dispersing particles from Example 2, optionally with pharmaceutically acceptable excipients, were filled into hollow hard capsules or elastic soft capsules to prepare capsule formulations.

Working Example 26 Tablets of curcumin self-dispersing particles: Curcumin self-dispersing particles and pharmaceutically acceptable excipients from Example 5 were mixed uniformly and then compressed to form tablets or shaped tablets.

Working Example 27 Patches of curcumin self-dispersing particles: Curcumin self-dispersing particles from Example 6 and other suitable materials (liner, matrix, pressure-sensitive adhesive, release liner, etc.) were used to prepare a thin sheet formulation that can be applied to the skin to produce systemic or local effects.

Working Example 28 Sprays of curcumin self-dispersing particles: Curcumin self-dispersing particles from Example 8 were dispersed in a suitable solvent (such as water) to obtain a dispersion with a suitable concentration. This dispersion was then filled into a spraying device to prepare a spray.

Working Example 29 Preparation Apparatus: Taking Example 1 as an example, Compound 38 (1.9 mg) and Compound 111 (3.0 mg) from Table 3 were mixed with 300 μL of DMSO in a mixing vessel (optionally with a stirrer) until uniform to obtain an organic mixture. Deionized water (pH 7.0) was then added, and the mixture was stirred continuously for 10 minutes to obtain a dispersion of curcumin self-dispersing particles. DMSO was removed from the dispersion using a dialysis machine to obtain an aqueous dispersion of curcumin self-dispersing particles. Approximately 1.0% w/w mannitol was added to the aqueous dispersion, which was then filled into vials and transferred to a freeze dryer to prepare lyophilized powder of curcumin self-dispersing particles. Further, the lyophilized powder was processed into different pharmaceutically acceptable formulations according to conventional methods, such as injections, capsules, tablets, patches, or sprays.

Working Example 30 Applications of Curcumin Self-Dispersing Particles: Modern research has shown that compounds with the chemical structures of general formulas I, II, III, or IV presented in this invention exhibit diverse properties and have various applications in medicine, optics, energy conversion, and other fields. For instance, compounds with the chemical structure shown in general formula IV have demonstrated a wide range of pharmacological activities in modern medical research, including anti-inflammatory, antioxidant, lipid-regulating, antiviral, anti-infective, antitumor, anticoagulant, anti-hepatic fibrosis, and anti-atherosclerotic effects, with low toxicity and minimal adverse reactions. However, in practical applications, the extremely low water solubility of compounds with the chemical structure shown in general formula IV leads to very low bioavailability, severely limiting their clinical application. In a specific application example of this invention, the provided curcumin self-dispersing particles confer micro-nano properties to these compounds. Therefore, when used in the preparation of therapeutic drugs, the water solubility of the drugs can be improved, thereby increasing their bioavailability. For example, when preparing antitumor drugs containing curcumin self-dispersing particles, their nano-sized characteristics can be utilized to achieve targeted delivery and improve drug efficacy. In another specific application example of this invention, due to the photochemical properties caused by the aggregation of compounds and their micro-nano characteristics, the provided curcumin self-dispersing particles can also be used to prepare luminescent micro-nano materials, energy conversion micro-nano materials, etc.

The following are comparative examples that do not meet the construction conditions of the curcumin self-dispersing particle system for comparative illustration.

Comparative Example 1 Combination of two acidic compounds (Group 1 in Table 6): The difference in pK_avalues was less than 2 units, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 2 Combination of two acidic compounds (Group 2 in Table 6): The pH value of the aqueous solution was 1 unit less than the pK_avalues of all compounds, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 3 Combination of an acidic compound and a conjugate acid salt of a basic compound (Group 3 in Table 6): The pH value of the aqueous solution was 2 units greater than the smallest pK_avalue of the compounds, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 4 Combination of an acidic compound and a basic compound (Group 4 in Table 6): The pH value of the aqueous solution was the same as the smallest pK_avalue of the compounds, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 5 Combination of an acidic compound and a basic compound (Group 5 in Table 6): The pH value of the aqueous solution was the same as the largest pK_avalue of the compounds, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 6 Combination of a permanently ionized compound and an acidic compound (Group 6 in Table 6): The pH value of the aqueous solution was the same as the pK_avalue of the acidic compound, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

Comparative Example 7 Combination of a compound without ionization capability and an acidic compound (Group 7 in Table 6): The pH value of the aqueous solution was the same as the pK_avalue of the acidic compound, and other conditions met the construction conditions of the curcumin self-dispersing particle system. Macroscopic precipitation was observed, and a uniformly dispersed particle system could not be obtained.

TABLE 3

Compound Number and Physicochemical Properties

No.
Property
MW
LogP¹
[S]²
pI
pK_a

1
NI
152.19
3.90
0.001
—
—

2
NI
152.19
4.25
0.341
—
—

3
NI
152.19
3.76
0.010
—
—

4
NI
178.23
4.55
0.000
—
—

5
NI
180.20
3.15
0.039
—
—

6
NI
182.17
2.59
0.155
—
—

7
NI
191.97
1.54
0.103
—
—

8
NI
202.25
5.19
0.000
—
—

9
NI
202.25
5.07
0.000
—
—

10
NI
202.25
5.41
0.000
—
—

11
NI
202.25
5.19
0.000
—
—

12
NI
208.21
3.13
0.021
—
—

13
NI
214.31
4.65
0.019
—
—

14
NI
188.14
0.26
0.568
—
—

15
NI
228.24
3.17
0.035
—
—

16
NI
232.23
2.74
0.011
—
—

17
NI
232.23
2.74
0.011
—
—

—

—
—
—
—
—

19
NI
252.09
0.96
5.390
—
—

20
NI
262.33
4.74
0.002
—
—

21
NI
267.32
3.07
0.233
—
—

22
NI
268.18
1.74
0.194
—
—

23
NI
252.31
6.33
0.000
—
—

24
NI
268.26
2.87
0.009
—
—

25
NI
272.30
4.73
0.001
—
—

26
NI
274.30
3.88
0.002
—
—

27
NI
276.29
3.38
0.012
—
—

28
NI
300.36
7.26
0.000
—
—

29
NI
306.31
4.82
0.000
—
—

30
NI
326.39
6.82
0.000
—
—

31
NI
334.30
4.60
0.000
—
—

32
NI
347.32
3.04
0.118
—
—

—

—
—
—
—
—

34
NI
464.11
5.73
0.000
—
—

35
NI
488.53
4.94
0.001
—
—

36
NI
488.66
8.11
0.000
—
—

37
NI
584.41
6.45
0.003
—
—

38
A
341.27
2.69
0.025
—
3.15

39
A
196.20
2.85
0.041
—
3.99

40
A
302.19
1.59
0.813
—
5.54

41
A
296.32
2.22
0.041
—
5.59

42
A
280.32
3.29
0.010
—
5.70

43
A
504.44
3.92
0.007
2.62
6.65

44
A
528.51
2.95
0.018
—
6.82

45
A
354.44
6.40
0.005
—
8.08

46
A
330.30
0.97
0.081
—
8.14

47
A
258.23
2.49
0.230
—
8.26

48
A
296.23
2.45
0.364
—
8.32

49
A
352.14
2.37
0.443
5.53
8.41

50
A
322.40
3.95
0.022
—
8.66

51
A
186.16
2.45
0.661
—
9.02

52
A
328.32
1.75
0.125
—
9.28

53
A
282.38
5.61
0.004
—
9.32

54
A
213.19
2.53
0.151
—
9.35

55
A
195.20
2.62
0.102
—
11.11

56
A
195.22
2.32
0.046
—
12.74

57
A
294.30
2.05
0.032
—
13.11

58
A
252.27
1.76
0.159
—
13.18

59
A
370.44
4.18
0.018
—
13.63

60
A
236.27
2.10
0.153
—
15.96

61
B
345.36
2.64
0.131
—
1.10

62
B
330.20
2.17
0.050
—
1.85

63
B
180.21
2.34
0.116
—
2.01

64
B
411.19
1.68
0.272
—
2.86

65
B
332.78
2.35
0.034
—
3.55

66
B
217.27
4.03
0.001
—
3.82

67
B
387.66
2.87
0.023
—
4.10

68
B
353.76
2.88
0.043
—
4.12

69
B
461.81
4.59
0.018
—
4.14

70
B
342.85
2.98
0.042
—
4.45

71
B
291.30
2.52
0.027
—
5.30

72
B
308.40
2.56
0.077
—
5.31

73
B
439.31
3.68
0.022
—
5.61

74
B
361.40
3.25
0.614
—
6.50

75
B
389.83
1.23
0.563
10.44
6.55

76
B
367.35
1.76
0.359
—
6.67

77
B
426.51
3.85
0.004
—
6.93

78
B
347.41
2.47
0.145
11.24
7.14

79
B
327.80
3.18
0.104
—
7.18

80
B
351.40
1.26
0.685
10.98
7.20

81
B
368.43
0.70
3.438
10.72
7.20

82
B
370.47
1.68
0.100
10.48
7.20

83
B
330.42
3.41
0.048
—
7.22

84
B
343.90
4.10
0.014
—
7.23

85
B
291.40
2.97
0.106
—
7.38

86
B
261.40
3.96
0.034
—
7.44

87
B
287.40
5.02
0.013
—
8.05

88
B
267.40
4.12
0.004
—
8.27

89
B
201.22
0.58
1.458
—
8.47

90
B
296.37
2.39
0.121
11.06
8.51

91
B
283.33
0.90
0.763
—
8.52

92
B
336.39
1.45
0.267
11.31
8.63

93
B
317.38
2.26
0.356
—
8.75

94
B
331.86
4.74
0.001
—
8.92

95
B
340.46
3.31
0.061
—
8.93

96
B
265.31
2.22
0.034
—
9.20

97
B
402.96
5.71
0.001
—
9.21

98
B
377.82
2.65
0.140
—
9.30

99
B
279.38
4.08
0.032
—
9.76

100
B
294.15
3.56
0.027
—
9.80

101
B
301.40
3.90
0.002
—
9.89

102
CA
522.61
3.85
90.000
—
6.93

103
CA
287.40
5.02
4.000
—
8.05

104
CA
461.94
0.45
—
9.28
8.95

105
CA
311.85
4.73
62.000
—
9.76

106
CB
457.25
0.26
1.000
—
−2.78

107
PC, A
469.30
−0.47
—
—
9.11

108
PC, B
394.31
0.78
—
—
3.63

109
PC
332.33
−0.51
—
—
—

110
PC, B
541.50
−0.62
—
—
3.48

111
A
368.39
3.40
0.007
—
7.80

112
A
338.36
3.43
0.008
—
7.80

113
A
308.33
3.50
0.014
—
7.80

—

—
—
—
—
—

Notes:

[NI] Non-ionizable; [A] Acid; [B] Base; [CA] Conjugate acid salt of base; [CB] Conjugate base salt of acid; [PC] Permanently ionized;

¹$LogP > 0$, compound is hydrophobic, otherwise hydrophilic;

²[S]: Solubility of the compound in water at room temperature and pressure (mg/mL), [S] <1 mg/mL, the compound is very slightly soluble or insoluble in water;

TABLE 4

Combinations of Compounds and Particle Size, Zeta Potential, and Distribution of Curcumin Self-Dispersing Particles

Combination
Compound
[W]¹
[R]²
[O]³
pH⁴
[W]⁵
Size_(nm)
Zeta_(mV)
PDI

1
38, 111
1.9, 3.0
2:3
300
7.0
20
121.8 ± 1.864
−42.2 ± 1.88
0.136 ± 0.044

2
39, 111
1.1, 3.0
2:3
300
7.0
15
145.8 ± 2.264
−50.2 ± 2.80
0.176 ± 0.021

3
40, 111
1.6, 3.0
2:3
300
7.4
15
103.3 ± 1.555
−36.1 ± 3.05
0.105 ± 0.086

4
41, 111
1.6, 3.0
2:3
300
7.8
15
142.7 ± 2.212
−49.2 ± 1.59
0.171 ± 0.061

5
42, 111
1.5, 3.0
2:3
300
7.8
15
92.21 ± 1.370
−32.4 ± 2.03
0.087 ± 0.058

6
56, 112
1.7, 2.0
3:2
200
9.8
20
144.5 ± 2.241
−49.8 ± 1.36
0.174 ± 0.018

7
57, 112
2.6, 2.0
3:2
300
9.8
20
86.40 ± 1.273
−30.4 ± 2.68
0.077 ± 0.002

8
58, 112
2.2, 2.0
3:2
300
9.8
20
159.5 ± 2.493
−54.8 ± 1.66
0.199 ± 0.024

9
59, 112
3.3, 2.0
3:2
300
9.8
20
166.9 ± 2.615
−57.3 ± 1.09
0.211 ± 0.082

10
60, 112
2.1, 2.0
3:2
300
9.8
20
153.1 ± 2.386
−52.7 ± 3.23
0.188 ± 0.001

11
106, 111, 112
2.4, 1.0, 0.9
2:1:1
300
7.0
25
130.1 ± 2.002
−45.0 ± 1.49
0.150 ± 0.052

12
102, 113
3.4, 3.0
2:3
300
4.6
25
104.8 ± 1.581
36.6 ± 1.29
0.108 ± 0.097

13
103, 113
1.9, 3.0
2:3
300
5.8
25
122.7 ± 1.879
42.5 ± 3.91
0.137 ± 0.043

14
104, 113
3.0, 3.0
2:3
300
5.8
25
134.4 ± 2.074
46.4 ± 1.90
0.157 ± 0.095

15
105, 113
2.0, 3.0
2:3
300
5.8
25
132.3 ± 2.039
45.7 ± 1.84
0.153 ± 0.011

16
61, 111
1.9, 2.0
1:1
200
9.8
20
148.5 ± 2.309
−51.1 ± 2.96
0.180 ± 0.098

17
62, 111
1.8, 2.0
1:1
200
9.8
20
198.4 ± 3.140
−67.8 ± 1.18
0.264 ± 0.074

18
63, 111
1.0, 2.0
1:1
200
9.8
20
130.7 ± 2.013
−45.2 ± 2.60
0.151 ± 0.081

19
64, 111
2.2, 2.0
1:1
200
9.8
20
132.2 ± 2.037
−45.7 ± 1.48
0.153 ± 0.042

20
65, 111
1.8, 2.0
1:1
200
9.8
20
120.4 ± 1.840
−41.8 ± 1.11
0.134 ± 0.008

21
66, 111
1.2, 2.0
1:1
200
9.8
20
135.5 ± 2.092
−46.8 ± 1.48
0.159 ± 0.055

22
67, 111
2.1, 2.0
1:1
200
9.8
20
132.8 ± 2.047
−45.9 ± 2.47
0.154 ± 0.042

23
68, 111
1.9, 2.0
1:1
200
9.8
20
97.37 ± 1.456
−34.1 ± 1.23
0.095 ± 0.025

24
69, 111
2.5, 2.0
1:1
200
9.8
20
158.2 ± 2.471
−54.4 ± 1.31
0.197 ± 0.048

25
70, 111
1.9, 2.0
1:1
200
9.8
20
189.2 ± 2.987
−64.7 ± 2.59
0.248 ± 0.078

26
71, 111
1.6, 2.0
1:1
200
9.8
20
146.6 ± 2.277
−50.5 ± 1.40
0.177 ± 0.041

27
72, 111
1.7, 2.0
1:1
200
9.8
20
101.1 ± 1.519
−35.3 ± 1.97
0.101 ± 0.049

28
73, 111
2.4, 2.0
1:1
200
9.8
20
133.4 ± 2.057
−46.1 ± 1.49
0.155 ± 0.062

29
74, 111
2.0, 2.0
1:1
200
4.5
20
118.4 ± 1.807
41.1 ± 1.56
0.130 ± 0.032

30
75, 112
2.3, 2.0
1:1
200
4.5
20
93.79 ± 1.396
32.9 ± 2.31
0.089 ± 0.019

31
76, 112
2.2, 2.0
1:1
200
4.5
20
111.1 ± 1.685
38.7 ± 1.08
0.118 ± 0.022

32
77, 112
2.5, 2.0
1:1
200
4.5
20
54.72 ± 0.745
19.9 ± 1.08
0.024 ± 0.070

33
78, 112
2.1, 2.0
1:1
200
4.5
20
93.56 ± 1.392
32.8 ± 1.55
0.089 ± 0.041

34
79, 112
1.9, 2.0
1:1
200
4.5
20
126.8 ± 1.947
43.9 ± 1.54
0.144 ± 0.082

35
80, 112
2.1, 2.0
1:1
200
4.5
20
129.8 ± 1.997
44.9 ± 1.44
0.149 ± 0.095

36
81, 112
2.2, 2.0
1:1
200
4.5
20
128.2 ± 1.970
44.4 ± 2.12
0.147 ± 0.094

37
82, 112
2.2, 2.0
1:1
200
4.5
20
86.33 ± 1.272
30.4 ± 1.43
0.077 ± 0.028

38
83, 112
2.0, 2.0
1:1
200
4.5
20
125.3 ± 1.922
43.4 ± 1.54
0.142 ± 0.041

39
84, 112
2.0, 2.0
1:1
200
4.5
20
98.06 ± 1.467
34.3 ± 1.55
0.096 ± 0.030

40
85, 112
1.7, 2.0
1:1
200
4.5
20
112.9 ± 1.715
39.3 ± 1.04
0.121 ± 0.082

41
86, 112
1.5, 2.0
1:1
200
4.5
20
155.7 ± 2.428
53.5 ± 1.70
0.192 ± 0.050

42
87, 112
1.7, 2.0
1:1
200
5.8
20
166.0 ± 2.600
57.0 ± 2.12
0.210 ± 0.064

43
88, 112
1.6, 2.0
1:1
200
5.8
20
122.6 ± 1.877
42.5 ± 1.59
0.137 ± 0.022

44
89, 112
1.2, 2.0
1:1
200
5.8
20
145.1 ± 2.253
50.0 ± 1.64
0.175 ± 0.022

45
90, 112
1.8, 2.0
1:1
200
5.8
20
162.0 ± 2.533
55.6 ± 1.76
0.203 ± 0.051

46
91, 113
1.8, 2.0
1:1
200
5.8
20
166.9 ± 2.616
57.3 ± 1.25
0.211 ± 0.097

47
92, 113
2.2, 2.0
1:1
200
5.8
20
148.1 ± 2.302
51.0 ± 2.46
0.180 ± 0.033

48
93, 113
2.1, 2.0
1:1
200
5.8
20
155.1 ± 2.418
53.3 ± 1.73
0.191 ± 0.044

49
94, 113
2.2, 2.0
1:1
200
5.8
20
81.76 ± 1.196
28.9 ± 1.20
0.069 ± 0.037

50
95, 113
2.2, 2.0
1:1
200
5.8
20
170.1 ± 2.669
58.3 ± 1.94
0.216 ± 0.034

51
96, 113
1.7, 2.0
1:1
200
5.8
20
127.3 ± 1.955
44.1 ± 1.01
0.145 ± 0.023

52
97, 113
2.6, 2.0
1:1
200
5.8
20
146.5 ± 2.276
50.5 ± 3.31
0.177 ± 0.011

53
98, 113
2.5, 2.0
1:1
200
5.8
20
168.4 ± 2.641
57.8 ± 2.30
0.214 ± 0.059

54
99, 113
1.8, 2.0
1:1
200
5.8
20
81.00 ± 1.183
28.6 ± 1.67
0.068 ± 0.067

55
100, 113
1.9, 2.0
1:1
200
5.8
20
144.0 ± 2.234
49.6 ± 1.92
0.173 ± 0.061

56
101, 113
2.0, 2.0
1:1
200
5.8
20
119.2 ± 1.820
41.4 ± 4.19
0.132 ± 0.000

57
108, 111
3.2, 3.0
1:1
300
5.0
25
192.2 ± 3.036
65.7 ± 1.38
0.253 ± 0.077

58
109, 111
2.7, 3.0
1:1
300
5.0
25
56.50 ± 0.775
20.5 ± 1.02
0.027 ± 0.084

59
110, 111
4.4, 3.0
1:1
300
5.0
25
103.2 ± 1.553
36.0 ± 1.72
0.105 ± 0.009

60
38, 111, 1
3.4, 1.8, 0.8
2:1:1
300
7.0
20
120.9 ± 1.848
−41.9 ± 1.75
0.134 ± 0.065

61
39, 111, 2
2.0, 1.8, 0.8
2:1:1
300
7.0
15
161.6 ± 2.527
−55.5 ± 5.45
0.202 ± 0.020

62
40, 111, 3
3.0, 1.8, 0.8
2:1:1
300
7.4
15
54.57 ± 0.742
−39.8 ± 3.57
0.024 ± 0.072

63
41, 111, 4
3.0, 1.8, 0.9
2:1:1
300
7.8
15
128.6 ± 1.977
−44.5 ± 1.51
0.147 ± 0.008

64
42, 111, 5
2.8, 1.8, 0.9
2:1:1
300
7.8
15
160.4 ± 2.507
−55.1 ± 4.48
0.200 ± 0.018

65
56, 112, 6
2.0, 1.7, 0.9
2:1:1
200
9.8
20
161.7 ± 2.529
−55.5 ± 1.88
0.202 ± 0.036

66
57, 112, 7
2.9, 1.7, 1.0
2:1:1
300
9.8
20
160.0 ± 2.500
−55.0 ± 1.16
0.200 ± 0.042

67
58, 112, 8
2.5, 1.7, 1.0
2:1:1
300
9.8
20
156.0 ± 2.434
−53.6 ± 1.97
0.193 ± 0.060

68
59, 112, 9
3.7, 1.7, 1.0
2:1:1
300
9.8
20
77.43 ± 1.123
27.4 ± 1.78
0.062 ± 0.049

69
60, 112, 10
2.4, 1.7, 1.0
2:1:1
300
9.8
20
178.2 ± 2.804
−61.0 ± 4.85
0.230 ± 0.057

70
106, 111, 11
4.6, 1.8, 1.0
2:1:1
300
7.0
25
104.0 ± 1.567
−36.3 ± 1.58
0.106 ± 0.061

71
102, 113, 12
5.2, 1.5, 1.0
2:1:1
300
4.6
25
78.07 ± 1.134
27.6 ± 1.90
0.063 ± 0.028

72
103, 113, 13
2.9, 1.5, 1.1
2:1:1
300
5.8
25
128.6 ± 1.977
44.5 ± 1.42
0.147 ± 0.077

73
104, 113, 14
4.6, 1.5, 0.9
2:1:1
300
5.8
25
147.0 ± 2.284
50.6 ± 5.89
0.178 ± 0.036

74
105, 113, 15
3.1, 1.5, 1.1
2:1:1
300
5.8
25
147.3 ± 2.288
50.7 ± 1.75
0.178 ± 0.093

75
61, 111, 16
3.5, 1.8, 1.2
2:1:1
200
9.8
20
96.39 ± 1.439
−33.7 ± 1.98
0.093 ± 0.041

76
62, 111, 17
3.3, 1.8, 1.2
2:1:1
200
9.8
20
100.3 ± 1.505
−35.1 ± 3.00
0.100 ± 0.076

77
63, 111, 19
1.8, 1.8, 1.3
2:1:1
200
9.8
20
160.1 ± 2.503
−55.0 ± 1.65
0.200 ± 0.077

78
64, 111, 20
4.1, 1.8, 1.3
2:1:1
200
9.8
20
149.7 ± 2.329
−51.5 ± 1.97
0.182 ± 0.095

79
65, 111, 21
3.3, 1.8, 1.3
2:1:1
200
9.8
20
147.1 ± 2.286
−50.7 ± 5.30
0.178 ± 0.061

80
90, 112, 22
3.0, 1.7, 1.3
2:1:1
200
5.8
20
113.1 ± 1.719
39.3 ± 1.89
0.121 ± 0.027

81
91, 113, 23
2.8, 1.5, 1.3
2:1:1
200
5.8
20
196.1 ± 3.102
67.0 ± 1.59
0.260 ± 0.037

82
92, 113, 24
3.4, 1.5, 1.3
2:1:1
200
5.8
20
133.9 ± 2.066
46.3 ± 1.26
0.156 ± 0.062

83
93, 113, 25
3.2, 1.5, 1.4
2:1:1
200
5.8
20
143.7 ± 2.228
49.5 ± 1.68
0.172 ± 0.003

84
94, 113, 26
3.3, 1.5, 1.4
2:1:1
200
5.8
20
111.9 ± 1.699
38.9 ± 6.87
0.119 ± 0.003

85
95, 113, 27
3.4, 1.5, 1.5
2:1:1
200
5.8
20
139.2 ± 2.153
48.0 ± 1.72
0.165 ± 0.064

86
96, 113 28
2.7, 1.5, 1.5
2:1:1
200
5.8
20
85.87 ± 1.264
30.2 ± 1.91
0.076 ± 0.032

87
97, 113, 29
4.0, 1.5, 1.5
2:1:1
200
5.8
20
194.5 ± 3.075
66.5 ± 1.00
0.257 ± 0.074

88
98, 113, 30
3.8, 1.5, 1.6
2:1:1
200
5.8
20
63.24 ± 0.887
22.7 ± 5.49
0.038 ± 0.073

89
99, 113, 31
2.8, 1.5, 1.7
2:1:1
200
5.8
20
115.8 ± 1.763
40.2 ± 1.69
0.126 ± 0.084

90
100, 113, 32
2.9, 1.5, 1.7
2:1:1
200
5.8
20
164.6 ± 2.577
56.5 ± 3.53
0.207 ± 0.001

91
101, 113, 34
3.0, 1.5, 2.3
2:1:1
200
5.8
20
175.9 ± 2.765
60.3 ± 1.11
0.226 ± 0.003

92
108, 111, 35
3.9, 1.8, 2.4
2:1:1
300
5.0
25
127.9 ± 1.965
44.3 ± 1.08
0.146 ± 0.009

93
109, 111, 36
3.3, 1.8, 2.4
2:1:1
300
5.0
25
76.45 ± 1.107
27.1 ± 2.52
0.060 ± 0.089

94
110, 111, 37
5.4, 1.8, 2.9
2:1:1
300
5.0
25
156.0 ± 2.433
53.6 ± 1.61
0.193 ± 0.080

95
102, 113, Poloxamer 188
3.4, 3.0, 0.6
2:3
300
4.6
25
112.8 ± 1.721
38.3 ± 2.89
0.112 ± 0.085

Notes:

The compound numbers in each combination correspond to the compound numbers in Table 3.

¹Mass (mg) of the corresponding compound;

²Molar ratio of compounds;

³Volume (μL) of organic solvent;

⁴pH of the aqueous solution;

⁵Volume (mL) of aqueous solution.

TABLE 5

Controllable Adjustment of Curcumin Self-Dispersing Particles

Combination
Compound
[W]¹
[R]²
[O]³
pH⁴
[W]⁵
Size_(nm)
Zeta_(mV)
PDI

Compound Ratio

1
38, 111
0.5, 3.0
1:6
250
7.4
40
205.7 ± 2.321
−40.7 ± 2.11
0.202 ± 0.004

2
38, 111
0.7, 3.0
1:4
250
7.4
40
123.8 ± 1.896
−50.0 ± 1.40
0.205 ± 0.008

3
38, 111
1.4, 3.0
1:2
250
7.4
40
101.3 ± 1.280
−51.0 ± 2.10
0.017 ± 0.012

4
38, 111
2.8, 3.0
1:1
250
7.4
40
109.7 ± 1.021
−45.7 ± 1.21
0.102 ± 0.014

5
38, 111
5.6, 3.0
2:1
250
7.4
40
1445 ± 52.22
−43.3 ± 1.78
0.251 ± 0.069

6
38, 111
11.1, 3.0
4:1
250
7.4
40
2026 ± 101.2
−48.7 ± 1.57
0.321 ± 0.109

7
38, 111
16.7, 3.0
6:1
250
7.4
40
3536 ± 150.2
−33.7 ± 2.51
0.373 ± 0.141

Aqueous Solution pH

8
39, 112
2.7, 3.0
1:1
100
8.0
20
3026 ± 111.2
−18.7 ± 1.37
0.411 ± 0.112

9
39, 112
2.7, 3.0
1:1
100
7.0
20
133.4 ± 1.396
−43.0 ± 1.80
0.185 ± 0.018

10
39, 112
2.7, 3.0
1:1
100
6.0
20
113.8 ± 1.796
−49.0 ± 1.31
0.115 ± 0.007

11
39, 112
2.7, 3.0
1:1
100
4.0
20
2726 ± 181.2
−6.71 ± 0.11
0.521 ± 0.212

Organic Solvent (300 μL)

12
109, 111
1.4, 3.0
1:2
THF
7.0
20
3437 ± 98.24
8.01 ± 2.04
0.501 ± 0.046

13
109, 111
1.4, 3.0
1:2
MeOH
7.0
30
4401 ± 132.1
3.12 ± 0.24
0.321 ± 0.041

14
109, 111
1.4, 3.0
1:2
MeOH-DMF
7.0
30
2763 ± 72.34
5.49 ± 0.14
0.445 ± 0.021

15
109, 111
1.4, 3.0
1:2
ACN
7.0
30
1023 ± 72.10
28.0 ± 8.24
0.381 ± 0.091

16
109, 111
1.4, 3.0
1:2
EtOH
7.0
30
553.8 ± 12.22
32.0 ± 4.14
0.281 ± 0.071

17
109, 111
1.4, 3.0
1:2
DMF
7.0
30
153.8 ± 2.312
42.0 ± 2.74
0.181 ± 0.021

18
109, 111
1.4, 3.0
1:2
DMSO
7.0
30
123.8 ± 1.706
49.0 ± 2.14
0.109 ± 0.017

Aqueous Solution (pH 7.4)

19
38, 111
2.8, 3.0
1:1
250
Barbiturate buffer
20
122.4 ± 1.025
−48.7 ± 1.71
0.112 ± 0.032

20
38, 111
2.8, 3.0
1:1
250
Phosphate buffer
20
118.7 ± 1.231
−46.7 ± 2.21
0.099 ± 0.004

21
38, 111
2.8, 3.0
1:1
250
Phosphate-citrate buffer
20
109.3 ± 2.211
−49.7 ± 1.09
0.107 ± 0.011

Notes:

The compound numbers in each combination correspond to the compound numbers in Table 3.

¹Mass (mg) of the corresponding compound;

²Molar ratio of compounds;

³Organic solvent (μL);

⁴pH of the aqueous solution;

⁵Aqueous solution (mL).

TABLE 6

Comparative Experiments on the Construction Conditions

of the Curcumin Self-Dispersing Particle System

Combination
Compound
[W]¹
[R]²
[O]³
pH⁴
[W]⁵

1
44, 111
3.5, 3.7
1:1
150
9.0
20

2
39, 111
3.0, 3.7
1:1
150
4.6
20

3
102, 111
3.9, 3.7
1:1
150
9.0
20

4
79, 112
3.3, 3.4
1:1
150
7.2
20

5
80, 112
3.5, 3.4
1:1
150
7.8
20

6
108, 113
3.9, 3.0
1:1
150
7.8
20

7
27, 111
2.8, 3.7
1:1
150
7.8
20

—

—
—
—

Notes:

The compound numbers in each combination correspond to the compound numbers in Table 3.

¹Mass (mg) of the corresponding compound;

²Molar ratio of compounds;

³Volume (μL) of organic solvent;

⁴pH of the aqueous solution;

⁵Volume (mL) of aqueous solution.

Claims

1. A curcumin self-dispersing particle system, comprising at least one compound having a chemical structure represented by general formula I, II, or III and at least one compound having a chemical structure represented by general formula IV, wherein said compounds are categorized and combined based on their ionization capability and ionization category, and interact at room temperature and pressure in an aqueous solution having a pH value of 0 to 14 to form a crystalline particle system uniformly dispersed in the aqueous solution:
2. The curcumin self-dispersing particle system according to claim 1, wherein the compound having a chemical structure represented by general formula I, II, III, or IV is selected from at least one of the following numbered compounds and/or their derivatives, salts, hydrates, and/or isosteres; wherein the compound having a chemical structure represented by general formula I, II, or III, comprising two six-membered rings and one five-membered ring fused together, is selected from at least one of the following numbered compounds:
3. The curcumin self-dispersing particle system according to claim 1, wherein the curcumin self-dispersing particle system is selected from at least one of the particle systems obtained from a combination of the following compounds:
4. The curcumin self-dispersing particle system according to claim 1, wherein the combination of compounds satisfies the following combination conditions: the pKa values of different compounds with ionization capability and their conjugate salts are denoted as pKan, n≥1, wherein the pKa value of the one or more compounds or their conjugate salts with the minimum pKa value is denoted as pKamin, the pKa value of the one or more compounds or their conjugate salts with the maximum pKa value is denoted as pKamax, the pKa value of one or more acidic compounds or their conjugate base salts with the minimum pKa value is denoted as pKamin-Acid, the pKa value of the one or more basic compounds or their conjugate acid salts with the maximum pKa value is denoted as pKamax-Base, and a pH value of the aqueous solution is denoted as pHa, when the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: the combination condition includes that the pKa value of the one or more compounds and/or the conjugate salts of one or more compounds with the minimum pKa value, i.e., pKamin, should be at least two units smaller than the pKa values of all other compounds in the combination, i.e., pKan≥pKamin+2;when the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: the combination condition includes that the pKa value of the one or more compounds and/or the conjugate salts of one or more compounds with the maximum pKa value, i.e., pKamax, should be at least two units larger than the pKa values of all other compounds in the combination, i.e., pKan≤pKamax−2;when the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: there is no requirement for the relative magnitude of the pKa values of the combined compounds;when the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: there is no requirement for the relative magnitude of the pKa values of the combined compounds;when the combined compounds are one or more acidic compounds and one or more basic compounds: there is no requirement for the relative magnitude of the pKa values of the combined compounds;when the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: there is no requirement for the relative magnitude of the pKa values of the combined compounds;when the combined compounds are one or more permanently ionized compounds and one or more basic compounds: there is no requirement for the relative magnitude of the pKa values of the combined compounds;when the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: the combination condition includes that the pKa value of the one or more acidic compounds with the minimum pKa value, i.e., pKamin-Acid, should be at least four units larger than the pKa value of the one or more basic compounds with the maximum pKa value, i.e., pKamax-Base, i.e., pKamin-Acid−pKamax-Base≥4;if a permanently ionized compound contains an acidic group capable of ionization, it shall also be treated as an acidic compound for comparison involving pKa relationships;one or more compounds without ionization capability can be added to each of the above combinations to form corresponding new combinations, compounds without ionization capability in the new combinations are not involved in the comparison of pKa values of compounds in the combination conditions.
5. The curcumin self-dispersing particle system according to claim 1, wherein a molar ratio of the compounds satisfies the following conditions: when the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: the molar ratio of the one or more compounds and/or the conjugate salts of one or more compounds with the minimum pKa value to all other compounds in the combination is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of all other compounds in the combination, i.e., the added non-ionizable compounds can partially or completely replace all other compounds in the original combination;when the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: the molar ratio of the one or more compounds and/or the conjugate salts of one or more compounds with the maximum pKa value to all other compounds in the combination is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of all other compounds in the combination, i.e., the added non-ionizable compounds can partially or completely replace all other compounds in the original combination;when the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: the molar ratio of the one or more acidic compounds to the one or more conjugate acid salts of basic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of the acidic compounds, i.e., the added non-ionizable compounds can partially or completely replace the acidic compounds in the original combination;when the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: the molar ratio of the one or more basic compounds to the one or more conjugate base salts of acidic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of the basic compounds, i.e., the added non-ionizable compounds can partially or completely replace the basic compounds in the original combination;when the combined compounds are one or more acidic compounds and one or more basic compounds: the molar ratio of the one or more acidic compounds to the one or more basic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount may be included in the molar amount of any compound in the combination depending on the preparation environment, i.e., the added non-ionizable compounds can partially or completely replace the compound in the original combination whose molar amount they are included in;when the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: the molar ratio of the one or more permanently ionized compounds to the one or more acidic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of the acidic compounds, i.e., the added non-ionizable compounds can partially or completely replace the acidic compounds in the original combination;when the combined compounds are one or more permanently ionized compounds and one or more basic compounds: the molar ratio of the one or more permanently ionized compounds to the one or more basic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of the basic compounds, i.e., the added non-ionizable compounds can partially or completely replace the basic compounds in the original combination;when the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: there are no requirements for the molar ratio between the one or more acidic compounds and the one or more basic compounds; the molar ratio of the one or more permanently ionized compounds to the acidic and basic compounds is 1:50 to 50:1; when one or more non-ionizable compounds are added, their molar amount is included in the molar amount of the one or more acidic compounds and/or the one or more basic compounds, i.e., the added non-ionizable compounds can partially or completely replace the one or more acidic compounds and/or the one or more basic compounds in the original combination.
6. The curcumin self-dispersing particle system according to claim 1, wherein the particles of the curcumin self-dispersing particle system are all crystalline particles having a diameter of 30 nm to 3000 nm.
7. The curcumin self-dispersing particle system according to claim 1, wherein an absolute value of a Zeta potential of the curcumin self-dispersing particle system in an aqueous solution having a pH value of 0 to 14 at room temperature and pressure is between 15 mV and 80 mV, wherein the Zeta potential is denoted as ζ: when the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than −15 mV, i.e., ζ≤−15 mV;when the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;when the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;when the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than −15 mV, i.e., ζ≤−15 mV;when the combined compounds are one or more acidic compounds and one or more basic compounds: depending on the preparation conditions, the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not greater than −15 mV, or not less than 15 mV, i.e., ζ≤−15 mV or ζ≥15 mV;when the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;when the combined compounds are one or more permanently ionized compounds and one or more basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;when the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: the Zeta potential of the prepared curcumin self-dispersing particle dispersion under the preparation conditions is not less than 15 mV, i.e., ζ≥15 mV;when one or more non-ionizable compounds are added to each of the above combinations to form corresponding new combinations, the Zeta potential of the curcumin self-dispersing particle dispersion prepared by a new combination under the preparation conditions remains consistent with the Zeta potential of the curcumin self-dispersing particle dispersion prepared by an original combination under the corresponding preparation conditions.
8. A method for preparing the curcumin self-dispersing particle system according to claim 1, comprising the following steps: (1) selecting at least one compound from the chemical structures shown in general formula I, II or III, and at least one compound from the chemical structures shown in general formula IV;(2) determining the pKa values of the selected compounds satisfying the combination conditions;(3) determining the molar ratio of the selected compounds;(4) preparing an aqueous solution with a pH value that satisfies the requirements;(5) combining the selected compounds with an organic solvent to obtain an organic mixture;(6) mixing the obtained organic mixture with the prepared aqueous solution to obtain a curcumin self-dispersing particle dispersion comprising the selected compounds;(7) optionally, removing the organic solvent from the curcumin self-dispersing particle dispersion to obtain a curcumin self-dispersing particle aqueous dispersion;(8) optionally, removing the aqueous phase from the curcumin self-dispersing particle aqueous dispersion to obtain curcumin self-dispersing particles comprising the selected compounds;(9) optionally, formulating curcumin self-dispersing particles comprising the selected compounds into various pharmaceutically acceptable dosage forms, including but not limited to injections, capsules, tablets, patches, sprays, or other suitable forms, or incorporating the particles into a matrix for non-pharmaceutical applications.
9. The curcumin self-dispersing particle system according to claim 1, wherein the aqueous solution satisfies the following requirements: when the combined compounds are one or more acidic compounds and/or one or more conjugate base salts of acidic compounds: the pH value of the aqueous solution should be at least two units greater than the minimum pKa value of all compounds in the combination, i.e., pHa≥pKamin+2;when the combined compounds are one or more basic compounds and/or one or more conjugate acid salts of basic compounds: the pH value of the aqueous solution should be at least two units less than the maximum pKa value of all compounds in the combination, i.e., pHa≤pKamax−2;when the combined compounds are one or more acidic compounds and one or more conjugate acid salts of basic compounds: the pH value of the aqueous solution should be at least two units less than the minimum pKa value of all compounds in the combination, i.e., pHa≤pKamin−2;when the combined compounds are one or more basic compounds and one or more conjugate base salts of acidic compounds: the pH value of the aqueous solution should be at least two units greater than the maximum pKa value of all compounds in the combination, i.e., pHa≥pKamax+2;when the combined compounds are one or more acidic compounds and one or more basic compounds: the pH value of the aqueous solution should be at least two units greater than the maximum pKa value of all compounds in the combination, or at least two units less than the minimum pKa value of all compounds in the combination, i.e., pHa≥pKamax+2 or pHa≤pKamin−2;when the combined compounds are one or more permanently ionized compounds and one or more acidic compounds: a pH value of the aqueous solution should be at least two units less than the minimum pKa value of the acidic compounds in the combination, i.e., pHa≤pKamin-Acid−2;when the combined compounds are one or more permanently ionized compounds and one or more basic compounds: a pH value of the aqueous solution should be at least two units greater than the maximum pKa value of the basic compounds in the combination, i.e., pHa≥PKamax-Base+2;when the combined compounds are one or more permanently ionized compounds, one or more acidic compounds, and one or more basic compounds: the pH value of the aqueous solution should be at least two units less than the minimum pKa value of the acidic compounds in the combination, and at least two units greater than the maximum pKa value of the basic compounds in the combination, i.e., pKamin-Acid−2≥pHa≥pKamax-Base+2;if a permanently ionized compound contains an acidic group capable of ionization, it shall also be treated as an acidic compound for comparison involving pH and/or pKa relationships;when one or more non-ionizable compounds are added to each of the above combinations to form corresponding new combinations, the aqueous solutions used in the preparation process of the new combinations are respectively the same as the original combinations;if the new combination contains only one or more permanently ionized compounds and one or more non-ionizable compounds, and the permanently ionized compounds do not contain an acidic group capable of ionization, there are no requirements for the relative magnitude between the pH value of the aqueous solution and the pKa value of the compound.
10. An apparatus for preparing the curcumin self-dispersing particle system according to claim 1, comprising: (1) at least one mixing module configured to mix the compound(s) with an organic solvent to obtain an organic mixture, and to mix the organic mixture with an aqueous solution to obtain a dispersion of curcumin self-dispersing particles;(2) at least one solvent removal module configured to remove the solvent from the curcumin self-dispersing particle dispersion to obtain an aqueous curcumin self-dispersing particle dispersion or curcumin self-dispersing particles;(3) at least one system preparation module configured to process the curcumin self-dispersing particles and/or the aqueous curcumin self-dispersing particle dispersion to obtain the curcumin self-dispersing particle system.
11. A method of diagnosing a condition in a subject, comprising administering to the subject a diagnostically effective amount of the curcumin self-dispersing particle system of claim 1.
12. A method of treating a condition in a subject, comprising administering to the subject a therapeutically effective amount of the curcumin self-dispersing particle system of claim 1.
13. A method of forming a luminescent micro-nano material, comprising incorporating the curcumin self-dispersing particle system of claim 1 into a matrix.
14. A method of forming an energy conversion micro-nano material, comprising incorporating the curcumin self-dispersing particle system of claim 1 into a matrix.

Priority Claims (1)

Number	Date	Country	Kind
202210541669.6	May 2022	CN	national

PCT Information

Filing Document	Filing Date	Country	Kind
PCT/CN2023/092026	5/4/2023	WO

A CURCUMIN SELF-DISPERSING PARTICLE SYSTEM, ITS PREPARATION METHOD, PREPARATION DEVICE, AND APPLICATIONS

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Date Filed

Date Published

Inventors

Original Assignees

CPC

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Abstract

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Priority Claims (1)

PCT Information