A pharmaceutical composition of scutellarein

Abstract

The application discloses a kind of wild scutellarein or its pharmaceutically acceptable salt and / or solvate pharmaceutical composition, it comprises nicotinamide, wherein the molar ratio of wild scutellarein or its pharmaceutically acceptable salt and / or solvate and nicotinamide is 1:10-10:1.The pharmaceutical composition provided by the application has higher cumulative dissolution rate and higher stability;It has significant alleviating effect on 5%IMQ-induced mouse psoriasis-like skin lesions, and provides a new treatment idea for preventing or treating psoriasis.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and specifically to a pharmaceutical composition of baicalein. Background Technology

[0002] Psoriasis (commonly known as "cowhide rash") is a chronic, relapsing, inflammatory skin disease mediated by abnormalities in the immune system. It not only affects the skin but can also impact internal organs and other tissues, causing systemic damage. Approximately 125 million people worldwide suffer from psoriasis, with over 7 million patients in China. The typical skin manifestation is red plaques covered with white scales, often accompanied by itching, pain, and other discomfort. It most commonly affects the scalp, elbows, knees, lower legs, and buttocks, and can also involve the genitals and fingernails / toenails. Besides affecting the skin, the disease can also impact various organ systems throughout the body. For example, some patients may experience arthritis, comorbidities such as hypertension and diabetes, and may also develop neuropsychiatric disorders such as depression, anxiety, and even suicidal tendencies. Currently, the mainstream view in dermatology is that psoriasis is related to genetic, environmental, and immune factors.

[0003] Psoriasis is generally classified into mild, moderate, and severe. Treatment for mild psoriasis primarily involves topical medications and phototherapy. Topical medications mainly consist of corticosteroids, vitamin D3 derivatives, compound preparations, and calcineurin inhibitors. Moderate to severe psoriasis requires systemic therapy, including traditional immunosuppressants such as methotrexate and cyclosporine, as well as traditional medications like retinoids. While traditional treatments can control symptoms to some extent, they carry safety risks and are not suitable for long-term use. Targeted therapy represents a significant advancement in systemic psoriasis treatment in recent years, improving both clinical benefits and safety, and further enriching treatment options for patients.

[0004] Previous studies have shown that Transient Receptor Potential Cation Channel (TRPV3) subfamily V member 3 is elevated in psoriatic lesions. Activation of this channel promotes the proliferation of immortalized HaCaT keratinocytes and the expression of pro-inflammatory factors. TRPV3 inhibitors can suppress keratinocyte proliferation and the expression of pro-inflammatory factors induced by TRPV3 activation. Therefore, TRPV3 could be an ideal target for treating psoriasis. Scutellarein, as a TRPV3 inhibitor, has been shown to have potential as a drug for the prevention or treatment of psoriasis.

[0005] However, baicalin (as shown in Formula I) flavonoids exhibit low bioavailability in biological systems, and the baicalin molecule contains four phenolic hydroxyl groups, making it easily oxidized, with low molecular stability and unsatisfactory drug-like properties.

[0006]

[0007] Formula I Therefore, it is desirable to develop a new product containing baicalin to improve the properties of baicalin products, making them more pharmaceutically effective, and especially to enhance their therapeutic effects on psoriasis. Summary of the Invention

[0008] The purpose of this invention is to provide a pharmaceutical composition of baicalein or its pharmaceutically acceptable salts and / or solvates to improve the problem of low bioavailability when baicalein is used alone, while having high stability, so that it has good prospects in terms of drug development.

[0009] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows: In a first aspect, the present invention relates to a pharmaceutical composition of baicalein or a pharmaceutically acceptable salt and / or solvate thereof, the pharmaceutical composition comprising nicotinamide, wherein the molar ratio of baicalein or a pharmaceutically acceptable salt and / or solvate thereof to nicotinamide is 1:10-10:1, preferably 1:4-4:1; more preferably 1:2-2:1.

[0010] In preparing the pharmaceutical composition of the present invention, the baicalein or its pharmaceutically acceptable salts and / or solvates used are preferably baicalein, further, the baicalein or nicotinamide is in solid form, and even further, the baicalein is in crystalline form, for example, with... Figure 1 The crystal forms shown in the X-ray powder diffraction patterns are basically consistent, but the present invention is not limited to this. Any known crystal form of baicalin can be applied to the present invention with the same principle.

[0011] The pharmaceutical composition of the present invention is one or more of the following: solid dosage form, semi-solid dosage form, liquid dosage form, and gaseous dosage form.

[0012] In some embodiments, the pharmaceutical composition further comprises at least one other pharmaceutically acceptable carrier, which is a filler and binder.

[0013] In some embodiments, the filler is selected from one or more of sucrose, starch, or microcrystalline cellulose; the binder is selected from one or more of hydroxypropyl cellulose, povidone K30, or croscarmellose sodium. Further, the filler is selected from microcrystalline cellulose, and the binder is selected from hydroxypropyl cellulose.

[0014] In some embodiments, the weight ratio of baicalein or its pharmaceutically acceptable salts and / or solvates to nicotinamide, the weight of fillers, and the weight of binders is 1:(1-5):(0.1-2), preferably 1:(2-4):(0.1-1).

[0015] In a second aspect, the present invention relates to the use of nicotinamide in the preparation of pharmaceutical compositions of baicalein or its pharmaceutically acceptable salts and / or solvates, said nicotinamide being used to reduce the degradation of baicalein and improve the stability of baicalein.

[0016] In a third aspect, the present invention relates to the use of the aforementioned baicalin pharmaceutical composition in the preparation of a medicament for treating psoriasis.

[0017] In some implementations, the psoriasis is psoriasis vulgaris, pustular psoriasis, or erythrodermic psoriasis.

[0018] In a fourth aspect, the present invention relates to a method for preparing the aforementioned pharmaceutical composition, comprising the following steps: (1) Mix baicalein or its pharmaceutically acceptable salts and / or solvates, 0% or 100% nicotinamide, and 0-100% filler evenly; (2) Optionally add the remaining filler and mix well; (3) Add binder to prepare soft material, then granulate; (4) Drying and granulation: After drying the wet granules, sieve and granulate them, and optionally mix them with the remaining nicotinamide to obtain the pharmaceutical composition.

[0019] In some implementations, the amount of filler used in step (1) is 10-60%.

[0020] In a fifth aspect, the present invention provides a pharmaceutical composition comprising baicalein or a pharmaceutically acceptable salt and / or solvate thereof and nicotinamide, said pharmaceutical composition being prepared according to the preparation method described above.

[0021] The beneficial effects of this invention are as follows: The pharmaceutical composition of baicalein or its pharmaceutically acceptable salts and / or solvates provided by this invention has higher cumulative dissolution and greater stability when combined with nicotinamide; it has a significant alleviating effect on 5% IMQ-induced psoriasis-like skin lesions in mice, providing a new drug development strategy for the prevention or treatment of psoriasis. Attached Figure Description

[0022] Figure 1 XRPD image of the baicalin raw material used in the embodiments of the present invention; Figure 2The dissolution curves are for the pharmaceutical compositions of Examples 1, 3, Comparative Example 1, and Comparative Example 2. Detailed Implementation

[0023] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the invention based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0024] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0025] The main instrument models and manufacturers used in the experiments of this invention are shown in Table 1.

[0026]

[0027] In this document, the term "solvent" refers to an associative compound formed by one or more solvent molecules with either baicalein or nicotinamide of the present invention. Solvents forming the solvate include, but are not limited to, water, methanol, and ethanol, with water being preferred. The solvent may be present in any chemical dosage form per molecule of baicalein or nicotinamide.

[0028] In this document, the term "pharmaceuticalally acceptable salt" refers to the organic and inorganic salts of baicalein or nicotinamide of the present invention. Pharmaceutically acceptable salts are well known in the art.

[0029] The baicalein raw material involved in this invention can be purchased directly from the market, or can be obtained by referring to existing literature (e.g., Literature 1: Zhou Rongguang et al., Preparation, purification and structural characterization of baicalin, Spectroscopy Laboratory, September 2011, Vol. 28, No. 5 Or, as in reference 2: Giuliana Righi et al., Efficient synthesis of scutellarein, Natural Product Research, Vol. 26, No. 14, July 2012, 1278-1284 (Self-prepared.) The baicalein raw material used in the following examples was prepared according to the method disclosed in Reference 2. The prepared baicalein raw material was characterized by XRPD, see [see figure]. Figure 1 The present invention will be further described below by way of specific embodiments.

[0030] Basic Example: Compatibility Experiment of Baicalein and Nicotinamide Baicalein and nicotinamide were mixed in the weight ratios specified in Table 3 below. After mixing, 10 g of sample was taken and placed at 60°C. The content of baicalein was detected at 0, 5, 10 and 30 days. The chromatographic conditions used for the content detection were the same as those used in Example 6 below for the determination of baicalein content. The detection results are shown in Table 2 below.

[0031] Table 2

[0032] The above results indicate that baicalein and nicotinamide have good compatibility at 60℃ and unexpectedly have the effect of preventing the degradation of baicalein.

[0033] Example 1: A pharmaceutical composition of baicalein prescription: Table 3

[0034] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein, nicotinamide, and 40% microcrystalline cellulose to a wet granulator and mix evenly; (2) Add the remaining microcrystalline cellulose and mix well; (3) Soft material was prepared and granulated using an 8% cross-linked sodium carboxymethyl cellulose aqueous solution as a binder; (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0035] Example 2: A pharmaceutical composition of baicalein prescription: Table 4

[0036] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein, nicotinamide, and 40% sucrose to a wet granulator and mix evenly; (2) Add the remaining sucrose and mix well; (3) Prepare soft material and granulate it using a 5% aqueous solution of polyvinyl ketone K30 as a binder; (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0037] Example 3: A pharmaceutical composition of baicalein prescription: Table 5

[0038] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein, nicotinamide, and 40% microcrystalline cellulose to a wet granulator and mix evenly; (2) Add the remaining microcrystalline cellulose and mix well; (3) Soft material was prepared and granulated using an 8% cross-linked sodium carboxymethyl cellulose aqueous solution as a binder; (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0039] Example 4: A pharmaceutical composition of baicalein prescription: Table 6

[0040] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein, nicotinamide, and 40% sucrose to a wet granulator and mix evenly; (2) Add the remaining sucrose and mix well; (3) A soft material was prepared using a 5% aqueous solution of hydroxypropyl cellulose as a binder, and then granulated. (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0041] Example 5: A pharmaceutical composition of baicalein prescription: Table 7

[0042] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein and 40% of microcrystalline cellulose to a wet granulator and mix evenly; (2) Add the remaining microcrystalline cellulose and mix well; (3) Soft material was prepared and granulated using an 8% cross-linked sodium carboxymethyl cellulose aqueous solution as a binder; (4) Drying and granulation: After drying the wet granules at 40°C, they are sieved and granulated, and then mixed with nicotinamide to obtain the drug composition.

[0043] Comparative Example 1: A pharmaceutical composition containing baicalein prescription: Table 8

[0044] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein and 40% of microcrystalline cellulose to a wet granulator and mix evenly; (2) Add the remaining microcrystalline cellulose and mix well; (3) Soft material was prepared and granulated using an 8% cross-linked sodium carboxymethyl cellulose aqueous solution as a binder; (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0045] Comparative Example 2: A pharmaceutical composition containing baicalein prescription: Table 9

[0046] Preparation method: (1) Add 400 tablets of the prescribed amount of baicalein and 40% of microcrystalline cellulose to a wet granulator and mix evenly; (2) Add the remaining microcrystalline cellulose and mix well; (3) Soft material was prepared and granulated using an 8% cross-linked sodium carboxymethyl cellulose aqueous solution as a binder; (4) Drying and granulation: The wet granules are dried at 40°C and then sieved to obtain the drug composition.

[0047] Example 6 Dissolution test Method for determining the content of baicalin: ①Chromatographic conditions: Agilent C 18 The chromatographic column (4.6 × 250 mm, 5 mm) was used, and the mobile phase was acetonitrile: phosphate aqueous solution (pH 3.0, 0.02 mol·L⁻¹). -1 The column temperature was 35℃, the detection wavelength was 336 nm, the flow rate was 1.0 mL / min, and the injection volume was 20 mL. (Sodium dihydrogen phosphate solution) = 25:75 (V / V).

[0048] ② Linearity: Accurately weigh 20 mg of baicalein reference standard into a volumetric flask, add methanol, sonicate to dissolve, and dilute to volume. Dilute the reference solution with methanol to concentrations of 12, 16, 20, 24, and 28 mg / mL. -1 A series of gradient solutions were prepared. The contents of these solutions at different concentrations were accurately weighed and determined by HPLC. The standard curve equation was obtained by plotting peak area (A) on the ordinate and concentration (C) on the abscissa: A = 0.9608C - 0.3381 (…). r =0.9997), linear range 12~28 mg·mL -1 .

[0049] Dissolution test method: The drug composition particles of Examples 1, 3 and Comparative Examples 1-2 were weighed separately, and the in vitro dissolution behavior of each drug composition particle was evaluated using the paddle method (Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV) [S]. Beijing: China Medical Science and Technology Press, 2020: 132-137). The paddle rotation speed was 100 r / min, and the dissolution medium was a solution containing 10 mg·mL SDS. -1The pH=6.8 phosphate aqueous solution was used for dissolution at a volume of 900 mL and a temperature of (37±0.5)℃. 10 mL samples of the dissolution medium were collected at mins 5, 15, 30, 45, 60, 90, and 120, with an equal volume of blank medium added simultaneously at the same temperature. After sampling, the samples were filtered through a 0.22 mm filter membrane. The drug dissolution rate was calculated using HPLC, and a dissolution-time curve was plotted. The results are as follows: Figure 2 As shown, compared with the drug composition particles of Comparative Examples 1-2, the drug composition particles of Examples 1 and 3 exhibited significantly increased dissolution rates and dissolution rates within 2 hours. Specifically, the drug composition particles of Examples 1 and 3 achieved a cumulative dissolution rate of over 68% at 5 minutes and over 78% at 15 minutes, while the drug composition particles of Comparative Examples 1-2 had cumulative dissolution rates below 11% and below 23% at 5 minutes and 15 minutes, respectively. At 120 minutes, the cumulative dissolution rate of the drug composition particles of Examples 1-2 was only 30%, while the drug composition particles of Examples 1 and 3 achieved over 85%. These results indicate that the mixture of baicalin and nicotinamide can significantly improve drug dissolution and increase the drug dissolution rate.

[0050] Example 7 Stability Experiment The samples from Examples 1-5 and Comparative Examples 1-2 were placed at 60°C, and their properties were observed and the content of baicalin was detected at 0, 5, 10, and 30 days, respectively. The results are shown in Table 10 below: The chromatographic conditions used for content detection were the same as those used for the determination of baicalin content in Example 6.

[0051] Table 10 Stability test results

[0052] Example 8: Effect of the combination of baicalin and nicotinamide on improving skin lesions in a 5% IMQ-induced mouse psoriasis model. Thirty-two C57BL / 6 mice, half male and half female, weighing 18-20g, were purchased from the Comparative Medicine Center of Yangzhou University. The mice were randomly divided into four groups (n=8 per group) based on sex. The mouse psoriasis model was established according to Example 1 of CN118178382A. During modeling, the following solutions were subcutaneously injected into the modeling area of ​​the mice: physiological saline, physiological saline containing 0.1% dexamethasone, physiological saline containing 0.2‰ baicalein and 0.2‰ nicotinamide in equal mass, and physiological saline containing 0.2‰ baicalein and 0.4‰ nicotinamide in equal mass, 100μL each time, twice daily. On days 1, 3, and 5 after modeling, the skin on the back of the mice was photographed and recorded. Clinical symptoms were assessed using the PASI scoring system.

[0053] The experimental results showed that the mice in the saline group had the most severe skin damage. Subcutaneous injection of a combination containing dexamethasone and different concentrations of baicalein and nicotinamide could alleviate psoriasis-like skin lesions on the back of mice to varying degrees and delay the appearance of imiquimod-induced skin damage.

[0054] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A pharmaceutical composition of baicalein or its pharmaceutically acceptable salts and / or solvates, characterized in that, The pharmaceutical composition comprises nicotinamide, wherein the molar ratio of baicalein or its pharmaceutically acceptable salt and / or solvate to nicotinamide is 1:10-10:

1.

2. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of baicalein or its pharmaceutically acceptable salts and / or solvates to nicotinamide is 1:4-4:1; further, 1:2-2:

1.

3. The pharmaceutical composition according to claim 1, characterized in that, The baicalein or its pharmaceutically acceptable salts and / or solvates are selected from baicalein; further, the baicalein or nicotinamide is in solid form, and even further, the baicalein is in crystalline form.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, and more particularly, the carrier is a filler and a binder.

5. The pharmaceutical composition according to claim 4, characterized in that, The weight ratio of the total weight of baicalein or its pharmaceutically acceptable salts and / or solvates to nicotinamide: the weight of filler: the weight of binder is 1:(1-5):(0.1-2), preferably 1:(2-4):(0.1-1).

6. The pharmaceutical composition according to claim 4, characterized in that, The filler is selected from any one or more of sucrose, starch, or microcrystalline cellulose; the binder is selected from any one or more of hydroxypropyl cellulose, povidone K30, or croscarmellose sodium; further, the filler is selected from microcrystalline cellulose, and the binder is selected from croscarmellose sodium.

7. The use of nicotinamide in a pharmaceutical composition for preparing baicalein or its pharmaceutically acceptable salts and / or solvates, characterized in that, The nicotinamide is used to reduce the degradation of baicalin or its pharmaceutically acceptable salts and / or solvates.

8. Use of the pharmaceutical composition according to any one of claims 1-6 in the preparation of a medicament for treating or preventing psoriasis, further wherein the psoriasis is psoriasis vulgaris, pustular psoriasis or erythrodermic psoriasis.

9. A method for preparing the pharmaceutical composition according to any one of claims 4-6, characterized in that, Includes the following steps: (1) Mix baicalein or its pharmaceutically acceptable salts and / or solvates, 0% or 100% nicotinamide, and 0-100% filler evenly; (2) Optionally add the remaining filler and mix well; (3) Add binder to prepare soft material, then granulate; (4) Drying and granulation: After drying the wet granules, sieve and granulate them, and optionally mix them with the remaining nicotinamide to obtain the pharmaceutical composition.

10. A pharmaceutical composition comprising baicalein or a pharmaceutically acceptable salt and / or solvate thereof and nicotinamide, prepared according to the method of claim 9.

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