P-menthane-3-β-ol-cyclodextrin inclusion complex co-crystal, preparation method thereof and pharmaceutical composition

Abstract

The application relates to the fields of pharmaceutical preparations and fine chemical technology, in particular to a patchouli alcohol-cyclodextrin inclusion compound eutectic crystal, a preparation method thereof and a pharmaceutical composition. The patchouli alcohol-cyclodextrin inclusion compound eutectic crystal is obtained by wrapping patchouli alcohol with cyclodextrin, and then co-crystallizing the cyclodextrin and the patchouli alcohol to form the inclusion compound eutectic crystal; the mass ratio of the patchouli alcohol to the cyclodextrin is 1: (1-20). Compared with traditional inclusion compounds, the patchouli alcohol-cyclodextrin inclusion compound eutectic crystal has a clear crystal structure and better stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations and fine chemical technology, in particular to a p-mentha-2,8-dien-1-ol-cyclodextrin inclusion complex co-crystal, a preparation method thereof and a pharmaceutical composition. BACKGROUND

[0002] P-mentha-2,8-dien-1-ol, also known as patchouli alcohol, is a tricyclic sesquiterpene compound existing in natural plants, with a molecular formula of C 15 H 26 O and a molecular weight of 222.37. It is a colorless crystal with a unique aroma characteristic. The volatile oil of p-mentha-2,8-dien-1-ol in traditional Chinese medicine is used for dampness, heat, and vomiting, etc. P-mentha-2,8-dien-1-ol, as its main component, has high potential medicinal value. However, p-mentha-2,8-dien-1-ol has poor water solubility (24℃ solubility is 41.8 mg / L) and is easy to volatilize, which limits its application in pharmaceutical preparations.

[0003] To solve the above problems, the existing technology mainly improves by using new preparation technology as the breakthrough point. For example, there is a method that can use amino hollow mesoporous silica (HMSN) as a carrier to load p-mentha-2,8-dien-1-ol, and then modify the HMSN to make it positively charged. NH2-HMSN is adsorbed in the negatively charged gastric mucosa mucus layer through electrostatic interaction, thereby increasing the adhesion and retention time of the carrier to the gastric mucosa. This new preparation has achieved good effect in the treatment of gastric ulcer, but it may not be suitable for other disease types, and there are problems such as complex preparation method and high production cost.

[0004] Therefore, it is necessary to provide a p-mentha-2,8-dien-1-ol pharmaceutical preparation with good water solubility, high stability and a relatively simple preparation method. SUMMARY

[0005] Based on this, one or more embodiments of the present application provide a p-mentha-2,8-dien-1-ol-cyclodextrin inclusion complex co-crystal, a pharmaceutical composition thereof and an application. The p-mentha-2,8-dien-1-ol-cyclodextrin inclusion complex of the present application has good water solubility, high stability and a relatively simple preparation method.

[0006] The technical scheme of the present application includes the following contents:

[0007] A p-mentha-2,8-dien-1-ol-cyclodextrin inclusion complex co-crystal, wherein the structure of the inclusion complex co-crystal comprises p-mentha-2,8-dien-1-ol and cyclodextrin coated on the surface of the p-mentha-2,8-dien-1-ol, and the mass ratio of the p-mentha-2,8-dien-1-ol to the cyclodextrin is 1: (1-20).

[0008] In one embodiment, the cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

[0009] When the cyclodextrin is β-cyclodextrin, the X-ray powder diffraction pattern of the broadleaf alcohol-cyclodextrin inclusion complex co-crystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.8°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°;

[0010] When the cyclodextrin is γ-cyclodextrin, the X-ray powder diffraction pattern of the broadleaf alcohol-cyclodextrin inclusion complex co-crystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.8°±0.2°, 7.4°±0.2°, 10.2°±0.2°, 10.4°±0.2°, 11.7°±0.2°, 14.0°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 27.1°±0.2°.

[0011] In one embodiment, the solubility of the broadleaf alcohol-cyclodextrin inclusion complex co-crystal in water at 24°C-26°C is 10 μg / mL-50 μg / mL.

[0012] A preparation method of the broadleaf alcohol-cyclodextrin inclusion complex co-crystal described above, comprising the following steps:

[0013] The broadleaf alcohol is dissolved in an organic solvent to obtain a broadleaf alcohol solution, and the organic solvent is miscible with water;

[0014] Under the conditions of stirring and heating, the broadleaf alcohol solution is injected into an aqueous solution of cyclodextrin to mix, to obtain a mixed solution, and the injection amount satisfies that the mixed solution contains broadleaf alcohol and cyclodextrin in a mass ratio of 1:(1-20);

[0015] The mixed solution is allowed to stand to crystallize.

[0016] In one embodiment, the organic solvent comprises at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol; and / or

[0017] The cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

[0018] In one embodiment, the preparation method satisfies one or more of the following conditions:

[0019] (1) the concentration of the p-menthane-3-carboxamid solution is 0.1 mg / mL to 10 mg / mL;

[0020] (2) the concentration of the aqueous cyclodextrin solution is 3 mg / mL to 50 mg / mL;

[0021] (3) the stirring speed is 50 rpm to 1000 rpm;

[0022] (4) the heating temperature is 30 °C to 60 °C;

[0023] (5) the speed of injecting the p-menthane-3-carboxamid solution into the aqueous cyclodextrin solution is 0.5 to 2 mL / min;

[0024] (6) the volume ratio of the organic solvent to water in the mixed solution is 3: (7 to 60).

[0025] In one embodiment, when the aqueous cyclodextrin solution is an aqueous β-cyclodextrin solution, the concentration is 3 mg / mL to 15 mg / mL;

[0026] when the aqueous cyclodextrin solution is an aqueous γ-cyclodextrin solution, the concentration is 3 mg / mL to 50 mg / mL.

[0027] In one embodiment, in the step of standing the mixed solution for crystallization:

[0028] the standing is performed at 20 °C to 30 °C; and / or

[0029] the standing time is 2 h to 48 h.

[0030] In one embodiment, after standing the mixed solution for crystallization, the solid is collected and dried;

[0031] Optionally, the drying temperature is 30 °C to 60 °C;

[0032] Optionally, the drying time is 1 h to 24 h.

[0033] A pharmaceutical composition comprising:

[0034] 1) the p-menthane-3-carboxamid-cyclodextrin inclusion complex co-crystal described above, and

[0035] 2) a pharmaceutically acceptable carrier and / or excipient.

[0036] This application utilizes a cocrystal formed by encapsulating patchouli alcohol with cyclodextrin and co-crystallizing the cyclodextrin and patchouli alcohol. Compared to traditional inclusion compounds, the patchouli alcohol-cyclodextrin inclusion compound cocrystal of this application exhibits a well-defined crystal structure and better stability. Unlike conventional cocrystal preparation methods that utilize hydrogen bonds or electrostatic interactions between the drug and cocrystal ligands to form crystals, the inclusion compound cocrystal leverages the inclusion compound formation capability of cyclodextrin and patchouli alcohol. The two components participate in crystal formation as an inclusion compound, increasing both the water solubility and stability of patchouli alcohol. Preferably, the solubility of the patchouli alcohol-cyclodextrin inclusion compound cocrystal in water is 10 μg / mL to 50 μg / mL. Preferably, the patchouli alcohol-cyclodextrin inclusion compound cocrystal of this application exhibits almost no degradation within 14 days at 25°C and 60°C. Attached Figure Description

[0037] Figure 1 These are optical microscope images of the white powders obtained in Examples 1 and 2 of this application, where the scale bar is 50 μm. Patchouli alcohol / β-cyclodextrin corresponds to the white powder in Example 1, and patchouli alcohol / γ-cyclodextrin corresponds to the white powder in Example 2.

[0038] Figure 2 The images show the H-NMR spectra of the white powder, patchouli alcohol, β-cyclodextrin, and γ-cyclodextrin prepared in Examples 1 and 2 of this application, wherein patchouli alcohol / β-cyclodextrin corresponds to the white powder in Example 1, and patchouli alcohol / γ-cyclodextrin corresponds to the white powder in Example 2.

[0039] Figure 3 The infrared spectra of the white powder, patchouli alcohol, β-cyclodextrin, and γ-cyclodextrin prepared in Examples 1 and 2 of this application are shown. Patchouli alcohol / β-cyclodextrin corresponds to the white powder in Example 1, and patchouli alcohol / γ-cyclodextrin corresponds to the white powder in Example 2.

[0040] Figure 4 The PXRD spectra of the white powder, β-cyclodextrin, and γ-cyclodextrin prepared in Examples 1 and 2 of this application are shown, where the horizontal axis is the angle 2θ (°) and the vertical axis is the intensity. Patchouli alcohol / β-cyclodextrin corresponds to the white powder in Example 1, and patchouli alcohol / γ-cyclodextrin corresponds to the white powder in Example 2.

[0041] Figure 5 This is a comparison chart of the DSC detection results of the white powder obtained in Examples 1 and 2 of this application and the patchouli alcohol monomer, wherein patchouli alcohol / β-cyclodextrin corresponds to the white powder in Example 1 and patchouli alcohol / γ-cyclodextrin corresponds to the white powder in Example 2.

[0042] Figure 6A comparison chart of the results of the stability analysis of the white powders prepared for Examples 1 and 2 of the present application, where the βCD-peltogynol corresponds to the white powder of Example 1 and the γCD-peltogynol corresponds to the white powder of Example 2. DETAILED DESCRIPTION

[0043] For the purposes of the present application, reference will be made to the accompanying drawings in which the preferred embodiments of the application are shown. The application may, however, be carried out in many different ways, and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the application to those skilled in the art.

[0044] The phrases "preferably", "more preferably" and the like do not each refer to the same preference; however, these phrases, alone or in combination, are used herein to mean "preferably", "more preferably" and the like, respectively, and each of the phrases "preferably", "more preferably" and the like have the weight or degree of preference indicated by their respective usage in the present disclosure. The use of these phrases in combination, e.g., "preferably more preferably", indicates that the first of the two preferences is more preferred than the second of the two preferences. The phrases "one or more of", "at least one of", and / or "one or more of the following" are each used to indicate a list following that phrase; however, these phrases are not exclusive of any other item that can also be a member of the group of items, including any item that can be a substitute for or in addition to those items already recited.

[0045] When a numerical range is disclosed herein, the range is continuous, and includes the minimum and maximum values, as well as each integer within the range. Further, when a range is disclosed, the range is inclusive of the minimum and maximum values, and of each integer within the range. In addition, where a number of ranges are provided, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. Still further, when a number of items is specified, "at least one" means one or more of those items.

[0046] All percentages, fractions and ratios are calculated based on the total mass of the composition of the present application, unless otherwise indicated. All amounts of the listed ingredients are given as the content of the active material, and therefore they do not include solvents or by-products that can be contained in the commercially available materials. The term "mass percentage content" can be denoted by the symbol "%". All molecular weights are expressed in terms of weight average molecular weight in Daltons, unless otherwise indicated. All formulations and tests are carried out at ambient conditions of 25°C, unless otherwise specified. "Including", "containing", "comprising", "having" or other like phrases used herein are meant to encompass non-exclusive inclusions, and are not intended to be limiting. The term "comprising" means that other steps and ingredients that do not affect the end result can be added. The compositions and methods / processes of the present application comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, steps or limitations described herein. The terms "efficacy", "performance", "effect", "efficiency" are not distinguished between herein.

[0047] "Pharmaceutically acceptable" means ligands, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for administration to patients and are commensurate with a reasonable benefit / risk ratio.

[0048] "Pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch, potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0049] As used herein, "drug" includes any agent, compound, composition or mixture that provides a physiological and / or pharmacological effect in or on the body, and often provides a beneficial effect. The "drug" is not particularly limited in the range of physiological and / or pharmacological effects in the body, and can be a systemic effect or can produce an effect only locally. The "drug" is not particularly limited in the activity, and can be an active substance that interacts with other substances, or can be an inert substance that does not interact.

[0050] The dosage form and administration method of the compound of the present application or a pharmaceutical composition thereof are not particularly limited.

[0051] Representative methods of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) injection, and topical administration.

[0052] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or solubilizers, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) humectants, e.g., glycerol; (c) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (d) solution retarders, e.g., paraffin; (e) absorption accelerators, e.g., quaternary ammonium compounds; (f) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (g) absorbents, e.g., kaolin and bentonite clay; and (h) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents. Solid compositions such as tablets, dragees, capsules, pills, and granules can optionally be prepared with coatings and shells, e.g., enteric coatings and other coatings or shells well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0053] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, as well as mixtures thereof. In addition, the liquid dosage forms can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and bentonite.

[0054] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0055] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0057] In one aspect of the present application, a p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, inclusion complex co-crystal is provided, which includes p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, and cyclodextrin wrapped around the p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, in the structure of the inclusion complex co-crystal, and the mass ratio of p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, to cyclodextrin is 1: (1-20).

[0058] Optionally, the cyclodextrin is β-cyclodextrin or γ-cyclodextrin;

[0059] When the cyclodextrin is β-cyclodextrin, the p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, inclusion complex co-crystal has characteristic diffraction peaks at the following 2θ (°) angles in the X-ray powder diffraction spectrum: 5.8°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°.

[0060] When the cyclodextrin is γ-cyclodextrin, the p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, inclusion complex co-crystal has characteristic diffraction peaks at the following 2θ (°) angles in the X-ray powder diffraction spectrum: 5.8°±0.2°, 7.4°±0.2°, 10.2°±0.2°, 10.4°±0.2°, 11.7°±0.2°, 14.0°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 27.1°±0.2°.

[0061] In one embodiment, the p-menthane-3-carboxylic acid, 8,8-dimethyl-8-(1-oxo-2,2-dihydro-1H-inden-6-yl)-, 9-hydroxy-, (9R)-, inclusion complex co-crystal has a solubility of 10 μg / mL-50 μg / mL in water at 24°C-26°C.

[0062] In an embodiment, when the cyclodextrin is β-cyclodextrin, the solubility of the ageratochromol-cyclodextrin inclusion complex co-crystal in water at 24-26°C is 10-20 μg / mL. For example, 10 μg / mL, 12 μg / mL, 13 μg / mL, 14 μg / mL, 15 μg / mL, 16 μg / mL, 17 μg / mL, 18 μg / mL, 19 μg / mL, 20 μg / mL, etc.

[0063] In an embodiment, when the cyclodextrin is γ-cyclodextrin, the solubility of the ageratochromol-cyclodextrin inclusion complex co-crystal in water at 24-26°C is 40-50 μg / mL. For example, 40 μg / mL, 41 μg / mL, 42 μg / mL, 43 μg / mL, 44 μg / mL, 45 μg / mL, 46 μg / mL, 47 μg / mL, 48 μg / mL, 49 μg / mL, 50 μg / mL, etc.

[0064] In another aspect of the present application, a preparation method of the ageratochromol-cyclodextrin inclusion complex co-crystal is provided, which can prepare the ageratochromol-cyclodextrin inclusion complex co-crystal as described above.

[0065] The preparation method of the present application combines the process principles of solvent injection method for preparing nanoparticles and anti-solvent method for crystallization. The key points are as follows: 1) selecting a water-miscible organic solvent as a good solvent for ageratochromol; 2) preparing the ageratochromol-cyclodextrin inclusion complex co-crystal by the solvent injection method.

[0066] The preparation method comprises the following steps:

[0067] S100: dissolving ageratochromol in an organic solvent to obtain an ageratochromol solution, the organic solvent being water-miscible;

[0068] S200: under the conditions of stirring and heating, injecting the ageratochromol solution into an aqueous cyclodextrin solution to mix, obtaining a mixed solution, the amount of injection satisfying that the mixed solution contains ageratochromol and cyclodextrin in a mass ratio of 1:(1-20);

[0069] S300: standing the mixed solution to crystallize.

[0070] The organic solvent, on the one hand, serves as a good solvent for ageratochromol, and can act as a diluent and a transfer medium for ageratochromol. When the organic solution of ageratochromol is injected into the aqueous cyclodextrin solution, the organic solvent can rapidly combine with water molecules, thereby promoting the dispersion of ageratochromol in water and the formation of the inclusion complex. On the other hand, the organic solvent can act as an anti-solvent for cyclodextrin, promoting the precipitation of the inclusion complex from the solution.

[0071] Optionally, the organic solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, ethylene glycol, and combinations thereof.

[0072] The pachouli alcohol solution has a suitable concentration to facilitate dispersion. Optionally, the concentration of the pachouli alcohol solution is 0.1 mg / mL to 10 mg / mL, such as 0.1 mg / mL, 0.5 mg / mL, 1 mg / mL, 5 mg / mL, 10 mg / mL, etc.

[0073] The cyclodextrin can be selected from β-cyclodextrin or γ-cyclodextrin as needed.

[0074] Optionally, the concentration of the aqueous cyclodextrin solution is 3 mg / mL to 50 mg / mL, such as 3 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, etc.

[0075] Further, when the aqueous cyclodextrin solution is an aqueous β-cyclodextrin solution, the concentration is 3 mg / mL to 15 mg / mL, such as 3 mg / mL, 5 mg / mL, 10 mg / mL, 12 mg / mL, 15 mg / mL, etc.

[0076] When the aqueous cyclodextrin solution is an aqueous γ-cyclodextrin solution, the concentration is 5 mg / mL to 50 mg / mL, further 10 mg / mL to 30 mg / mL, such as 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, etc.

[0077] In S200, stirring and heating promote the dissolution of the cyclodextrin and improve the dispersion of the pachouli alcohol in the aqueous cyclodextrin solution, thereby affecting the coating result and the subsequent crystallization result. Therefore, suitable stirring and heating are needed.

[0078] Optionally, the stirring speed is 50 rpm to 1000 rpm. This speed, in combination with the remaining parameters of step S200, is conducive to the formation of a suitable crystal form of the inclusion compound. Further, the stirring speed can be selected from 100 rpm to 1000 rpm, such as 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, etc.

[0079] Optionally, the heating temperature is 30°C to 60°C. This temperature, in combination with the remaining parameters of step S200, is conducive to the formation of the inclusion compound.

[0080] Optionally, the speed of injecting the pachouli alcohol solution into the aqueous cyclodextrin solution is 0.5 to 2 mL / min. This speed, in combination with the remaining parameters of step S200, is conducive to the formation of a suitable crystal form of the inclusion compound.

[0081] In some embodiments, the speed of injecting the patchouli alcohol solution into the aqueous solution of cyclodextrin is selected from 0.5-2 mL / min, such as 0.5 mL / min, 1 mL / min, 1.5 mL / min, 2 mL / min, etc.

[0082] In S200, the patchouli alcohol solution is injected into the aqueous solution of cyclodextrin to obtain a mixed solution. The amount of injection satisfies that the mixed solution contains patchouli alcohol and cyclodextrin in a mass ratio of 1:(1-20). The appropriate amount of patchouli alcohol is injected into the aqueous solution of cyclodextrin to better disperse and obtain the inclusion compound of the required crystal form.

[0083] In some embodiments, the mass ratio of patchouli alcohol and cyclodextrin in the mixed solution is 1:(1-20), such as 1:1, 1:2, 1:5, 1:8, 1:10, 1:12, 1:15, 1:18, 1:20, etc.

[0084] Optionally, the volume ratio of the organic solvent to water in the mixed solution is 3:(7-60).

[0085] To obtain the above-mentioned optimal concentration and volume ratio, after the injection of the patchouli alcohol solution is completed, the organic solvent can be optionally supplemented. The organic solvent is preferably the organic solvent used for preparing the patchouli alcohol solution in step S100.

[0086] Further, in the crystallization step of standing the mixed solution:

[0087] The standing is performed at 20-30°C; and / or

[0088] The standing time is 2-48 h.

[0089] Further, after the mixed solution is stood and crystallized, the solid is collected and dried.

[0090] Optionally, the drying temperature is 30-60°C.

[0091] Optionally, the drying time is 1-48 h.

[0092] In still another aspect of the present application, a pharmaceutical composition is also provided, which comprises:

[0093] 1) the patchouli alcohol-cyclodextrin inclusion compound co-crystal according to any one of the technical solutions described above, and

[0094] 2) a pharmaceutically acceptable carrier and / or excipient.

[0095] In still another aspect of the present application, an improvement experiment on the stability and solubility of the patchouli alcohol-cyclodextrin inclusion compound co-crystal according to any one of the technical solutions described above is also provided.

[0096] The application will be further described in detail below with specific examples. The raw materials used in the following examples are commercially available, unless otherwise specified.

[0097] 1. Preparation of inclusion complex co-crystal

[0098] Example 1

[0099] This example provides a preparation process of a patchouli alcohol-cyclodextrin inclusion complex co-crystal S1, using β-cyclodextrin as the raw material. The specific steps are as follows:

[0100] 1) Prepare β-cyclodextrin aqueous solution and patchouli alcohol solution respectively, wherein the solvent of patchouli alcohol is ethanol, the concentration of patchouli alcohol solution is 5 mg / mL, and the concentration of β-cyclodextrin aqueous solution is 8 mg / mL.

[0101] 2) Heat the cyclodextrin aqueous solution to 60°C, and inject the patchouli alcohol solution into the 20 mL cyclodextrin aqueous solution at a speed of 1 mL / min under the condition of 1000 rpm stirring, continue to stir for 30 minutes to obtain a mixed solution.

[0102] 3) Stop heating and stirring, cool the mixed solution to 20°C, and place it at 20°C for 24 hours until the crystals in the solution are completely precipitated.

[0103] 4) Filter to obtain white solid, wash it with ethanol for 3 times, then place the product at 60°C for drying for 24 hours to obtain white powder, which is patchouli alcohol-cyclodextrin inclusion complex co-crystal S1, and the yield of the product is 85% based on patchouli alcohol.

[0104] Example 2

[0105] This example provides a preparation process of a patchouli alcohol-cyclodextrin inclusion complex co-crystal S2, using γ-cyclodextrin as the raw material. The specific steps are as follows:

[0106] 1) Prepare γ-cyclodextrin aqueous solution and patchouli alcohol solution respectively, wherein the solvent of patchouli alcohol is methanol, the concentration of patchouli alcohol solution is 3 mg / mL, and the concentration of γ-cyclodextrin aqueous solution is 15 mg / mL.

[0107] 2) Heat the cyclodextrin aqueous solution to 50°C, and inject the patchouli alcohol solution into the 7 mL cyclodextrin aqueous solution at a speed of 0.5 mL / min under the condition of 50 rpm stirring, add 2 mL of ethanol, continue to stir for 0.5 minutes to obtain a mixed solution.

[0108] 3) Stop heating and stirring, cool the mixed solution to 25°C, and place it for 12 hours until the crystals in the solution are completely precipitated.

[0109] 4) The white solid was obtained by filtration, washed three times with methanol, and then the product was placed at 40°C and vacuum dried for 12 hours to obtain the white powder, which is patchouli alcohol-cyclodextrin inclusion complex eutectic S2. The yield of the product, based on patchouli alcohol, is 90%.

[0110] 2. Characterization

[0111] The patchouli alcohol-cyclodextrin inclusion complex eutectic S1 and S2 were characterized by morphology, H-NMR, infrared spectroscopy, X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). The specific characterization results are as follows:

[0112] 2.1 Morphological observation

[0113] The white powders obtained in Examples 1 and 2 were respectively placed on glass slides, and the morphology of each sample was observed and recorded under an optical microscope (10×20). The results are as follows. Figure 1 As shown, Figure 1 The scale bar is 50 μm.

[0114] Figure 1 The white powders obtained in Examples 1 and 2 both exhibit distinct crystalline forms, appearing as lumps (white powder obtained in Example 1) and rods (white powder obtained in Example 2), respectively. Under the same experimental conditions, cyclodextrin did not precipitate as a solid in the solvent. This indicates that the white powders obtained in Examples 1 and 2 are crystalline.

[0115] 2.2 H-NMR characterization

[0116] Patchouli alcohol, β-cyclodextrin, γ-cyclodextrin, and the white powders prepared in Examples 1 and 2 were dissolved in DMSO-d6 and analyzed by 1H NMR spectroscopy. The results are as follows: Figure 2 The H-NMR data of the white powder in Example 1 contained signals of patchouli alcohol and β-cyclodextrin, respectively. The H-NMR data of the white powder in Example 2 contained signals of patchouli alcohol and γ-cyclodextrin, indicating that the white powder prepared in Example 1 or 2 is composed of patchouli alcohol and the corresponding cyclodextrin, confirming that the white powder prepared in Examples 1 and 2 is a eutectic.

[0117] 2.3 Infrared Characterization

[0118] Patchouli alcohol, β-cyclodextrin, γ-cyclodextrin, and the white powders prepared in Examples 1 and 2 were subjected to infrared spectroscopy detection, and the detection results are as follows: Figure 3 . Figure 3 The characteristic peak of patchouli alcohol is at 1468 cm⁻¹. -1 1454 cm -1 1366 cm -1 1323cm -1 1286 cm-1 , 1187 cm -1 , 1154 cm -1 , 1104 cm -1 , 1048 cm -1 , 1041 cm -1 , 1008 cm -1 , 996 cm -1 , 984 cm -1 , 996 cm -1 , 930 cm -1 , 913 cm -1 , 887 cm -1 , 854 cm -1 , 815 cm -1 , 776 cm -1 , 736 cm -1 , 646 cm -1 , 567 cm -1 , 529 cm -1 , 493 cm -1 ; the characteristic peaks of the cyclodextrin are between 400 cm -1 ~2000 cm -1 ; compared with the two, the infrared spectrum of the white powder prepared in Examples 1 and 2 disappears most of the characteristic peaks related to pogostol, and the infrared spectrum as a whole is consistent with cyclodextrin (corresponding to β-cyclodextrin and γ-cyclodextrin respectively), indicating that the inclusion complex of pogostol and cyclodextrin is formed, and the characteristic peaks of pogostol in the structure are covered by cyclodextrin. It is proved that the white powder prepared in Examples 1 and 2 is an inclusion complex.

[0119] 2.4 XRD characterization

[0120] PXRD analysis was performed on pogostol, β-cyclodextrin, γ-cyclodextrin, and the white powder prepared in Examples 1 and 2, respectively, and the analysis results are as follows Figure 4 .

[0121] The X-ray powder diffraction pattern of the white powder of Example 1 has characteristic diffraction peaks at the following 2θ (°) angles: 5.8°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°;

[0122] The X-ray powder diffraction pattern of the white powder of Example 2 has characteristic diffraction peaks at the following 2 theta (°) angles: 5.8°±0.2°, 7.4°±0.2°, 10.2°±0.2°, 10.4°±0.2°, 11.7°±0.2°, 14.0°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 27.1°±0.2°.

[0123] As can be seen from the comparison, the diffraction peaks of the XRD of each inclusion eutectic are completely different from the characteristic peaks of each cyclodextrin and patchouli alcohol, indicating that it is not a simple physical mixture, but a new crystal form, and the HNMR results show that the crystal contains both cyclodextrin and patchouli alcohol components, so it can be determined as a patchouli alcohol-cyclodextrin inclusion eutectic.

[0124] 2.5 DSC characterization

[0125] The patchouli alcohol, white powder prepared in Examples 1 and 2 were respectively subjected to DSC detection, and the detection results are as follows Figure 5 Patchouli alcohol is an oily compound at room temperature, according to Figure 5 , the melting points of the inclusion eutectics after the formation of the eutectic with cyclodextrin are 294.8°C (patchouli alcohol-cyclodextrin inclusion eutectic prepared in Example 1) and 291.2°C (patchouli alcohol-cyclodextrin inclusion eutectic prepared in Example 2), respectively, indicating that the thermal stability of the patchouli alcohol after forming the inclusion eutectic is significantly improved.

[0126] 3. Improvement of physicochemical properties

[0127] 3.1 Water solubility

[0128] The patchouli alcohol, patchouli alcohol-cyclodextrin inclusion eutectics (S1 and S2) prepared in Examples 1 and 2 were respectively subjected to water solubility detection, and it was found that the solubility of patchouli alcohol free drug in water was less than 1 μg / mL at 25°C, the solubility of patchouli alcohol-cyclodextrin inclusion eutectic S1 was 15 μg / mL, and the solubility of patchouli alcohol-cyclodextrin inclusion eutectic S2 was 43 μg / mL.

[0129] 3.2 Stability

[0130] The patchouli alcohol-cyclodextrin inclusion eutectics (S1 and S2) prepared in Examples 1 and 2 were respectively subjected to stability detection, and the specific method was as follows:

[0131] The patchouli alcohol-cyclodextrin inclusion eutectics S1 and S2 were respectively subjected to accelerated stability test according to the method recorded in the pharmacopoeia standard, and the experimental results are as followsFigure 6 According to Figure 6 Both of the clathrate co-crystals do not degrade at 25°C and 60°C within 14 days.

[0132] The technical features of the above-described embodiments can be combined in any manner. For brevity, all possible combinations of the technical features in the above-described embodiments are not described, but as long as the combinations of the technical features do not contradict each other, they should be considered within the scope of the present disclosure.

[0133] The above-described embodiments only express several implementation manners of the present application, facilitate specific and detailed understanding of the technical solutions of the present application, but should not be understood as a limitation on the scope of patent protection. It should be pointed out that, for ordinary skilled persons in the art, a number of modifications and improvements can be made without departing from the concept of the present application, and these are within the scope of protection of the present application. It should be understood that, on the basis of the technical solutions provided by the present application, the technical solutions obtained by logical analysis, reasoning or limited experiments by those skilled in the art are within the scope of protection of the appended claims of the present application. Therefore, the scope of protection of the present patent should be based on the contents of the appended claims, and the description and drawings can be used to explain the contents of the claims.

Claims

1. A p-mentha-1,8-dien-7-ol-cyclodextrin inclusion complex co-crystal, characterized in that, The structure of the clathrate eutectic includes patchouli alcohol and a cyclodextrin coated on the surface of the patchouli alcohol, and the mass ratio of the patchouli alcohol to the cyclodextrin is 1:(1-20); The cyclodextrin is β-cyclodextrin or γ-cyclodextrin; When the cyclodextrin is β-cyclodextrin, the X-ray powder diffraction pattern of the patchouli alcohol-cyclodextrin clathrate eutectic has characteristic diffraction peaks at the following 2θ (°) angles: 5.8°±0.2°, 6.5°±0.2°, 6.8°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.3°±0.2°, 13.7°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 17.4°±0.2°, 18.0°±0.2°, 20.8°±0.2°, 21.4°±0.2°; When the cyclodextrin is γ-cyclodextrin, the X-ray powder diffraction pattern of the patchouli alcohol-cyclodextrin clathrate eutectic has characteristic diffraction peaks at the following 2θ (°) angles: 5.8°±0.2°, 7.4°±0.2°, 10.2°±0.2°, 10.4°±0.2°, 11.7°±0.2°, 14.0°±0.2°, 14.8°±0.2°, 15.6°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 21.2°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 27.1°±0.2°.

2. The p-menthane-3-carboxamide-cyclodextrin inclusion complex co-crystal of claim 1, wherein, The solubility of the patchouli alcohol-cyclodextrin clathrate eutectic in water at 24-26°C is 10-50 μg / mL.

3. A process for the preparation of the p-menthane-3-β-ol-cyclodextrin inclusion complex co-crystal of claim 1 or 2, characterized in that, The method comprises the following steps: The patchouli alcohol is dissolved in an organic solvent to obtain a patchouli alcohol solution, and the organic solvent is miscible with water; The patchouli alcohol solution is injected into an aqueous cyclodextrin solution under stirring and heating to obtain a mixed solution, and the injection amount satisfies that the mixed solution contains patchouli alcohol and cyclodextrin in a mass ratio of 1:(1-20); The mixed solution is left to stand and crystallize.

4. The production method according to claim 3, characterized by, The organic solvent comprises at least one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropyl alcohol and ethylene glycol; and / or The cyclodextrin is β-cyclodextrin or γ-cyclodextrin.

5. The production method according to claim 3 or 4, characterized by, The preparation method satisfies one or more of the following conditions: (1) The concentration of the patchouli alcohol solution is 0.1-10 mg / mL; (2) The concentration of the aqueous cyclodextrin solution is 3-50 mg / mL; (3) The stirring speed is 50-1000 rpm; (4) The heating temperature is 30-60°C; (5) The injection speed of the patchouli alcohol solution into the aqueous cyclodextrin solution is 0.5-2 mL / min; (6) The volume ratio of the organic solvent to water in the mixed solution is 3:(7-60).

6. The production method according to claim 5, wherein When the aqueous cyclodextrin solution is an aqueous β-cyclodextrin solution, the concentration is 3-15 mg / mL; The aqueous solution of the cyclodextrin is an aqueous solution of γ-cyclodextrin, and the concentration is 3 mg / mL to 50 mg / mL.

7. The production method according to claim 3 or 4, characterized by, The mixed solution is left to stand, and the step of crystallization is performed by: The standing is performed at 20°C to 30°C; and / or The standing time is 2 h to 48 h.

8. The production method according to claim 3 or 4, characterized by, After the mixed solution is left to stand and crystallization is performed, the solid is collected and dried. The drying temperature is 30°C to 60°C. The drying time is 1 h to 24 h.

9. A pharmaceutical composition, characterized by, It comprises: 1) the broadleaf sage alcohol-cyclodextrin inclusion co-crystal of claim 1 or 2, and 2) a pharmaceutically acceptable carrier.

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