Pharmaceutical inclusion complexes, methods of making and uses thereof

Abstract

This invention relates to pharmaceutical inclusion compounds, their preparation methods, and uses. Specifically, it provides a buggerfuran inclusion compound and its preparation method, wherein the inclusion compound comprises buggerfuran, cyclodextrin compounds, and optionally a high molecular weight polymer. This inclusion compound has a simple composition, high encapsulation efficiency, stability, and high safety, and can be used to prepare various liquid and solid dosage forms.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a drug inclusion complex, its preparation method, and its uses. Background Technology

[0002] Buagafuran is a derivative of agarwood furan, a chemical component found in agarwood. It belongs to the furan-type sesquiterpenes and is prepared through chemical synthesis. In various animal studies, buagafuran has shown anti-anxiety effects and low toxicity. Its chemical structure is as follows:

[0003] Burgerfuran is an oily liquid at room temperature. Its furan ring structure endows it with lipophilicity and specific pharmacological activities. The presence of an epoxy ether bond and a double bond in its structure constitutes the main sites of its chemical instability. Prolonged storage at room temperature leads to degradation and a decrease in concentration, necessitating long-term storage in a refrigerator (2–8°C). Burgerfuran lacks large polar groups, exhibiting overall hydrophobicity and poor water solubility. The rigid bicyclic structure, epoxy ether bond, and nonpolar groups in burgerfuran contribute to its low solubility and instability, posing a challenge to the development of burgerfuran formulations.

[0004] Studies have shown that preparing bugfuran solid dispersions using solid dispersion technology can improve the in vitro dissolution and stability of bugfuran, facilitating long-term storage. However, the preparation of solid dispersions requires the use of large amounts of organic solvents, placing specific demands on the production environment. Other studies have explored the preparation of self-emulsifying / self-microemulsifying bugfuran formulations, which can avoid the use of organic solvents while simultaneously improving the stability and dissolution rate of bugfuran. However, these formulations require significant amounts of surfactants and co-surfactants, raising concerns about long-term tolerability. Furthermore, all of the aforementioned studies incorporated antioxidants to ensure the stability of bugfuran, and the relevant dosage forms are primarily limited to oral solid dosage forms.

[0005] In clinical practice, bugfuran requires long-term administration for the treatment of anxiety and depression, resulting in poor compliance with conventional oral dosage forms such as tablets or capsules. On the other hand, studies have shown that bugfuran exerts its anti-anxiety and antidepressant effects by acting on ion channels in the brain (Chen Chunlin et al., Electrophysiological mechanism of bugfuran's anti-anxiety and antidepressant effects, Acta Pharmaceutica Sinica, 2013, 48(1):38-44). Therefore, increasing the concentration of bugfuran in the brain would be more conducive to its efficacy.

[0006] It is evident that the dosage form of bugufuran requires further investigation. Summary of the Invention

[0007] To address the problems in the prior art, this invention provides a bugfuran inclusion complex and its preparation method. The inclusion complex prepared by this invention has a simple composition, overcomes the shortcomings of the prior art, eliminates the need for antioxidants, and solves the problems of poor stability, poor water solubility, and inconvenient storage of bugfuran. For example, measurements show that at 25°C, the solubility of the bugfuran hydroxypropyl betacyclodextrin inclusion complex prepared by this invention in water reaches 4.4 mg / ml, which is more than 4000 times higher than the solubility of bugfuran raw material. Therefore, it is particularly suitable for preparing liquid formulations, thereby enriching the dosage forms for clinical applications of bugfuran and contributing to the development of formulations with different release rates and brain-targeting agents.

[0008] Specifically, in a first aspect, the present invention provides a method for preparing a bougerfuran inclusion complex, comprising: (1) Provide an aqueous solution of cyclodextrin and a solution of bougerfuran or bougerfuran in ethanol; (2) Mix the cyclodextrin aqueous solution and the bugfuran, or mix the cyclodextrin aqueous solution and the bugfuran ethanol solution; (3) The mixture obtained in step (2) is subjected to a washing step and an optional drying step to obtain the Bougfuran inclusion complex; in: The cyclodextrin aqueous solution comprises cyclodextrin compounds, water, and optionally a high molecular weight polymer; The bouguran ethanol solution contains bouguran and ethanol.

[0009] Those skilled in the art will understand that the above methods include the following two types of technical solutions: Class 1: A method for preparing bougerfuran inclusion compounds, comprising: (1) Provide an aqueous solution of cyclodextrin and bougerfuran; (2) Mix the cyclodextrin aqueous solution and the bugfuran; (3) The mixture obtained in step (2) is subjected to a washing step and an optional drying step to obtain the Bougfuran inclusion complex; in: The cyclodextrin aqueous solution comprises cyclodextrin compounds, water, and optionally a high molecular weight polymer.

[0010] Category 2: A method for preparing bougerfuran inclusion compounds, comprising: (1) Provide an aqueous solution of cyclodextrin and an ethanolic solution of bougerfuran; (2) Mix the cyclodextrin aqueous solution and the bougerfuran ethanol solution; (3) The mixture obtained in step (2) is subjected to a washing step and an optional drying step to obtain the Bougfuran inclusion complex; in: The cyclodextrin aqueous solution comprises cyclodextrin compounds, water, and optionally a high molecular weight polymer; The bouguran ethanol solution contains bouguran and ethanol.

[0011] Those skilled in the art will understand that "optional" means the presence or absence of the object it defines. For example, "the cyclodextrin aqueous solution comprises a cyclodextrin compound, water, and optionally a polymer" means that the cyclodextrin aqueous solution comprises a cyclodextrin compound and water, or that the cyclodextrin aqueous solution comprises a cyclodextrin compound, water, and a polymer. As another example, "the mixture obtained in step (2) is subjected to a washing step and optionally a drying step to obtain a bougerfuran inclusion complex" means that "the mixture obtained in step (2) is subjected to a washing step and a drying step to obtain a bougerfuran inclusion complex," or "the mixture obtained in step (2) is subjected to a washing step to obtain a bougerfuran inclusion complex."

[0012] In some embodiments, the mass ratio of the cyclodextrin compound to the bugfuran is 5.7:1 to 11.7:1 (e.g., 5.7:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.5:1, 11:1, 11.5:1, 11.6:1 or 11.7:1), preferably 7.7:1 to 11.6:1, and more preferably 11.5:1 to 11.6:1.

[0013] In some embodiments, the mass ratio of the cyclodextrin compound to the water is 1:1 to 1.5:1 (e.g., 1:1, 1.1:1, 1.11:1, 1.12:1, 1.125:1, 1.13:1, 1.14:1, 1.15:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1), preferably 1.1:1 to 1.2:1, and more preferably 1.125:1.

[0014] In some embodiments, when providing the cyclodextrin aqueous solution and the bougerfuran ethanol solution in step (1), the volume (mL) of the ethanol to the mass (g) of the water is 1:7 to 1:3 (e.g., 1:7, 1:6, 1:5, 1:4 or 1:3), preferably 1:5 to 1:3, and more preferably 1:4.

[0015] In some embodiments, when the cyclodextrin aqueous solution contains the polymer, the mass ratio of the polymer to the water is 0.002:1 to 0.004:1 (e.g., 0.002:1, 0.0021:1, 0.0022:1, 0.0023:1, 0.0024:1, 0.0025:1, 0.0026:1, 0.0027:1, 0.0028 ... The ratios are 0029:1, 0.003:1, 0.0031:1, 0.0032:1, 0.0033:1, 0.0034:1, 0.0035:1, 0.0036:1, 0.0037:1, 0.0038:1, 0.0039:1 or 0.004:1, preferably 0.002:1 to 0.003:1, and more preferably 0.0025:1 to 0.003:1.

[0016] In some embodiments, the polymer includes hydroxypropyl methylcellulose, povidone (such as povidone K30), or polyethylene glycol (such as polyethylene glycol 6000).

[0017] In some embodiments, the polymer is hydroxypropyl methylcellulose.

[0018] In some embodiments, the mixing time is 20-30 hours (e.g., 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours or 30 hours), preferably 20-25 hours, and more preferably 24 hours.

[0019] In some embodiments, the cyclodextrin compounds are cyclodextrins and their derivatives.

[0020] In some embodiments, the cyclodextrin compounds include alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, or methyl beta cyclodextrin, etc.

[0021] In some embodiments, the cyclodextrin compound is hydroxypropyl betacyclodextrin or hydroxypropyl gammacyclodextrin.

[0022] In some embodiments, when the cyclodextrin compound is hydroxypropyl beta-cyclodextrin, the aqueous cyclodextrin solution contains the polymer.

[0023] In some embodiments, when the cyclodextrin compound is hydroxypropyl gamma cyclodextrin, the aqueous cyclodextrin solution may or may not contain the polymer.

[0024] In some embodiments, the washing is carried out using n-hexane.

[0025] In some implementations, the mixing is stirring.

[0026] In some embodiments, the mixing is carried out at room temperature (e.g., 20-30°C).

[0027] In some implementations, the drying is freeze-drying.

[0028] In some implementations, the ethanol is 95% ethanol or anhydrous ethanol.

[0029] In a second aspect, the present invention provides a buggerfuran inclusion compound, which is prepared by the aforementioned method.

[0030] In a third aspect, the present invention provides a buggerfuran inclusion complex comprising buggerfuran, a cyclodextrin compound, and optionally a high molecular weight polymer.

[0031] Those skilled in the art will understand that "comprising bugfuran, cyclodextrin compounds, and optionally a polymer" means "comprising bugfuran and cyclodextrin compounds," or "comprising bugfuran, cyclodextrin compounds, and a polymer."

[0032] In some embodiments, the mass ratio of the cyclodextrin compound to the bugfuran is 5.7:1 to 11.7:1 (e.g., 5.7:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.5:1, 11:1, 11.5:1, 11.6:1 or 11.7:1), preferably 7.7:1 to 11.6:1, and more preferably 11.5:1 to 11.6:1.

[0033] In some embodiments, when the bug-furan inclusion complex comprises the polymer, the mass ratio of the cyclodextrin compound to the polymer is 350:1 to 450:1 (e.g., 350:1, 355:1, 360:1, 365:1, 370:1, 375:1, 380:1, 385:1, 390:1, 395:1, 400:1, 405:1, 410:1, 415:1, 420:1, 425:1, 430:1, 435:1, 440:1, 445:1, or 450:1), preferably 375:1 to 450:1.

[0034] In some embodiments, the polymer includes hydroxypropyl methylcellulose, povidone (such as povidone K30), or polyethylene glycol (such as polyethylene glycol 6000).

[0035] In some embodiments, the polymer is hydroxypropyl methylcellulose.

[0036] In some embodiments, the cyclodextrin compounds are cyclodextrins and their derivatives.

[0037] In some embodiments, the cyclodextrin compounds include alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, or methyl beta cyclodextrin, etc.

[0038] In some embodiments, the cyclodextrin compound is hydroxypropyl betacyclodextrin or hydroxypropyl gammacyclodextrin.

[0039] In some embodiments, when the cyclodextrin compound is hydroxypropyl betacyclodextrin, the bug furan inclusion complex contains the polymer.

[0040] In some embodiments, when the cyclodextrin compound is hydroxypropyl gamma cyclodextrin, the bug furan inclusion complex may or may not contain the polymer.

[0041] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the aforementioned bug-furan inclusion complex.

[0042] In some embodiments, the pharmaceutical composition is prepared using the aforementioned bugfuran inclusion complex.

[0043] In some embodiments, the pharmaceutical composition is a liquid or solid formulation.

[0044] In some embodiments, the liquid formulation is a powder for injection, an oral liquid, or a syrup, etc.

[0045] In some embodiments, the solid dosage form is granules, tablets, capsules, or orally disintegrating films, etc.

[0046] In a fifth aspect, the present invention provides the use of the aforementioned bugfuran inclusion complex or the aforementioned pharmaceutical composition in the preparation of anti-anxiety and antidepressant drugs.

[0047] In addition, the present invention also provides the aforementioned bugfuran inclusion complex or the aforementioned pharmaceutical composition for use in treating anxiety and depression.

[0048] Furthermore, the present invention also provides a method for treating and / or preventing anxiety and depression, comprising administering to a subject in need an effective amount of the aforementioned burgerfuran inclusion complex or the aforementioned pharmaceutical composition.

[0049] The term "prevention" refers to a method implemented to prevent or delay the occurrence of a disease, condition, or symptom in a subject; the term "treatment" refers to a method implemented to obtain a beneficial or desired clinical outcome. For the purposes of this invention, a beneficial or desired clinical outcome includes, but is not limited to, alleviating symptoms, reducing the extent of the disease, stabilizing (i.e., no longer worsening) the state of the disease, delaying or slowing the progression of the disease, improving or alleviating the state of the disease, and relieving symptoms (whether partial or complete), whether detectable or undetectable. Furthermore, "treatment" can also refer to prolonged survival compared to the expected survival (if no treatment was received).

[0050] "Subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0051] "Effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the substance / molecule's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before or in the early stages of the disease.

[0052] Beneficial effects

[0053] 1) The inclusion complex of this invention has a high encapsulation efficiency; 2) The inclusion complex of the present invention has high stability and can exist stably under high temperature, high humidity and / or light conditions; 3) The active component of the inclusion compound of the present invention has high solubility in furan; 4) The active component of the inclusion compound of the present invention, the furan, can dissolve rapidly; 5) The inclusion complex of this invention has a simple composition and high safety; 6) The preparation method of the inclusion compound of the present invention is simple and low in cost, and is suitable for industrial production; 7) The inclusion complex of this invention is convenient to store and transport; 8) The inclusion complex of this invention can be easily processed into various solid and liquid dosage forms; 9) This invention realizes the solidification of liquid drugs, which facilitates the long-term storage of drugs. Attached Figure Description

[0054] Figure 1DSC spectra of the bugfuran inclusion complex and bugfuran active pharmaceutical ingredient prepared in the embodiments of the present invention.

[0055] Figure 2 In vitro dissolution curves of the bugfuran inclusion complex and bugfuran active pharmaceutical ingredient prepared in the embodiments of the present invention.

[0056] Figure 3 The in vitro dissolution curves of the Bougourfuran inclusion complex prepared in this embodiment of the invention are shown in the influence factor test.

[0057] Figure 4 Blood drug concentration-time curves of the bugfuran inclusion complex prepared in Example 1 of this invention and the control drug in a pharmacokinetic study. Detailed Implementation

[0058] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Raw materials, equipment, or instruments used without specified manufacturers are all commercially available conventional products. For example, hydroxypropyl betacyclodextrin and hydroxypropyl gammacyclodextrin can be purchased from Zibo Qianhui Biotechnology Co., Ltd., hydroxypropyl methylcellulose can be purchased from Dow Chemical Company, povidone can be purchased from BASF Corporation, and polyethylene glycol can be purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd. Furthermore, in the following examples, bugfuran can be dissolved in either 95% ethanol or anhydrous ethanol; the two solvents are equally effective. The following examples use 95% ethanol as an example for illustration.

[0059] Example 1 Preparation of Bougourfuran inclusion complex

[0060] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0061] Example 2 Preparation of Bougerfuran Inclusion Complex

[0062] Weigh 9g of hydroxypropyl gamma cyclodextrin and dissolve it in 8g of water. Separately, take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, and add it to the cyclodextrin aqueous solution. Stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0063] Example 3 Preparation of Bougourfuran inclusion complex

[0064] Weigh 9g of hydroxypropyl gamma cyclodextrin and 0.024g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0065] Example 4 Preparation of Bougourfuran inclusion complex

[0066] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 1.17g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0067] Comparative Example 1: Preparation of Bougourfuran Inclusion Complex

[0068] Weigh 7.5g of hydroxypropyl gamma cyclodextrin and dissolve it in 15g of water. Separately, take 0.64g of bürgfuran, dissolve it in about 2ml of 95% ethanol, and add it to the cyclodextrin aqueous solution. Stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0069] Comparative Example 2: Preparation of Bougourfuran Inclusion Complex

[0070] Weigh 6g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 9g of water, and separately take 0.52g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0071] Comparative Example 3: Preparation of Bougourfuran Inclusion Complex

[0072] Weigh 9g of hydroxypropyl betacyclodextrin and dissolve it in 8g of water. Separately, take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, and add it to the cyclodextrin aqueous solution. Stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0073] Comparative Example 4: Preparation of Bougourfuran Inclusion Complex

[0074] Weigh 9g of hydroxypropyl betacyclodextrin, dissolve it in 8g of water, add 0.02g of povidone K30, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0075] Comparative Example 5: Preparation of Bougourfuran Inclusion Complex

[0076] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of polyethylene glycol 6000, dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0077] Comparative Example 6: Preparation of Bougourfuran Inclusion Complex

[0078] Weigh 9g of hydroxypropyl betacyclodextrin and 0.04g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0079] Comparative Example 7: Preparation of Bougourfuran Inclusion Complex

[0080] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 16h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0081] Comparative Example 8: Preparation of Bougourfuran Inclusion Complex

[0082] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 0.78g of bürgfuran, dissolve it in about 4ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0083] Comparative Example 9: Preparation of Bougourfuran Inclusion Complex

[0084] Weigh 9g of hydroxypropyl betacyclodextrin and 0.02g of hydroxypropyl methylcellulose (substituted type 2910, viscosity 5mPa·s), dissolve them in 8g of water, and separately take 1.6g of bürgfuran, dissolve it in about 2ml of 95% ethanol, add it to the cyclodextrin aqueous solution, stir at room temperature for 24h, wash with n-hexane and dry to obtain the bürgfuran inclusion complex.

[0085] Example 5 Preparation of Bougourfuran Inclusion Complex Capsules

[0086] The bougerfuran inclusion complexes prepared according to Examples 1-4 are filled into gelatin hollow capsules to obtain bougerfuran inclusion complex capsules.

[0087] Example 6 Preparation of oral soluble membrane of Bougourfuran inclusion complex

[0088] prescription: The Bougourfuran inclusion complexes prepared in Examples 1-4; Hydroxypropyl methylcellulose; Polyethylene glycol 400; The mass ratio of bugufuran, hydroxypropyl methylcellulose, and polyethylene glycol 400 in the inclusion complex is 1.5:20:12.

[0089] Preparation method: Take the prescribed amount of bugufuran inclusion complex, add 10 times the amount of purified water and disperse evenly, then add the prescribed amounts of hydroxypropyl methylcellulose and polyethylene glycol 400 in sequence, stir evenly, degas and spread evenly on a glass plate, and then dry and cut to obtain the final product.

[0090] Example 7 Preparation of Bougerfuran Inclusion Compound Granules

[0091] prescription: The Bougourfuran inclusion complexes prepared in Examples 1-4; Mannitol; 70% ethanol; The mass ratio of bouguran to mannitol in the inclusion complex is 1.5:70. 70% ethanol is used in appropriate amounts.

[0092] Preparation method: Take the prescribed amount of burgdorffuran inclusion complex and mannitol, mix them three times through a 60-mesh sieve, add an appropriate amount of 70% ethanol to make a soft material, granulate it through a 24-mesh sieve, put the wet granules into a 40℃ oven to dry, and after drying for 30 minutes, granulate them through a 24-mesh sieve to obtain the final product.

[0093] Example 8 Preparation of Bougerfuran Tablets

[0094] prescription: The Bougourfuran inclusion complexes prepared in Examples 1-4; Microcrystalline vitamins; Cross-linked polyvinylpyrrolidone; Magnesium stearate; The mass ratio of bugufuran, microcrystalline vitamins, crospovidone, and magnesium stearate in the inclusion complex is 1.5:7:3:0.2.

[0095] Preparation method: Take the prescribed amount of each material, pass them through a 60-mesh sieve three times, mix them, and compress the powder directly into tablets using an 11mm diameter punch.

[0096] Example 9 Preparation of lyophilized powder injection of Bougourfuran inclusion complex

[0097] Weigh 9g of hydroxypropyl gamma cyclodextrin and dissolve it in 8g of water. Separately, add 0.78g of bugfuran to the cyclodextrin aqueous solution and stir at room temperature for 24h. After pre-freezing the liquid, place it in a freeze dryer for freeze drying. Wash with n-hexane to remove unencapsulated bugfuran, and finally remove n-hexane to obtain freeze-dried powder for injection.

[0098] Test case

[0099] 1. Determination of encapsulation efficiency of inclusion complex

[0100] Take an appropriate amount of the inclusion compound (equivalent to 15 mg of bugfuran), place it in a 25 ml brown volumetric flask, add ethanol and shake to dissolve and dilute to the mark, then shake well; accurately measure 5 ml of this solution and place it in a 20 ml brown volumetric flask, add ethanol to dilute to the mark, shake well, filter, and use the filtrate as the test solution. Separately, take 15 mg of bugfuran reference standard, dissolve and dilute it in 100 ml of ethanol to prepare a solution containing 0.15 mg of bugfuran per ml, as the reference solution. Accurately inject 10 μl each of the reference solution and the test solution into the liquid chromatograph, and determine according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512). The chromatographic conditions are: column: octylsilane-bonded silica gel as the packing material; mobile phase: acetonitrile:water = 80:20 (v / v); flow rate: 1.0 ml·min. -1 Column temperature: 40℃; Detection wavelength: 196nm; Injection volume: 10μl; Record the chromatogram and calculate the bougerfuran content in the inclusion compound using the external standard method based on peak area. The encapsulation efficiency of the inclusion compound can be calculated using the following formula based on the content: Encapsulation rate (%) = Bouguerfuran content in the inclusion compound × weight of the inclusion compound / amount of Bouguerfuran fed × 100%.

[0101] The test results for each sample are shown in Table 1: Table 1. Encapsulation efficiency determination results of Bougerfuran inclusion complexes

[0102] The results showed that the encapsulation efficiency of the bougerfuran inclusion complexes of the present invention (such as the inclusion complexes prepared in Examples 1-4) was higher than that of the inclusion complexes prepared in Comparative Examples 1-9. In particular, the encapsulation efficiency of the bougerfuran inclusion complexes of the present invention (such as the inclusion complexes prepared in Examples 1-4) was two times or more than that of the inclusion complexes prepared in Comparative Examples 1, 2, 3, and 8, and even up to nearly 7 times, showing a significant advantage in encapsulation efficiency.

[0103] 2. DSC determination of inclusion complex

[0104] DSC was determined using a thermal analysis method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0661). 5-10 mg of sample was placed in a sealed crucible and analyzed using a METTLER DSC3 STAR differential scanning calorimeter. The heating rate was 10 °C / min, from -25 °C to 200 °C, with nitrogen as the carrier gas. The sample chromatograms were recorded. Exemplary DSC chromatograms of the bugfuran inclusion complex and bugfuran active pharmaceutical ingredient are shown below. Figure 1 .

[0105] As can be seen from the figure, the inclusion complexes prepared in this invention (such as those prepared in Examples 1-4) have completely removed the free, unincluded Bougman, and the DSC spectrum will no longer show the endothermic peak of Bougman.

[0106] 3. Solubility determination

[0107] Excess amounts of bugfuran raw material, bugfuran inclusion complex prepared according to the examples (such as Examples 1 and 2), and control drug (bugfuran particles obtained according to the solid dispersion preparation method of patent CN202111481813.3) were added to Erlenmeyer flasks containing an appropriate amount of purified water. The samples were sealed and placed in a shaker (water bath temperature 25.0℃, rotation speed 120rpm) for 24 hours. Samples were filtered, and the concentration of bugfuran in the samples was calculated by the external standard method based on the peak area according to the chromatographic conditions under the "Determination of Encapsulation Rate of Inclusion Complex" section. The results are shown in Table 2. Table 2 Solubility Measurement Results

[0108] The results showed that the solubility of the inclusion complex prepared by the present invention was significantly improved compared with the solubility of burgdorffran raw material and the control drug. In particular, the solubility of the inclusion complex prepared in Examples 1 and 2 of the present invention was improved by more than a thousand times, and even more than 4,000 times, compared with the solubility of burgdorffran raw material.

[0109] 4. Determination of dissolution curve of inclusion complex

[0110] The inclusion complexes prepared in the examples (such as Examples 1 and 2) were filled into gelatin empty capsules at a specification of 15 mg. The capsules were placed in a settling basket and tested according to the dissolution and release assay method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method II). 500 ml of 0.3% sodium dodecyl sulfate solution was used as the dissolution medium, and the rotation speed was 75 rpm. The procedure was followed, and 5 ml samples were taken at 5, 10, 15, 30, and 60 minutes, with 5 ml of the solution added as a supplement. The solution was filtered, and the filtrate was used as the test solution. Separately, approximately 75 mg of bugfuran reference standard was placed in a 25 ml amber volumetric flask, diluted to the mark with ethanol, and shaken well. 1.0 ml of this standard was accurately measured and placed in a 100 ml amber volumetric flask, diluted to the mark with 0.3% sodium dodecyl sulfate solution, and shaken well. This was used as the reference solution (each 1 ml contained 0.03 mg of bugfuran). Accurately measure 20 μl of the reference solution and the test solution respectively, inject them into the high performance liquid chromatograph, record the peak area, calculate the dissolution rate at each time point using the external standard method, and plot the dissolution curve.

[0111] The in vitro dissolution profiles of capsules made from brugrynur active pharmaceutical ingredient in Examples 1 and 2 are as follows: Figure 2 As shown.

[0112] The results showed that the in vitro dissolution rate and extent of the inclusion complex of the present invention were significantly increased compared with the active pharmaceutical ingredient, and the sample exhibited rapid dissolution characteristics.

[0113] 5. Stability study of inclusion complex

[0114] The Bougman inclusion complex prepared in Example 1 was placed under influencing factor tests (high temperature, high humidity, and light), and samples were taken at predetermined time points to determine DSC, active ingredient content, impurity content, and dissolution curve.

[0115] The DSC determination method is the same as in item 2 above. The results show that there is no endothermic peak of Bouguerfuran in the DSC spectra of all samples, indicating that no free Bouguerfuran was present during the placement of the inclusion complex.

[0116] The method for determining the content of active ingredients is the same as in item 1 above, and the method for determining the content of impurities is as follows: Accurately weigh an appropriate amount of sample (approximately equivalent to 10 mg of bugfuran), place it in a round-bottom centrifuge tube, add 2 ml of water, vortex for 20 min, add 5 ml of n-hexane, and centrifuge for 20 min (3000 rpm). Collect the supernatant to obtain the test solution. Accurately weigh an appropriate amount of bugfuran reference standard, dissolve and dilute it in n-hexane to prepare a solution containing approximately 4 μg per ml, as the reference solution. Accurately inject 10 μl of the blank solvent, reference solution, and test solution into the liquid chromatograph, and determine the chromatogram according to the high-performance liquid chromatography method (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512). The chromatographic conditions are: column: octylsilane-bonded silica gel as the packing material; mobile phase: acetonitrile:water = 72:28 (v / v); flow rate: 1.0 mL / min. -1 Column temperature: 40℃; Detection wavelengths: 196nm and 240nm; Injection volume: 10μL. Record the chromatogram up to twice the retention time of the main component peak. Start integrating at 5.7 min in the chromatogram of the test solution. The relative retention time of impurity C is 0.27 (relative response factor 1.1), and the relative retention time of impurity 1602 is 0.59 (relative response factor 2.1). When there are responses at the same retention time positions at 196nm and 240nm, the one with the largest response is used in the calculation, and the results are not repeated.

[0117] Calculate the percentage content of each impurity in the sample using the following formula:

[0118] In the formula R u The peak area of ​​each impurity in the test solution; R s This represents the peak area of ​​bürgfuran in the reference solution; C s The concentration of bugfuran reference standard in the reference solution is in mg / ml; C u The concentration of bugfuran in the test solution is expressed in mg / ml. F The relative response factor for each impurity is 1 (for unknown impurities, the relative response factor is calculated as 1).

[0119] The results of the determination of the content of active ingredients and impurities in the inclusion complex are shown in Table 3: Table 3. Results of experiments on factors affecting the content of active ingredients and impurities in Bougerfuran inclusion complexes.

[0120] 注 Because cyclodextrin is hygroscopic, no naked samples were placed under high humidity conditions.

[0121] The results of the determination of active ingredient content and impurity content of burgdorferi raw material after 5 days of exposure to light and high temperature (because the sample had completely volatilized after 10 days and could not be measured, only the data for 5 days were measured) are shown in Table 4: Table 4. Results of experiments on factors affecting the content of bugufuran and impurities in bugufuran raw materials.

[0122] The comparative results of the active ingredient content and impurity content in the above-mentioned influencing factor test showed that under light and high temperature conditions, the stability of the bugfuran inclusion complex was significantly improved compared with that of the bugfuran raw material. Furthermore, the stability was further improved after the inclusion complex was packaged.

[0123] The method for determining the dissolution profile is the same as in section 4 above. The results are shown in [see attached table]. Figure 3 The results showed that all samples in the influencing factor test and the 0-day sample exhibited rapid dissolution, and the rate and extent of dissolution were similar between the two samples.

[0124] 6. Pharmacokinetic studies

[0125] SD rats were randomly divided into two groups and administered, by gavage, the inclusion complex sample from Example 1 and the control drug (prepared by referring to the solid dispersion preparation method of patent CN202111481813.3, which prepared a drug composition containing approximately 10% bugfuran from bugfuran and povidone K30) in aqueous solution. The dosage, calculated as bugfuran, was 16 mg / kg. Blood samples were collected from the orbital venous plexus at 5 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood drug concentration was determined by HPLC-MS / MS under the following chromatographic conditions: Chromatographic column: Water Symmetry C8 (3.5 μM, 2.1 × 50 mm), column temperature: 35 °C, mobile phase: methanol (0.1% FA): water (0.1% FA) = 75:25 gradient elution, flow rate: 0.2 mL / min Plotting blood drug concentration-time curves as follows Figure 4 As shown.

[0126] Based on the curves, the pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin software, including the time to peak plasma concentration, peak concentration, and AUC of the positive control drug in rats after oral administration of the aqueous solution. 0-t The peak plasma concentrations were 0.6 h, 19.3 ng / mL, and 45.1 h·ng / mL, respectively; the peak plasma concentrations and AUCs after administration of the inclusion compound in Example 1 were... 0-tThe peak concentrations of the parent drug in rat plasma were 1.04 h, 24.5 ng / mL, and 56.9 h·ng / mL, respectively. The results showed that after oral administration of the bugfuran drug composition prepared in this invention to rats, the peak concentrations of the parent drug in plasma and the AUC were [not specified]. 0-t Higher than the control drug.

[0127] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A method for preparing bougerfuran inclusion compounds, comprising: (1) Provide an aqueous solution of cyclodextrin and a solution of bougerfuran or bougerfuran in ethanol; (2) Mix the cyclodextrin aqueous solution and the bugfuran, or mix the cyclodextrin aqueous solution and the bugfuran ethanol solution; (3) The mixture obtained in step (2) is subjected to a washing step and an optional drying step to obtain the Bougfuran inclusion complex; in: The cyclodextrin aqueous solution comprises cyclodextrin compounds, water, and optionally a high molecular weight polymer; The bouguran ethanol solution contains bouguran and ethanol.

2. The method of claim 1, wherein, The method further has one or more features selected from (i)-(iii): (i) The mass ratio of the cyclodextrin compound to the bugfuran is 5.7:1 to 11.7:1, preferably 7.7:1 to 11.6:1, and more preferably 11.5:1 to 11.6:1; (ii) The mass ratio of the cyclodextrin compound to the water is 1:1 to 1.5:1, preferably 1.1:1 to 1.2:1, and more preferably 1.125:1; (iii) When providing the cyclodextrin aqueous solution and the bougerfuran ethanol solution in step (1), the ratio of the volume (mL) of the ethanol to the mass (g) of the water is 1:7 to 1:3, preferably 1:5 to 1:3, and more preferably 1:

4.

3. The method of claim 1 or 2, wherein, The method further has one or more features selected from (i)-(iv): (i) When the cyclodextrin aqueous solution contains the polymer, the mass ratio of the polymer to the water is 0.002:1 to 0.004:1, preferably 0.002:1 to 0.003:1, and more preferably 0.0025:1 to 0.003:1; (ii) The polymers include hydroxypropyl methylcellulose, povidone (such as povidone K30) or polyethylene glycol (such as polyethylene glycol 6000), etc. Preferably, the polymer is hydroxypropyl methylcellulose; (iii) The mixing time is 20-30 h, preferably 20-25 h, and more preferably 24 h; (iv) The cyclodextrin compounds are cyclodextrins and their derivatives; Preferably, the cyclodextrin compounds include alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, or methyl beta cyclodextrin, etc. Preferably, the cyclodextrin compound is hydroxypropyl betacyclodextrin or hydroxypropyl gammacyclodextrin.

4. The method of claim 3, wherein, When the cyclodextrin compound is hydroxypropyl betacyclodextrin, the cyclodextrin aqueous solution contains the polymer. When the cyclodextrin compound is hydroxypropyl gamma cyclodextrin, the aqueous cyclodextrin solution may or may not contain the polymer.

5. The method according to any one of claims 1-4, wherein, The method further has one or more features selected from (i)-(v): (i) The washing is carried out using n-hexane; (ii) The mixing is stirring; (iii) The mixing is carried out at room temperature (e.g., 20-30°C); (iv) The drying process described is freeze-drying; (v) The ethanol is 95% ethanol or anhydrous ethanol.

6. A burgerfuran inclusion complex prepared by the method described in any one of claims 1-5.

7. Bougerfuran inclusion complexes comprising Bougerfuran, cyclodextrin compounds, and optionally, a high molecular weight polymer.

8. The Bougourfuran inclusion compound of claim 7, wherein, The buggerfuran inclusion complex further has one or more technical features selected from (i)-(iv): (i) The mass ratio of the cyclodextrin compound to the bugfuran is 5.7:1 to 11.7:1, preferably 7.7:1 to 11.6:1, and more preferably 11.5:1 to 11.6:1; (ii) When the bug-furan inclusion complex contains the polymer, the mass ratio of the cyclodextrin compound to the polymer is 350:1 to 450:1, preferably 375:1 to 450:1; (iii) The polymers include hydroxypropyl methylcellulose, povidone (such as povidone K30) or polyethylene glycol (such as polyethylene glycol 6000), etc. Preferably, the polymer is hydroxypropyl methylcellulose; (iv) The cyclodextrin compounds are cyclodextrins and their derivatives; Preferably, the cyclodextrin compounds include alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, or methyl beta cyclodextrin, etc. Preferably, the cyclodextrin compound is hydroxypropyl beta-cyclodextrin or hydroxypropyl gamma-cyclodextrin; Preferably, when the cyclodextrin compound is hydroxypropyl beta-cyclodextrin, the bug-furan inclusion complex contains the polymer; when the cyclodextrin compound is hydroxypropyl gamma-cyclodextrin, the bug-furan inclusion complex may or may not contain the polymer.

9. A pharmaceutical composition comprising the bugfuran inclusion complex according to any one of claims 6-8; Preferably, the pharmaceutical composition is prepared using the bug-furan inclusion complex according to any one of claims 6-8; Preferably, the pharmaceutical composition is a liquid or solid dosage form; Preferably, the liquid preparation is a powder for injection, an oral liquid, or a syrup, etc. Preferably, the solid dosage form is granules, tablets, capsules, or oral disintegrating film, etc.

10. Use of the burgdorferiin inclusion complex according to any one of claims 6-8 or the pharmaceutical composition according to claim 9 in the preparation of an anxiolytic and antidepressant drug.

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