A eutectic mixture with solubilizing and absorption-promoting effect and a drug-loaded composition

Abstract

The present application relates to a kind of eutectic mixture with solubilization and absorption promotion effect, it includes: first component and second component;The first component is fatty acid, second component is amine-based compound;The first component and second component form eutectic mixture after mixing;The eutectic mixture dissolved in water can form stable copolymer similar to micelle, the copolymer can improve the solubility of poorly soluble drug molecules in water and promote drug absorption. Using the eutectic mixture and poorly soluble drug molecules are prepared together, it can be used to improve the solubility of poorly soluble drug, improve the permeability of poorly soluble drug to biological barrier and then improve bioavailability, can take representative surfactant to solubilize and promote the penetration of poorly soluble drug molecules, solve the problem of existing surfactant sensitization.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug-loaded compositions, in particular to a eutectic mixture with solubilization and absorption promotion effect and a drug-loaded composition, which has excellent solubilization and absorption promotion effect on pharmaceutical ingredients. BACKGROUND

[0002] Solubility and permeability are important properties in drug discovery, which are key properties related to formulation and drug efficacy. 40% of marketed drugs and 90% of candidate compounds are poorly soluble compounds. For these poorly soluble compounds, liquid formulations cannot be developed due to the lack of physiologically acceptable safe solvents; even if solid or semi-solid formulations can be prepared, the drug cannot be dissolved at the administration site, or the dissolved drug molecules cannot cross the biological barrier (such as the small intestine mucosa in oral administration, the cornea in eye administration, and the stratum corneum in transdermal administration), resulting in limited drug absorption or low bioavailability. Therefore, solubilization and absorption promotion of drug molecules are very important research topics in pharmaceutical sciences.

[0003] Surfactant solubilization is the most commonly used solubilization and absorption promotion strategy in the field of drug-loaded compositions. Surfactant molecules contain hydrophilic and lipophilic groups, which can self-assemble into micellar structures in water to increase the solubility of poorly soluble drugs. Surfactant molecules can disrupt the directional arrangement of molecules in biological membranes, or extract lipid components from biological membranes through surfactant micelles, thereby reducing the barrier effect of biological membranes. Some studies have also found that micelles can penetrate biological barriers such as small intestine mucosa as a whole, thereby promoting the transmembrane absorption of the loaded drug. However, existing surfactants have strong sensitization, such as polyoxyethylene castor oil or Tween. Before administration of formulations containing these surfactants, other drugs are often given to patients for pre-desensitization treatment. Recent studies have found that the PEG hydrophilic group in these surfactants is the culprit of allergic reactions, and this situation may be more common than we realize (M.C. Castells and E.J. Phillips, New Engl J Med 384, 2020, 643-649. J. de Vrieze, Science 371, 2021, 10-11. M.A. Bruusgaard-Mouritsen, et al. Clin Exp Allergy 51, 2021, 463-470. C.A. Stone, et al. J Aller Cl Imm-Pract 7, 2019, 1533-1540).

[0004] Therefore, developing a new compound or composition for solubilization and absorption of drug molecules, instead of using surfactants, is of great significance to solve the problem of sensitization caused by the existing surfactant solubilization, improve the bioavailability of drugs, ensure the safety of drug-loaded compositions, and expand the range of adaptors of drug-loaded compositions. SUMMARY

[0005] (I) Technical problems to be solved

[0006] In view of the above-mentioned defects and deficiencies of the prior art, the present application provides a eutectic mixture with solubilization and absorption effects and a drug-loaded composition, which can effectively improve the problems of poor drug formability and low bioavailability of poorly soluble drugs, solve the problem of sensitization caused by the existing surfactant solubilization, and improve the safety of drug-loaded compositions.

[0007] (II) Technical solutions

[0008] In order to achieve the above-mentioned purposes, the main technical solutions adopted by the present application include:

[0009] In a first aspect, the present application provides a eutectic mixture with solubilization and absorption effects, which comprises: a first component and a second component; the first component is a fatty acid, and the second component is an amine-containing compound; the first component and the second component form a eutectic mixture after mixing;

[0010] The eutectic mixture can form stable copolymers similar to micelles when dissolved in water, and the copolymers can improve the solubility of poorly soluble drug molecules in water and promote drug absorption.

[0011] The eutectic mixture described above can be used to improve the drug formability of poorly soluble drugs, improve the permeability of poorly soluble drugs to biological barriers, and thus improve the bioavailability.

[0012] According to a preferred embodiment of the present application, the fatty acid is selected from fatty acids with a carbon chain length of 10 or more C; further preferably, the fatty acid is selected from one or a combination of two or more of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, linolenic acid, and linoleic acid.

[0013] According to a preferred embodiment of the present application, the amine-containing compound is a compound containing primary and / or secondary amines; further preferably, the amine-containing compound is meglumine or lysine or a combination thereof.

[0014] According to a preferred embodiment of the present application, the molar ratio of the first component to the second component is 4:1 to 1:4; more preferably, it is 2:1 to 1:1.

[0015] According to a preferred embodiment of the present application, the preparation method of the eutectic mixture is as follows:

[0016] The fatty acid and the amine-containing compound are dissolved in an organic solvent (such as ethanol, etc.) or a mixed solvent of an organic solvent (such as ethanol, etc.) and water, stirred uniformly at room temperature or under heating, and the solvent is removed to obtain the eutectic mixture. The method for removing the solvent is: first, evaporation (such as rotary evaporation) is used to remove most of the organic solvent, a small amount of residual organic solvent (a small amount of organic solvent and water) is allowed to remain, and then freeze-drying or vacuum drying is used to further remove the solvent.

[0017] In a second aspect, the present application also relates to a drug-loaded composition comprising a poorly soluble drug and the eutectic mixture with solubilization and absorption promotion effect according to any one of the above embodiments.

[0018] In the present application, the poorly soluble drug refers to a drug with low solubility in water or physiological body fluid, thereby affecting the drugability and / or bioavailability thereof, and belongs to the poorly soluble drug classified as the second and fourth in the currently widely accepted biopharmaceutics classification system; or,

[0019] In the present application, the poorly soluble drug is determined according to the method for determining the solubility of a drug in the Chinese Pharmacopoeia (2020 edition), which is suitable for a drug with strong fat solubility and poor solubility in physiological body fluid. It must be pointed out that the chemical structure of the drug itself is not a decisive factor affecting the present application.

[0020] Specifically, the "poorly soluble drug" in the present application refers to a drug with a solubility of less than 1 g in 100 ml of water at 25°C; for example, an alkaloid anticancer drug, a statin and a fibrate hypolipidemic drug, an antibiotic, or an immunosuppressant; preferably, the poorly soluble drug is one or more selected from paclitaxel, docetaxel, camptothecin, topotecan, irinotecan and derivatives thereof, fenofibrate, simvastatin, amphotericin B, itraconazole, cyclosporin A and rapamycin.

[0021] According to a preferred embodiment of the present application, in the drug-loaded composition, the mass ratio of the poorly soluble drug to the eutectic mixture is 0.01-10.

[0022] According to a preferred embodiment of the present application, the preparation method of the drug-loaded composition is as follows: the poorly soluble drug is dissolved in an organic solvent (such as ethanol, etc.), the eutectic mixture is added for dissolution, the organic solvent is removed by rotary evaporation or not, and then water is added to disperse uniformly, thereby obtaining a clear or slightly opalescent solution.

[0023] In a third aspect, the present application also relates to the application of the combination of the fatty acid and the amine-containing compound in improving the solubility of the poorly soluble drug molecule in water and promoting the absorption of the drug molecule.

[0024] The application includes: using the combination of the fatty acid and the amine-containing compound and the poorly soluble drug molecule to prepare a liquid drug preparation.

[0025] (III) Beneficial Effects

[0026] The present application provides a eutectic mixture with solubilization and absorption promotion effect, which can solubilize and promote penetration of poorly soluble drug molecules with surfactants. The components of the eutectic mixture are all from natural substances (such as fatty acids and lysine) or substances recognized as safe (such as meglumine), and do not contain PEG, thus solving the problem of existing surfactant sensitization, improving the bioavailability of poorly soluble drugs, ensuring the safety of drug-loaded compositions, improving the drugability of poorly soluble drugs, and widening the application range of drug-loaded compositions. DETAILED DESCRIPTION

[0027] In order to better explain the present application, the present application is described in detail below in combination with specific embodiments.

[0028] The eutectic mixture provided in the embodiments of the present application is mainly composed of fatty acids and amine-containing compounds. In the research on the drug preparation method and solubilization method of poorly soluble drugs, the inventors surprisingly found that fatty acids and amine-containing compounds (such as meglumine or lysine) can form a eutectic mixture, and more importantly, they can copolymerize in water (form a copolymer), forming a micelle-like structure. Among them, the amine-containing compound is crucial to the stability of the copolymer. Fatty acids and their salts themselves have a certain surface activity and can form a micelle structure under certain conditions, and can be used as a detergent. However, due to hydrolysis, high fatty acid salts cannot form stable micelles in water at room temperature. For example, when sodium oleate is dissolved in water, it hydrolyzes to form oleic acid and precipitates, becoming a turbid emulsion. Unless in a strong alkaline environment or at high temperature (50°C), the hydrolysis can be inhibited to form a transparent micelle solution. Obviously, this is not suitable for drug delivery.

[0029] In the present application, the eutectic mixture formed by fatty acids and amine-containing compounds can be dissolved in water to form a clear and transparent solution. Molecular simulation found that fatty acids spontaneously aggregate in water to form aggregates with carbon chains inside and carboxyl groups outside. The amine group and the carboxyl group are in dynamic interaction, forming a stable copolymer that prevents the precipitation of fatty acids. The critical aggregation concentration (CAC) of the copolymer is measured by the transition of the ACQ fluorescence probe from "OFF" to "ON". With the extension of the carbon chain of the fatty acid or the presence of double bonds, the CAC of the aggregate decreases, even lower than the critical micelle concentration (CMC) of commonly used surfactants, which indicates that the copolymer has good solubilization effect. In addition, high fatty acids themselves have good penetration promotion or P-gP inhibition effect. In view of the above mechanism, the eutectic mixture formed by fatty acids and amine-containing compounds has potential drug solubilization and absorption promotion effect.

[0030] For a better understanding of the above technical solutions, the following will be described and verified in conjunction with exemplary embodiments of the present application. However, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more clear and thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0031] Examples 1-8

[0032] Examples 1-8 are all meglumine-containing eutectic mixtures: take the amount of meglumine and fatty acid in Table 1, mix, add 20 mL of anhydrous ethanol, dissolve, stir for 12 h. Rotary evaporation at 60°C under reduced pressure to dryness, collect the rotary evaporation product, freeze-dry, and obtain.

[0033] Table 1: Dosage of meglumine and each fatty acid and CAC and melting point of eutectic mixture

[0034]

[0035]

[0036] The melting points of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid and meglumine are 31.5, 44-46, 54, 63, 67-72, 13-14, -12 and 128-129°C, respectively. It is found that the melting points of each mixture in the examples are lower than that of meglumine (Table 1), indicating the formation of eutectic mixtures.

[0037] The critical aggregation concentration CAC of each eutectic mixture is shown in Table 1. Experiments show that as the carbon chain length of the fatty acid increases and the unsaturated bond increases, the CAC gradually decreases, even lower than the critical micelle concentration of common surfactants. Prepare 1% (mass fraction) and 0.5% aqueous solutions of each mixture in the examples, respectively, and investigate the solubility of paclitaxel, cyclosporin A and itraconazole in them, and compare with the same concentration of surfactants Cremophor EL and Tween 80 aqueous solution. The comparison results are shown in Table 2. At the same concentration, the solubilizing ability of most eutectic mixtures (especially examples 2-8) is stronger than that of common surfactants.

[0038] Table 2: Comparison of solubilizing ability of meglumine-containing examples and different surfactants for paclitaxel, cyclosporin A and itraconazole

[0039]

[0040]

[0041] Examples 9-15

[0042] Examples 9-15 are all eutectic mixtures containing lysine: Take the amount of lysine and fatty acid in Table 3, mix, add 20 mL of anhydrous ethanol, dissolve, stir for 12 h. Evaporate to dryness at 60 °C under reduced pressure, collect the rotary evaporation product, and freeze-dry to obtain the product. The CAC of each eutectic mixture is shown in Table 3.

[0043] Table 3: Amount of lysine and fatty acid used in each example and CAC and melting point of the eutectic mixture

[0044]

[0045]

[0046] The melting points of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and lysine are 31.5, 44-46, 54, 63, 67-72, 13-14, -12, and 212-214 °C, respectively. It was found that the melting points of the mixtures in each example were lower than that of lysine (Table 3), indicating the formation of eutectic mixtures. The critical aggregation concentration CAC of each eutectic mixture is shown in Table 3. Similarly, as the carbon chain length of the fatty acid increases and the number of unsaturated bonds increases, the CAC gradually decreases, even below the critical micelle concentration of common surfactants. Prepare 1% (mass concentration) and 0.5% aqueous solutions of each example mixture, and investigate the solubility of paclitaxel, cyclosporin A, and itraconazole in them (see Table 4), and compare with the same concentration of Cremophor EL and Tween 80 aqueous solutions (Table 2). As can be seen from Table 4, at the same concentration, the solubilizing ability of most of the eutectic mixtures (especially Examples 11-15) is stronger than that of common surfactants.

[0047] Table 4: Comparison of the solubilizing ability of each example containing lysine and different surfactants for paclitaxel, cyclosporin A, and itraconazole

[0048]

[0049]

[0050] Examples 16-23

[0051] Examples 16-23 are the application of eutectic mixtures: preparation of paclitaxel aqueous solution combination formula.

[0052] According to the prescription amount listed in Table 5, dissolve paclitaxel in ethanol, add the eutectic mixture (prepared from Examples 4-8 and Examples 13-15) to dissolve, and then dilute with normal saline to 6 mL to obtain a stable and clear transparent aqueous solution, indicating that the eutectic mixture of the present application has a solubilizing effect on paclitaxel, can replace surfactants, and solves the problem of surfactant sensitization.

[0053] Table 5 Paclitaxel aqueous solution combination formula

[0054]

[0055]

[0056] Examples 24-31

[0057] Examples 24-31 are the application of the eutectic mixture: preparation of cyclosporin A aqueous solution combination formula.

[0058] According to the prescription amount listed in Table 6, cyclosporin A was dissolved in ethanol, and the eutectic mixture (prepared from Examples 4-8 and Examples 13-15) was added to dissolve, and then ethanol was removed by rotary evaporation, and diluted with normal saline to 25 mL, to obtain a stable and clear transparent aqueous solution, indicating that the eutectic mixture of the present application has a solubilizing effect on cyclosporin A, and can replace the surfactant and solve the problem of surfactant sensitization.

[0059] Table 6 Cyclosporin A aqueous solution combination formula

[0060]

[0061] Examples 32-39

[0062] Examples 32-39 are the application of the eutectic mixture: preparation of itraconazole aqueous solution combination formula.

[0063] According to the prescription amount listed in Table 7, itraconazole was dissolved in ethanol, and the eutectic mixture (prepared from Examples 4-8 and Examples 13-15) was added to dissolve, and then diluted with normal saline to 20 mL, to obtain a stable and clear transparent aqueous solution, indicating that the eutectic mixture of the present application has a solubilizing effect on itraconazole, and can replace the surfactant and solve the problem of surfactant sensitization.

[0064] Table 7 Itraconazole aqueous solution combination formula

[0065]

[0066] Examples 40-51

[0067] Examples 40-51 are eutectic mixtures of fatty acids and meglumine in different molar ratios (4:1, 2:1, 1:4): Take the amounts of meglumine and fatty acids in Table 8, mix, add 50 mL of absolute ethanol, dissolve, stir for 12 h. Evaporate to dryness at 60 °C under reduced pressure, collect the evaporated product, and lyophilize to obtain the product. Prepare 1% (mass fraction) aqueous solutions of the mixtures of each example, and investigate the solubility of cyclosporin A in each (Table 8). The results show that cyclosporin A has similar solubility in 1% (mass fraction) aqueous solutions of each example compared with the eutectic mixture of fatty acids and meglumine in a ratio of 1:1 (Table 2).

[0068] Table 8 Amounts of meglumine and each fatty acid and the solubilizing capacity of 1% (mass fraction) aqueous mixtures for cyclosporin A

[0069]

[0070]

[0071] Examples 52-60

[0072] Examples 52-60 are eutectic mixtures of fatty acids and lysine in different molar ratios (4:1, 2:1, 1:4): Take the amounts of lysine and fatty acids in Table 9, mix, add 50 mL of absolute ethanol, dissolve, stir for 12 h. Evaporate to dryness at 60 °C under reduced pressure, collect the evaporated product, and lyophilize to obtain the product. Prepare 1% (mass fraction) aqueous solutions of the mixtures of each example, and investigate the solubility of cyclosporin A in each (Table 9). The results show that cyclosporin A has similar solubility in 1% (mass fraction) aqueous solutions of each example compared with the eutectic mixture of fatty acids and lysine in a ratio of 1:1 (Table 4).

[0073] Table 9 Amounts of lysine and each fatty acid and the solubilizing capacity of 1% (mass fraction) aqueous mixtures for cyclosporin A

[0074]

[0075]

[0076] It should be finally pointed out that the above embodiments are only used to illustrate the technical solutions of the present application, but not to limit the same; although the above embodiments only verify the solubilizing ability of the eutectic mixture on typical poorly soluble drugs such as paclitaxel, cyclosporin A and itraconazole, it is understood that the eutectic mixture provided by the present application also has good solubilizing and penetration promoting effects on other poorly soluble drugs, which include docetaxel, camptothecin, topotecan, irinotecan and its derivatives, fenofibrate, simvastatin, amphotericin B and rapamycin, etc. The poorly soluble drugs can be replaced by the surface active agent to prepare stable and clear transparent aqueous injection of the poorly soluble drugs, so as to greatly improve the bioavailability of the drugs.

[0077] Although the present application has been described in detail with reference to the foregoing embodiments, it should be understood that those skilled in the art can make modifications to the technical solutions described in the foregoing embodiments, or make equivalent replacements to some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A drug-loaded composition, characterized in that, It comprises: a poorly soluble drug and a eutectic mixture, wherein the poorly soluble drug is cyclosporine A, and the eutectic mixture is a eutectic mixture composed of oleic acid or linoleic acid and lysine. The preparation method is as follows: oleic acid and lysine, or linoleic acid and lysine, are dissolved in anhydrous ethanol, evaporated to dryness, the product is collected, and freeze-dried to obtain the product; wherein the molar ratio of oleic acid to lysine or linoleic acid to lysine is 4:1, 2:1, or 1:

4. Then, an aqueous solution of the eutectic composition was prepared, and cyclosporine A was dissolved in the aqueous solution, wherein the mass percentage of the eutectic composition in the aqueous solution was 1%.

2. The application of an aqueous solution of a eutectic mixture of oleic acid or linoleic acid and lysine in the preparation of an aqueous solution of cyclosporine A, characterized in that, The eutectic mixture is a eutectic mixture composed of oleic acid or linoleic acid and lysine. The preparation method is as follows: dissolve oleic acid and lysine, or linoleic acid and lysine in anhydrous ethanol, evaporate to dryness, collect the product, and freeze-dry to obtain the product. The molar ratio of oleic acid to lysine or linoleic acid to lysine is 4:1, 2:1 or 1:4; the mass percentage of the eutectic composition in the aqueous solution is 1%.

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