Butylphthalide inclusion compound eutectic crystal, pharmaceutical composition and application

Abstract

The invention relates to the field of fine chemical engineering and application, in particular to a butylphthalide inclusion compound eutectic crystal, a pharmaceutical composition and application, a preparation method of the butylphthalide inclusion compound eutectic crystal fuses process principles of nanoparticle preparation by a solvent injection method and crystallization by an anti-solvent method, and the key points are as follows: 1) an organic solvent miscible with water is selected as a good solvent of butylphthalide; and 2) preparing the inclusion compound eutectic of butylphthalide and cyclodextrin by a solvent injection method. According to the butylphthalide inclusion compound cocrystal, the water solubility, the stability and the bioavailability of a medicine are remarkably improved.

Description

Technical Field

[0001] The present application relates to the field of fine chemicals and applications, and specifically to a butylphthalide inclusion complex cocrystal, a pharmaceutical composition and applications. Background Art

[0002] Butylphthalide (butylphenyl peptide), also known as apigenin A, has the same structure as L-apigenin A extracted from celery seeds. It is a synthetic racemate with a chemical formula of C 12 H 14 O2, with a molecular weight of 190.238, a CAS number of 6066-49-5, and a trade name of Enbipu, is a new drug for the treatment of ischemic stroke. It has the effects of anti-platelet aggregation, restoring blood circulation in brain tissue, and improving brain nerve function. It has an improving effect on the damage of central nervous function in patients with acute ischemic stroke and can promote functional recovery of patients.

[0003] Butylphthalide is an oily liquid at room temperature, with fat solubility and relatively poor water solubility. Currently, there are two forms of butylphthalide, one is oral soft capsules, and the other is intravenous injection. The active ingredients in the injection are prepared into inclusion complexes with inclusion agents to increase water solubility.

[0004] There are reports on butylphthalide inclusion complexes using cyclodextrin as an inclusion agent, which can improve water solubility and bioavailability. However, in the preparation process of the inclusion complex, an excessive amount of cyclodextrin needs to be added, which is difficult to separate from the product and the inclusion rate is relatively low.

[0005] In view of this, it is necessary to provide a new type of butylphthalide inclusion compound, which has a simple preparation step, and on the one hand, the solidified butylphthalide is easy to store, and on the other hand, the water solubility and bioavailability can be well improved. Summary of the invention

[0006] Based on this, the purpose of the present application includes providing a butylphthalide inclusion complex cocrystal, a pharmaceutical composition and an application. The butylphthalide inclusion complex cocrystal effectively improves the water solubility, stability and bioavailability of butylphthalide, and can be used as an intermediate to facilitate the development of subsequent formulation processes.

[0007] One aspect of the present application provides a butylphthalide inclusion compound co-crystal, which is prepared by the following steps:

[0008] Dissolving butylphthalide in an organic solvent to obtain an organic solution of butylphthalide; wherein the organic solvent is miscible with water;

[0009] Under the conditions of providing dispersing force and heating, dissolving the inclusion main component in water to obtain an inclusion solution, wherein the inclusion main component includes cyclodextrin; then injecting the organic solution of butylphthalide into the inclusion solution, and optionally supplementing the organic solvent to obtain a mixed solution;

[0010] The dispersing force and heating were stopped, and the resulting mixed solution was allowed to stand.

[0011] In some embodiments, the mass volume ratio of the inclusion host component in the inclusion solution is 1 mg / mL to 100 mg / mL;

[0012] The mass volume ratio of the butylphthalide in the butylphthalide organic solution is 1 mg / mL to 20 mg / mL;

[0013] The molar ratio of butylphthalide to the inclusion body in the mixed solution is 1:(0.5-50).

[0014] In some embodiments, the inclusion main component is α-cyclodextrin, and the mass volume ratio of the α-cyclodextrin in the inclusion solution is 40 mg / mL to 100 mg / mL.

[0015] In some embodiments, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.6±0.2°, 6.7±0.2°, 11.3±0.2°, 11.9±0.2°, 12.6±0.2°, 12.9±0.2°, 13.4±0.2°, 14.6±0.2°, 14.8±0.2°, 15. 2±0.2°, 15.6±0.2°, 17.0±0.2°, 17.4±0.2°, 18.5±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 23.9±0.2°, 27.9±0.2°, 30.0±0.2°, 35.2.±0.2°, 36.8±0.2°, 37.5±0.2°;

[0016] Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 2.5×10 3 μg / mL~2.6×10 3 μg / mL.

[0017] In some embodiments, the inclusion main component is β-cyclodextrin, and the mass volume ratio of the β-cyclodextrin in the inclusion solution is 2 mg / mL to 25 mg / mL.

[0018] In some embodiments, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.5±0.2°, 6.1±0.2°, 9.2±0.2°, 9.7±0.2°, 10.1±0.2°, 10.7±0.2°, 12.1±0.2°, 14.6±0.2°, 15.1±0.2°, 17.7±0.2°, 18.6±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.5±0.2°, 23.4±0.2°, 24.0±0.2°, 24.9±0.2°, 26.0±0.2°, 27.0±0.2°, 29.4±0.2°;

[0019] Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 390 μg / mL to 410 μg / mL.

[0020] In some embodiments, the inclusion main component is γ-cyclodextrin, and the mass volume ratio of the γ-cyclodextrin in the inclusion solution is 3 mg / mL to 50 mg / mL.

[0021] In some embodiments, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 7.4±0.2°, 10.5±0.2°, 11.5±0.2°, 11.8±0.2°, 12.0±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.7±0.2°, 18 .2±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 22.4±0.2°, 23.7±0.2°, 24.2±0.2°, 24.5±0.2°, 25.4±0.2°, 26.8±0.2°, 27.3±0.2°, 27.7±0.2°;

[0022] Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 70 μg / mL to 90 μg / mL.

[0023] In some embodiments, the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, ethylene glycol and combinations thereof; and / or

[0024] The providing of the dispersing force comprises: stirring at 50 rpm to 1000 rpm; and / or

[0025] The heating temperature is 30°C to 60°C; and / or

[0026] The time for injecting the organic solution of butylphthalide is 0.5min to 30min.

[0027] In some embodiments, the volume ratio of the organic solvent to water in the mixed solution is 3:(7-60).

[0028] In some embodiments, in the step of allowing the obtained mixed solution to stand:

[0029] The standing is performed at 4°C to 30°C; and / or

[0030] The standing time is 4 hours to 72 hours.

[0031] In some embodiments, after the obtained mixed solution is allowed to stand, the method further comprises the steps of:

[0032] Collect the solid precipitated after standing, and optionally wash the solid with water and / or a crystallization solvent; then dry at 30-60° C.;

[0033] Furthermore, the drying time is 1 hour to 48 hours.

[0034] Another aspect of the present application provides a pharmaceutical composition comprising:

[0035] 1) the butylphthalide inclusion compound cocrystal described in any of the above technical solutions, and

[0036] 2) Pharmaceutically acceptable carriers or excipients.

[0037] Another aspect of the present application provides the use of the butylphthalide inclusion complex co-crystal or pharmaceutical composition described in any of the above technical solutions in the preparation of drugs for preventing and treating diseases such as tissue pathological damage or nerve cell damage caused by ischemia and hypoxia.

[0038] In some embodiments, the disease is selected from ischemic stroke, vascular dementia, muscular atrophy, angina pectoris and myocardial infarction. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 A schematic diagram of a process for preparing a butylphthalide inclusion compound co-crystal in one embodiment of the present application;

[0040] Figure 2 Optical microscope photos of white powders and butylphthalide prepared in Examples 1 to 3 of the present application, wherein the scale is 50 μm, butylphthalide / αCD corresponds to white powder I in Example 1, butylphthalide / βCD corresponds to white powder II in Example 2, and butylphthalide / γCD corresponds to white powder III in Example 3;

[0041] Figure 3H-NMR spectra of white powders, butylphthalide and cyclodextrins prepared in Examples 1 to 3 of the present application, wherein αCD corresponds to α-cyclodextrin, βCD corresponds to β-cyclodextrin, γCD corresponds to γ-cyclodextrin, butylphthalide-αCD corresponds to white powder I in Example 1, butylphthalide-βCD corresponds to white powder II in Example 2, and butylphthalide-γCD corresponds to white powder III in Example 3;

[0042] Figure 4 The infrared spectra of the white powder, butylphthalide and each cyclodextrin prepared in Examples 1 to 3 of the present application, wherein γCD-API refers to γ-cyclodextrin, αCD-API refers to α-cyclodextrin, βCD-API refers to β-cyclodextrin, butylphthalide-αCD corresponds to the white powder I of Example 1, butylphthalide-βCD corresponds to the white powder II of Example 2, and butylphthalide-γCD corresponds to the white powder III of Example 3;

[0043] Figure 5 The PXRD spectra of the white powders and cyclodextrins prepared in Examples 1 to 3 of the present application, wherein the abscissa is the angle 2θ (°), the ordinate is the intensity, butylphthalide / α-cyclodextrin corresponds to the white powder I of Example 1, butylphthalide / β-cyclodextrin corresponds to the white powder II of Example 2, and butylphthalide / γ-cyclodextrin corresponds to the white powder III of Example 3;

[0044] Figure 6 The DSC spectra of the white powders and cyclodextrins prepared in Examples 1 to 3 of the present application, wherein the abscissa is temperature (°C), the ordinate is heat flow rate (W / g), butylphthalide / αCD corresponds to white powder I of Example 1, butylphthalide / βCD corresponds to white powder II of Example 2, and butylphthalide / γCD corresponds to white powder III of Example 3;

[0045] Figure 7 This is a comparison chart of the water solubility of butylphthalide inclusion complex cocrystals and butylphthalide of Examples 1 to 3 of the present application, wherein the abscissa is time (min), the ordinate is concentration (μg / mL), butylphthalide / αCD corresponds to white powder I of Example 1, butylphthalide / βCD corresponds to white powder II of Example 2, and butylphthalide / γCD corresponds to white powder III of Example 3. DETAILED DESCRIPTION

[0046] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0047] The words "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that may provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.

[0048] When a numerical range is disclosed herein, the above range is considered to be continuous and includes the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0049] Unless otherwise specified, all percentages, fractions and ratios are calculated by the total mass of the composition of the present invention. Unless otherwise specified, all masses of the listed ingredients are given to the content of active substances, so they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" herein can be represented by the symbol "%". Unless otherwise specified, all molecular weights in this article are weight average molecular weights expressed in Daltons. Unless otherwise specified, all formulations and tests in this article occur in an environment of 25°C. "Including", "including", "containing", "containing", "having" or other variants herein are intended to cover non-closed inclusions, and these terms are not distinguished. The term "comprising" means that other steps and ingredients that do not affect the final result can be added. The composition and method / process of the present invention include, consist of and are essentially composed of the necessary elements and restrictions described herein and any additional or optional ingredients, components, steps or restrictions described herein. The terms "efficacy", "performance", "effect" and "efficacy" are not distinguished between herein.

[0050] "Pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0051] "Pharmaceutically acceptable carrier" refers to 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 that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, 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) 10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0052] As used herein, "drug" includes any agent, compound, composition or mixture that provides physiological and / or pharmacological effects in vivo or in vitro, and often provides beneficial effects. The scope of the physiological and / or pharmacological effects produced by the "drug" in vivo is not particularly limited, and may be systemic effects or may only produce effects locally. The activity of the "drug" is not particularly limited, and may be an active substance that can interact with other substances, or an inert substance that does not interact.

[0053] The dosage form and administration method of the compound of the present invention or its pharmaceutical composition are not particularly limited.

[0054] Representative routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

[0055] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills and granules may be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that may be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the above-mentioned excipients.

[0056] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices. For example, the suspension may contain a suspending agent, specifically, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methylate and agar or mixtures of these substances.

[0057] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0058] Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants, which are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0060] In one aspect of the present application, a butylphthalide inclusion compound cocrystal is provided, which is prepared by the following steps:

[0061] S100: dissolving butylphthalide in an organic solvent to obtain an organic solution of butylphthalide; wherein the organic solvent is miscible with water;

[0062] S200: Under the conditions of providing dispersing force and heating, dissolving the inclusion main component in water to obtain an inclusion solution, wherein the inclusion main component includes cyclodextrin; then injecting an organic solution of butylphthalide into the inclusion solution, and optionally adding an organic solvent to obtain a mixed solution;

[0063] S300: Stop providing the dispersing force and heating, and let the obtained mixed solution stand.

[0064] In some embodiments, the mass volume ratio of the inclusion host component in the inclusion solution is 1 mg / mL to 100 mg / mL;

[0065] The mass volume ratio of butylphthalide in the organic solution of butylphthalide is 1 mg / mL to 20 mg / mL;

[0066] The molar ratio of butylphthalide to cyclodextrin in the mixed solution is 1:(1-50).

[0067] In some embodiments, the mass volume ratio of the inclusion body component in the inclusion solution can be selected from 1 mg / mL to 100 mg / mL, for example, 1 mg / mL, 10 mg / mL, 20 mg / mL, 50 mg / mL, 80 mg / mL, 100 mg / mL, etc., and the mass volume ratio of butylphthalide in the organic solution of butylphthalide can be selected from 1 mg / mL to 20 mg / mL, for example, 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, etc., and the molar ratio of butylphthalide and the inclusion body component in the mixed solution after injection can be 1:1 to 1:50, preferably 1:1 to 1:20, for example, 1:1, 1:5, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50, etc.

[0068] In some embodiments, the inclusion host component includes α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0069] In some embodiments, the inclusion main component is α-cyclodextrin, and the mass volume ratio of α-cyclodextrin in the inclusion solution is 40 mg / mL to 100 mg / mL.

[0070] Furthermore, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.6±0.2°, 6.7±0.2°, 11.3±0.2°, 11.9±0.2°, 12.6±0.2°, 12.9±0.2°, 13.4±0.2°, 14.6±0.2°, 14.8±0.2°, 15.2±0 .2°, 15.6±0.2°, 17.0±0.2°, 17.4±0.2°, 18.5±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 23.9±0.2°, 27.9±0.2°, 30.0±0.2°, 35.2.±0.2°, 36.8±0.2°, 37.5±0.2°.

[0071] Furthermore, the solubility of butylphthalide inclusion complex eutectic in water is 2.5×10 3 μg / mL~2.6×10 3 μg / mL.

[0072] In some embodiments, the inclusion main component is β-cyclodextrin, and the mass volume ratio of β-cyclodextrin in the inclusion solution is 2 mg / mL to 25 mg / mL.

[0073] Furthermore, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.5±0.2°, 6.1±0.2°, 9.2±0.2°, 9.7±0.2°, 10.1±0.2°, 10.7±0.2°, 12.1±0.2°, 14.6±0.2°, 15.1±0.2°, 17.7±0.2°, 18.6±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.5±0.2°, 23.4±0.2°, 24.0±0.2°, 24.9±0.2°, 26.0±0.2°, 27.0±0.2°, and 29.4±0.2°.

[0074] Furthermore, the solubility of the butylphthalide inclusion complex cocrystal in water is 390 μg / mL to 410 μg / mL.

[0075] In some embodiments, the inclusion main component is γ-cyclodextrin, and the mass volume ratio of γ-cyclodextrin in the inclusion solution is 3 mg / mL to 50 mg / mL.

[0076] Further, the X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 7.4±0.2°, 10.5±0.2°, 11.5±0.2°, 11.8±0.2°, 12.0±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.7±0.2°, 18.2± 0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 22.4±0.2°, 23.7±0.2°, 24.2±0.2°, 24.5±0.2°, 25.4±0.2°, 26.8±0.2°, 27.3±0.2°, 27.7±0.2°.

[0077] Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 70 μg / mL to 90 μg / mL.

[0078] The preparation method of the butylphthalide inclusion compound co-crystal of the present application combines the process principles of preparing nanoparticles by solvent injection method and crystallization by anti-solvent method. The key lies in: 1) selecting an organic solvent miscible with water as a good solvent for butylphthalide; 2) preparing the butylphthalide and cyclodextrin inclusion compound co-crystal by solvent injection method.

[0079] Specifically, the preparation method comprises the steps of:

[0080] S100: dissolving butylphthalide in an organic solvent to obtain an organic solution of butylphthalide; wherein the organic solvent has a property of being miscible with water;

[0081] S200: Under the conditions of providing dispersing force and heating, dissolving the inclusion main component in water to obtain an inclusion solution, wherein the inclusion main component includes cyclodextrin; then injecting an organic solution of butylphthalide into the inclusion solution, and optionally adding an organic solvent to obtain a mixed solution,

[0082] S300: Stop providing the dispersing force and heating, and let the obtained mixed solution stand.

[0083] The organic solvent in the above steps, on the one hand, serves as a good solvent for butylphthalide, and can be used as a diluent and transfer medium for butylphthalide. When the organic solution of butylphthalide is injected into the inclusion solution, the organic solvent can quickly combine with water molecules, thereby promoting the dispersion of butylphthalide in water and the formation of inclusion complex; on the other hand, the organic solvent can serve as an anti-solvent for the inclusion main component, promoting the precipitation of the inclusion complex from the solution.

[0084] Optionally, the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, ethylene glycol, and combinations thereof.

[0085] The following combination Figure 1 Further description of the preparation method:

[0086] S100 provides organic solution of butylphthalide

[0087] Take butylphthalide and dissolve it in an organic solvent to prepare an organic solution of butylphthalide. Figure 1 The prepared organic solution of butylphthalide, butylphthalide solution, can be connected to a peristaltic pump to facilitate subsequent injection into the inclusion main solution for coating. The butylphthalide in the organic solution has a suitable concentration to facilitate dispersion.

[0088] In some embodiments, the weight volume ratio of butylphthalide in its organic solution is 1 mg / mL to 50 mg / mL, and can further be 1 mg / mL to 20 mg / mL, for example: 1 mg / mL, 3.6 mg / mL, 5 mg / mL, 7.2 mg / mL, 20 mg / mL, etc.

[0089] S200 Solvent Injection

[0090] Under the conditions of providing dispersing force and heating, the inclusion main component is dissolved in water to obtain an inclusion solution, and then the organic solution of butylphthalide is added to the inclusion solution to obtain a mixed solution. Figure 1 The main component of the inclusion complex, cyclodextrin, can be placed in a container equipped with a stirring device, and water can be added to dissolve it to obtain a cyclodextrin solution, and then the butylphthalide solution can be injected into it at a suitable rate through a peristaltic pump.

[0091] It can be understood that the dispersing force provided in step S200 not only promotes the dissolution of the inclusion main component, but also improves the dispersion effect of butylphthalide in the inclusion solution.

[0092] In one embodiment, providing the dispersing force comprises: stirring at 50 rpm to 1000 rpm. The rotation speed is combined with the other parameters of step S200 to facilitate the formation of a suitable crystal inclusion compound. Further, the stirring speed can be selected from 100 rpm to 1000 rpm, for example, 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm, 800 rpm, 900 rpm, 1000 rpm, etc.

[0093] In some embodiments, the heating temperature is 30° C. to 60° C. This temperature, combined with other parameters of step S200 , is conducive to the formation of inclusion complexes.

[0094] In some embodiments, the time for injecting the organic solution of butylphthalide is controlled within 0.5 min to 30 min, and optimally about 5 min. This rate, combined with the other parameters of step S200, is conducive to the formation of inclusion complexes of suitable crystal forms.

[0095] In some embodiments, the weight volume ratio of the inclusion body component in the inclusion solution is 1 mg / mL to 100 mg / mL, and can be further selected from 40 mg / mL-100 mg / mL, 2 mg / mL-25 mg / mL, 3 mg / mL-50 mg / mL, etc. For example, 3 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, etc.

[0096] In some embodiments, the inclusion body component is α-cyclodextrin, and the mass volume concentration of α-cyclodextrin in its aqueous solution is 40 mg / mL to 100 mg / mL, and further is 70 mg / mL to 90 mg / mL, for example 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, etc.

[0097] In some embodiments, the inclusion body component is β-cyclodextrin, and the mass volume concentration of β-cyclodextrin in its aqueous solution is 2 mg / mL to 25 mg / mL, and further 10 mg / mL to 20 mg / mL, for example 3 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, etc.

[0098] In some embodiments, the inclusion body component is γ-cyclodextrin, and the mass volume concentration of γ-cyclodextrin in its aqueous solution is 3 mg / mL to 50 mg / mL, and further 10 mg / mL to 30 mg / mL, for example 3 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 45 mg / mL, 50 mg / mL, etc.

[0099] In step S200, the active solvent of the drug component of suitable concentration and volume is injected into the inclusion solution of suitable concentration and volume in order to better disperse and obtain the inclusion compound of the desired crystal form.

[0100] In some embodiments, the molar ratio of butylphthalide to the inclusion main component in the mixed solution is 1:(0.5-50), for example 1:0.5, 1:10, 1:15, 1:20, 1:30, 1:40, 1:50.

[0101] In some embodiments, the molar ratio of butylphthalide and the inclusion main component in the mixed solution is 1:(1-10), and can be further selected from 1:(3-5), 1:(2-4), 1:(5-8), etc. For example, the optional molar ratios are 1:4.3, 1:3.1, 1:6.5, etc.

[0102] In some embodiments, the volume ratio of the organic solvent to water in the mixed solution is 1:20 to 3:7.

[0103] To obtain the above-mentioned preferred concentration and volume ratio, after the organic solution of butylphthalide is completely injected, an organic solvent may be optionally added. The organic solvent is preferably the organic solvent used to prepare the organic solution of butylphthalide in step S100.

[0104] S300 Crystallization

[0105] After the injection is completed and the mixture is fully dispersed in step S200, the dispersing force and heating are stopped, and the obtained mixed solution is allowed to stand.

[0106] In some embodiments, in step S300, the mixed solution is allowed to stand at 4° C. to 30° C. Further, the standing time may be 4 h to 72 h until the crystallization is complete.

[0107] In some embodiments, after the obtained mixed solution is allowed to stand, the method further comprises the steps of: solid-liquid separation to obtain a solid;

[0108] Optionally, the solid is washed with water and / or a crystallization solvent, preferably with ice water or a pre-cooled crystallization solvent, to reduce losses; the composition of the crystallization solvent is such as the solvent composition in the mixed solution; in some embodiments, the crystallization solvent is a mixed solvent with a volume ratio of organic solvent to water of 3:(7-60);

[0109] Then, the mixture is dried at 30°C to 60°C; further, the drying time may be 1 hour to 48 hours, in order to obtain relatively pure dry crystals.

[0110] The pharmaceutical composition of the present application comprises:

[0111] 1) the butylphthalide inclusion compound crystals described in any of the above technical solutions, and

[0112] 2) Pharmaceutically acceptable carriers or excipients.

[0113] The butylphthalide inclusion compound crystal and the pharmaceutical composition described in any of the above technical solutions can be used to prepare drugs for preventing and treating diseases such as tissue pathological damage or nerve cell damage caused by ischemia and hypoxia.

[0114] In some embodiments, the disease is selected from ischemic stroke, vascular dementia, muscular atrophy, angina pectoris and myocardial infarction.

[0115] The present invention is further described in detail below in conjunction with specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.

[0116] 1. Preparation

[0117] Example 1

[0118] This embodiment provides a drug inclusion compound I, which includes a drug active ingredient butylphthalide and an inclusion main component α-cyclodextrin that encapsulates the drug active ingredient.

[0119] The specific preparation process of drug inclusion compound I is as follows:

[0120] 1) Dissolve butylphthalide in an organic solvent to prepare a 20 mg / mL butylphthalide organic solution, wherein the organic solvent is methanol.

[0121] 2) Dissolve α-cyclodextrin in water at 45°C and 50 rpm to obtain a 50 mg / mL aqueous solution of α-cyclodextrin; take 9 mL (0.46 mmol) of the aqueous solution and inject 1 mL of the above-mentioned organic solution of butylphthalide (0.105 mmol), continue stirring for 1 minute, and obtain a mixed solution I.

[0122] 3) Stop stirring and heating, cool the mixed solution I to 30°C, continue stirring for 0.5h~4h, and let it stand for 12h until the crystals in the solution are completely precipitated.

[0123] 4) The white solid I was obtained by suction filtration, and dried at 40°C for 48 hours to obtain a white powder I. The yield was 50% based on butylphthalide.

[0124] Example 2

[0125] This embodiment provides a drug inclusion compound II, which includes a drug active ingredient butylphthalide and an inclusion main component β-cyclodextrin that encapsulates the drug active ingredient.

[0126] The specific preparation process of drug inclusion complex II is as follows:

[0127] 1) Prepare a 15 mg / mL aqueous solution of β-cyclodextrin and a 7.2 mg / mL organic solution of butylphthalide, wherein the organic solvent in the organic solution of butylphthalide is ethanol.

[0128] 1) Dissolve butylphthalide in an organic solvent to obtain a 7.2 mg / mL butylphthalide organic solution, wherein the organic solvent is ethanol.

[0129] 2) Dissolve β-cyclodextrin in water at 45°C and 50 rpm to obtain a 15 mg / mL β-cyclodextrin aqueous solution; take 9 mL (0.12 mmol) of the aqueous solution and inject 1 mL of the above-mentioned butylphthalide (0.038 mmol) organic solution, continue stirring for 1 minute, and obtain a mixed solution II.

[0130] 3) Stop heating and stirring, cool the mixed solution II to 10°C, and leave it for 12 hours until the crystals in the solution are completely precipitated.

[0131] 4) The white solid II was filtered off and washed three times with 4°C water; then dried at 40°C for 48 hours to obtain a white powder II with a yield of 80% based on butylphthalide.

[0132] Example 3

[0133] This embodiment provides a drug inclusion compound III, which includes a drug active ingredient butylphthalide and an inclusion main component γ-cyclodextrin that encapsulates the drug active ingredient.

[0134] The specific preparation process of drug inclusion complex III is as follows:

[0135] 1) Dissolve butylphthalide in an organic solvent to obtain a 3.6 mg / mL organic solution of butylphthalide, wherein the organic solvent is acetonitrile.

[0136] 2) Dissolve γ-cyclodextrin in water at 50°C and 50 rpm to obtain a 20 mg / mL γ-cyclodextrin aqueous solution; take 8 mL (0.123 mmol) of the aqueous solution and inject 1 mL (0.019 mmol) of the above-mentioned butylphthalide organic solution, add 3 mL of acetonitrile, and continue stirring for 3 minutes to obtain a mixed solution III.

[0137] 3) Stop heating and stirring, cool the mixed solution III to 4°C, and leave it for 8 hours until the crystals in the solution are completely precipitated.

[0138] 4) The white solid III was filtered off and washed three times with 4°C water; then dried at 40°C for 48 hours to obtain a white powder III with a yield of 85% based on butylphthalide.

[0139] 2. Characterization

[0140] The white powders prepared in Examples 1 to 3 were characterized respectively, including morphology, H-NMR, infrared spectrum, X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). The characterization results are as follows: 2.1. Morphology observation The white powders of Examples 1 to 3 were respectively placed on a glass slide, and the morphology of each sample was observed and recorded under an optical microscope (10×20); the results are as follows Figure 2 shown.

[0141] Figure 2 The white powders of Examples 1 to 3 all have clear crystal forms, among which white powder I is needle-shaped crystals, and white powder II and white powder III are transparent block crystals with a diameter of 20 to 50 μm. Under the same experimental conditions, cyclodextrin does not precipitate solids in the solvent, indicating that the white powders obtained in Examples 1 to 3 are a type of crystal.

[0142] 2.2.H-NMR characterization

[0143] Butylphthalide, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the crystals prepared in each embodiment (white powder I, white powder II, and white powder III) were dissolved in DMSO-d6 and subjected to nuclear magnetic resonance hydrogen spectrum detection. The detection results are as follows: Figure 3 The H-NMR data of the crystals of each example simultaneously contained signals of butylphthalide and α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, confirming that the crystals were composed of two components. This indicates that the white powder obtained in Examples 1 to 3 is a eutectic.

[0144] 2.3. Infrared characterization

[0145] Take butylphthalide, γ-cyclodextrin, and the cocrystal (white powder III) prepared in Example 3 and perform infrared spectroscopy detection respectively. The detection results are as follows: Figure 4 . Figure 4 The characteristic peak of butylphthalide is at 692.4 cm-1 、706.8cm -1 、740.2cm -1 、915.9cm -1 、965.7cm -1 、982.1cm -1 、1012.64cm -1 、1057.5cm -1 、1111.5cm -1 、1192.4cm -1 、1210.9cm -1 、1240.0cm -1 、1282.8cm -1 、1345.5cm -1 、1464.7cm -1 、1612.2cm -1 etc.; the characteristic peak of cyclodextrin is at 400cm -1 -2000cm -1 Compared with the above two, most of the characteristic peaks of butylphthalide in the infrared spectrum of the cocrystal (white powder III) prepared in Example 3 disappeared, and its infrared spectrum was consistent with that of cyclodextrin as a whole, indicating that the drug and cyclodextrin formed an inclusion complex, so that the characteristic peaks of butylphthalide in the structure were covered by cyclodextrin. This shows that the white powder prepared in Examples 1 to 3 is an inclusion complex.

[0146] XRD characterization

[0147] The PXRD analysis of butylphthalide, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the inclusion compound eutectic (white powder I, white powder II, and white powder III) prepared in each embodiment was performed respectively. The analysis results are as follows: Figure 5 .

[0148] The XRD diffraction peaks of white powder Ⅰ are at 5.6±0.2°, 6.7±0.2°, 11.3±0.2°, 11.9±0.2°, 12.6±0.2°, 12.9±0.2°, 13.4±0.2°, 14.6±0.2°, 14.8±0.2°, 15.2±0.2°, 15.6±0.2°, 17.0±0.2°, 17.4±0.2°, 18.5±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 23.9±0.2°, 27.9±0.2°, 30.0±0.2°, 35.2±0.2°, 36.8±0.2°, and 37.5±0.2°;

[0149] The XRD diffraction peaks of white powder II are at 5.5±0.2°, 6.1±0.2°, 9.2±0.2°, 9.7±0.2°, 10.1±0.2°, 10.7±0.2°, 12.1±0.2°, 14.6±0.2°, 15.1±0.2°, 17.7±0.2°, 18.6±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.5±0.2°, 23.4±0.2°, 24.0±0.2°, 24.9±0.2°, 26.0±0.2°, 27.0±0.2°, and 29.4±0.2°;

[0150] The XRD diffraction peaks of white powder III are at 7.4±0.2°, 10.5±0.2°, 11.5±0.2°, 11.8±0.2°, 12.0±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.7±0.2°, 18.2±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 22.4±0.2°, 23.7±0.2°, 24.2±0.2°, 24.5±0.2°, 25.4±0.2°, 26.8±0.2°, 27.3±0.2°, and 27.7±0.2°.

[0151] By comparison, the XRD diffraction peaks of each inclusion complex co-crystal are completely different from the characteristic peaks of each cyclodextrin and butylphthalide, indicating that it is not a simple physical mixture, but a new crystal form is formed. In addition, the HNMR results show that the crystal contains both cyclodextrin and butylphthalide, so it can be determined to be a cyclodextrin inclusion complex co-crystal of butylphthalide.

[0152] DSC characterization

[0153] α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the inclusion compound cocrystals prepared in each embodiment (white powder I, white powder II, and white powder III) were subjected to DSC analysis. The analysis results are as follows: Figure 6 . Figure 6 The results show that the melting points of the inclusion compound eutectic formed by butylphthalide and cyclodextrin are 282.9°C (Example 1), 302.5°C (Example 2) and 315.1°C (Example 3), respectively, while the melting point of butylphthalide is known to be 67.23°C. This indicates that the thermal stability of butylphthalide after forming the inclusion compound eutectic is significantly improved compared with butylphthalide (oil-like at room temperature).

[0154] 2.6. Solubility determination

[0155] The solubility (25° C.) of butylphthalide and the inclusion compound eutectic (white powder I, white powder II, white powder III) prepared in each example in water is shown in Table 1.

[0156] Table 1 Drug solubility data

[0157]

[0158] According to Table 1, compared with the solubility of free butylphthalide in water (277.1 μg / mL), the solubility of white powder I increased to 2.54 mg / mL (increased by about 10 times), the solubility of white powder II increased to 399.3 μg / mL, and the solubility of white powder III decreased to 80.0 μg / mL. It can be seen that the butylphthalide inclusion complex eutectic of the present application has significantly enhanced water solubility compared to butylphthalide.

[0159] 3. Pharmacokinetic testing

[0160] 3.1. Materials and pretreatment

[0161] Twelve adult healthy SD rats were randomly divided into 4 groups, 3 rats in each group; 56 mg / kg of self-developed free butylphthalide and three inclusion compound cocrystal preparations were given by gavage. Blood was collected from the orbits of SD rats before administration and at 5min, 10min, 15min, 30min, 45min and 1, 2, 3, 4, 5, 6, 8, 12, 24h after administration, and placed in heparinized EP tubes, centrifuged, and the upper plasma was taken and stored in a -80℃ refrigerator for testing.

[0162] 3.2. Processing of plasma samples

[0163] Take 200 μL of plasma sample, add 800 μL of ethyl acetate, vortex for 3 min, and centrifuge for 10 min (8000 r / min); aspirate 700 μL of supernatant, blow dry the solvent with a nitrogen blower, add 300 μL of methanol to re-dissolve, and centrifuge for 10 min (12000 r / min); aspirate 150 μL of supernatant and detect the concentration by HPLC.

[0164] Data processing

[0165] The pharmacokinetic processing software PKsolve was used to calculate the relevant pharmacokinetic parameters. The calculation results are shown in Table 2

[0166] Table 2 Pharmacokinetic parameters

[0167]

[0168] According to Table 2, based on the pharmacokinetic index AUC, the free butylphthalide is 69.36 μg / ml·min, and the oral bioavailability of the three inclusion compound cocrystals is increased by 3 times (white powder I), 5 times (white powder II), and 2.5 times (white powder III), respectively. It can be seen that the butylphthalide inclusion compound cocrystal of the present application has a significant improvement in bioavailability compared to butylphthalide.

[0169] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0170] The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to interpret the contents of the claims.

Claims

1. A butylphthalide inclusion compound eutectic, characterized in that: The butylphthalide inclusion compound cocrystal is prepared by the following steps: Dissolving butylphthalide in an organic solvent to obtain an organic solution of butylphthalide; wherein the organic solvent is miscible with water; Under the conditions of providing dispersing force and heating, dissolving the inclusion main component in water to obtain an inclusion solution, wherein the inclusion main component includes cyclodextrin; then injecting the organic solution of butylphthalide into the inclusion solution, and optionally supplementing the organic solvent to obtain a mixed solution; The dispersing force and heating were stopped, and the resulting mixed solution was allowed to stand.

2. The butylphthalide inclusion compound eutectic according to claim 1, characterized in that: The mass volume ratio of the inclusion main component in the inclusion solution is 1 mg / mL to 100 mg / mL; The mass volume ratio of the butylphthalide in the butylphthalide organic solution is 1 mg / mL to 20 mg / mL; In the mixed solution, the molar ratio of butylphthalide to the inclusion main component is 1:(0.5-50).

3. The butylphthalide inclusion compound eutectic according to claim 2, characterized in that: The inclusion main component is α-cyclodextrin, and the mass volume ratio of the α-cyclodextrin in the inclusion solution is 40 mg / mL to 100 mg / mL.

4. The butylphthalide inclusion compound eutectic according to claim 3, characterized in that: The X-ray powder diffraction pattern of the butylphthalide inclusion complex cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.6±0.2°, 6.7±0.2°, 11.3±0.2°, 11.9±0.2°, 12.6±0.2°, 12.9±0.2°, 13.4±0.2°, 14.6±0.2°, 14.8±0.2°, 15.2±0. 2°, 15.6±0.2°, 17.0±0.2°, 17.4±0.2°, 18.5±0.2°, 19.3±0.2°, 20.1±0.2°, 21.1±0.2°, 23.9±0.2°, 27.9±0.2°, 30.0±0.2°, 35.2.±0.2°, 36.8±0.2°, 37.5±0.2°; Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 2.5×10 3 μg / mL~2.6×10 3 μg / mL.

5. The butylphthalide inclusion compound eutectic according to claim 2, characterized in that: The inclusion main component is β-cyclodextrin, and the mass volume ratio of the β-cyclodextrin in the inclusion solution is 2 mg / mL to 25 mg / mL.

6. The butylphthalide inclusion compound eutectic according to claim 5, characterized in that: The X-ray powder diffraction pattern of the butylphthalide inclusion compound cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 5.5±0.2°, 6.1±0.2°, 9.2±0.2°, 9.7±0.2°, 10.1±0.2°, 10.7±0.2°, 12.1±0.2°, 14.6±0.2°, 15.1±0.2°, 17.7±0.2°, 18.6±0.2°, 18.9±0.2°, 19.9±0.2°, 20.7±0.2°, 21.5±0.2°, 23.4±0.2°, 24.0±0.2°, 24.9±0.2°, 26.0±0.2°, 27.0±0.2°, 29.4±0.2°; Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 390 μg / mL to 410 μg / mL.

7. The butylphthalide inclusion compound eutectic according to claim 2, characterized in that: The inclusion main component is γ-cyclodextrin, and the mass volume ratio of the γ-cyclodextrin in the inclusion solution is 3 mg / mL to 50 mg / mL.

8. The butylphthalide inclusion compound eutectic according to claim 7, characterized in that: The X-ray powder diffraction pattern of the butylphthalide inclusion compound cocrystal has characteristic diffraction peaks at the following 2θ (°) angles: 7.4±0.2°, 10.5±0.2°, 11.5±0.2°, 11.8±0.2°, 12.0±0.2°, 14.2±0.2°, 14.9±0.2°, 15.8±0.2°, 16.7±0.2°, 18.2±0 .2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.2±0.2°, 21.8±0.2°, 22.4±0.2°, 23.7±0.2°, 24.2±0.2°, 24.5±0.2°, 25.4±0.2°, 26.8±0.2°, 27.3±0.2°, 27.7±0.2°; Furthermore, the solubility of the butylphthalide inclusion complex eutectic in water is 70 μg / mL to 90 μg / mL.

9. The butylphthalide inclusion compound co-crystal according to any one of claims 1 to 8, characterized in that: The organic solvent is selected from methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, ethylene glycol and combinations thereof; and / or The providing of the dispersing force comprises: stirring at 50 rpm to 1000 rpm; and / or The heating temperature is 30°C to 60°C; and / or The time for injecting the organic solution of butylphthalide is 0.5min to 30min.

10. The butylphthalide inclusion compound cocrystal according to claims 1 to 8, characterized in that: The volume ratio of the organic solvent to water in the mixed solution is 3:(7-60).

11. The butylphthalide inclusion compound co-crystal according to any one of claims 1 to 8, characterized in that: In the step of allowing the obtained mixed solution to stand: The standing is performed at 4°C to 30°C; and / or The standing time is 4 hours to 72 hours.

12. The butylphthalide inclusion compound co-crystal according to any one of claims 1 to 8, characterized in that: After the obtained mixed solution is allowed to stand, the method further comprises the steps of: Collect the solid precipitated after standing; optionally wash the solid with water and / or a crystallization solvent; and then dry at 30° C. to 60° C.; Furthermore, the drying time is 1 hour to 48 hours.

13. A pharmaceutical composition, characterized in that It includes: 1) The butylphthalide inclusion compound cocrystal according to any one of claims 1 to 12, and 2) Pharmaceutically acceptable carriers or excipients.

14. Use of the butylphthalide inclusion complex cocrystal according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 11 in the preparation of a drug for preventing and treating diseases of tissue pathological damage or nerve cell damage caused by ischemia and hypoxia.

15. The use according to claim 14, characterized in that: The disease is selected from ischemic stroke, vascular dementia, muscular atrophy, angina pectoris and myocardial infarction.

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