Hippophae rhamnoides flavone solid dispersion as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a hippophae rhamnoides flavone solid dispersion and a preparation method thereof.The hippophae rhamnoides flavone solid dispersion comprises hippophae rhamnoides flavone and a carrier material, the mass ratio of the hippophae rhamnoides flavone to the hydrophilic carrier material is 1: 4-1: 7, and the carrier material is povidone. The solubility of the solid dispersion is remarkably improved, the dosage of auxiliary materials is relatively small, the preparation process is simple and controllable, and the technical bottleneck of low solubility of the seabuckthorn flavone is effectively solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a solid dispersion of sea buckthorn flavonoids, its preparation method, and its application. Background Technology

[0002] Sea buckthorn, the dried, ripe fruit of *Hippophae rhamnoides* L., a plant belonging to the Elaeagnaceae family, has a long history of medicinal use in China. Sea buckthorn flavonoids, flavonoids extracted from sea buckthorn, are rich in various active ingredients such as quercetin, isorhamnetin, kaempferol, ionin, and robinin. Numerous studies both domestically and internationally have demonstrated that sea buckthorn flavonoids possess multiple pharmacological activities, including antioxidant, hypoglycemic, hypolipidemic, antitumor, immunomodulatory, hepatoprotective, and radiation-protective effects, showing broad prospects for development and application.

[0003] However, sea buckthorn flavonoids are poorly soluble drugs with poor water solubility, resulting in slow dissolution rate after oral administration, limited gastrointestinal absorption, low bioavailability, and difficulty in achieving effective blood drug concentrations, which seriously limits their clinical efficacy.

[0004] To address the aforementioned issues, existing technologies often employ solid dispersion technology to solubilize and modify poorly soluble drugs. Solid dispersions are homogeneous systems formed by highly dispersing drugs in molecular, amorphous, or microcrystalline states within a hydrophilic carrier. This can significantly improve the specific surface area, wettability, and dissolution rate of the drug, thereby enhancing its bioavailability.

[0005] Existing patents related to solid dispersions of sea buckthorn flavonoids suffer from issues such as a low proportion of active ingredients and a lack of direct and systematic disclosure of data on the solubility improvement of sea buckthorn flavonoids in actual systems after solid dispersion technology treatment. Instead, they introduce large amounts of excipients during the solid dispersion preparation stage and subsequent formulation processing before examining the dissolution effect. This approach may mask the dissolution characteristics of the active ingredient itself, making it difficult to accurately assess the true dissolution behavior and solubilizing effect of sea buckthorn flavonoid solid dispersions. Therefore, systematically examining the specific changes in the solubility of sea buckthorn flavonoids after modification with solid dispersion technology, and actively exploring ways to reduce the amount of inactive excipients while ensuring dissolution performance, is of great significance for promoting its practical application. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies, such as low solubility and poor bioavailability of sea buckthorn flavonoids, high proportion of excipients in solid dispersions, and insufficient evaluation of solubilization effect, and to provide a solid dispersion of sea buckthorn flavonoids with significantly improved solubility, relatively low excipient dosage, and simple and controllable preparation process, as well as its preparation method.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, a solid dispersion of sea buckthorn flavonoids is provided, comprising sea buckthorn flavonoids and a carrier material, wherein the mass ratio of sea buckthorn flavonoids to the hydrophilic carrier material is 1:4 to 1:7, and the carrier material is polyvinylpyrrolidone (PVP K30).

[0008] Testing showed that the solid dispersion exhibited a saturated solubility in pH 1.2 hydrochloric acid buffer, pH 6.8 phosphate buffer, or purified water that was more than 50 times higher than that of untreated sea buckthorn flavonoid raw material.

[0009] A second aspect of the present invention provides a method for preparing the sea buckthorn flavonoid solid dispersion described in the first aspect, comprising the following steps: (1) Add sea buckthorn flavonoids and hydrophilic carrier materials to anhydrous ethanol at a mass ratio of 1:4 to 1:7, stir or sonicate to completely dissolve them, and form a uniform and transparent mixed solution. (2) The mixed solution is subjected to rotary evaporation at 50-60°C to remove most of the ethanol solvent, resulting in a viscous substance; (3) Transfer the obtained viscous substance to a petri dish and spread it evenly, and vacuum dry it at 40-60°C to completely remove the residual solvent; (4) The dried material is crushed appropriately with a pulverizer and passed through a 100-mesh sieve to obtain the sea buckthorn flavonoid solid dispersion.

[0010] Preferably, the hydrophilic carrier material is polyvinylpyrrolidone (PVP) K30.

[0011] Preferably, the rotary evaporation temperature is 50°C and the vacuum drying temperature is 40°C.

[0012] Thirdly, a solid dispersion of sea buckthorn flavonoids is provided, comprising sea buckthorn flavonoids, a hydrophilic carrier, and a crystal form inhibitor, wherein the hydrophilic carrier is a composite carrier of povidone PVP K30 and poloxamer Pluronic F68, and the mass ratio of sea buckthorn flavonoids to PVP K30 to Pluronic F68 is 1:(2–4):(1–3); the crystal form inhibitor is selected from L-proline or citric acid, and its amount is 0.5–2% of the total solid mass.

[0013] Preferably, the crystal form inhibitor is L-proline, and the dosage is 1.0 wt%.

[0014] Fourthly, a method for preparing the sea buckthorn flavonoid solid dispersion described in the third aspect is provided, comprising the following steps: (a) Dissolve sea buckthorn flavonoids, PVP K30, Pluronic F68 and crystal form inhibitor in anhydrous ethanol, and sonicate for 10–20 minutes to obtain a clear solution; (b) Under stirring conditions, the solution obtained in step (a) is slowly added dropwise to deionized water pre-cooled at 4°C, with the volume of the antisolvent being 5–10 times the volume of the ethanol; (c) Continue stirring for 30 minutes to allow the complex to precipitate. (d) Filter under reduced pressure and collect the precipitate; (e) The precipitate was freeze-dried under vacuum for 24 hours to obtain a solid dispersion.

[0015] Preferably, the dropping rate in step (b) is 1–2 mL / min.

[0016] Preferably, the pre-freezing temperature for freeze drying is -50°C, and the drying pressure is ≤10 Pa.

[0017] A fifth aspect of the present invention also provides a pharmaceutical composition comprising the sea buckthorn flavonoid solid dispersion of the first or second aspect described above, and pharmaceutically acceptable excipients, which can be used to prepare oral formulations such as tablets, capsules, and granules.

[0018] By implementing the above technical solution, compared with the prior art, the present invention has the following beneficial effects: The solid dispersion of sea buckthorn flavonoids prepared by this invention has a saturated solubility in various dissolution media that is more than 50 times higher than that of the raw material, effectively solving the technical bottleneck of low solubility of sea buckthorn flavonoids.

[0019] This invention focuses on the saturated solubility of the solid dispersion itself in different solvents, rather than its dissolution after formulation, so as to more realistically and objectively evaluate the solubilizing effect of solid dispersion technology on sea buckthorn flavonoids.

[0020] This invention employs a reasonable drug-carrier ratio, which significantly reduces the amount of inactive excipients while ensuring excellent solubilization. This is beneficial for increasing the drug loading of active ingredients in subsequent formulations, reducing the volume of medication, improving patient compliance, and providing the possibility for the development of high-dose formulations (such as sustained-release formulations). Detailed Implementation

[0021] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the following embodiments are only used to explain the present invention and do not limit the scope of protection of the present invention in any way.

[0022] Example 1: Preparation of Seabuckthorn Flavonoid Solid Dispersion S1. Weigh 10 g of sea buckthorn flavonoid raw material and 40 g of povidone PVP K30 (mass ratio 1:4), place them in a clean and dry beaker, add an appropriate amount of anhydrous ethanol, and stir until completely dissolved to form a uniform and transparent mixed solution.

[0023] S2. Transfer the above solution to a rotary evaporator and evaporate it under reduced pressure in a 50°C water bath to remove most of the ethanol until the contents become viscous.

[0024] S3. Transfer the viscous material to a petri dish, spread it evenly, and place it in a vacuum drying oven. Dry it at 40°C for 24 hours to completely remove residual solvent.

[0025] S4. Take out the dried material, grind it appropriately with a pulverizer, and pass it through a 100-mesh sieve to obtain the sea buckthorn flavonoid solid dispersion.

[0026] Example 2 The solid dispersion was prepared by feeding sea buckthorn flavonoids and PVP K30 at a mass ratio of 1:5 (i.e., 10 g : 50 g) and following the same steps as in Example 1.

[0027] Example 3 The solid dispersion was prepared by feeding seabuckthorn flavonoids and PVP K30 at a mass ratio of 1:7 (i.e., 10 g : 70 g) and following the same steps as in Example 1.

[0028] Example 4 The difference from Example 1 is that in step S1, 10 g of sea buckthorn flavonoids, 30 g of PVP K30, and 20 g of Pluronic F68 (mass ratio 1:3:2) were placed in a clean, dry beaker, and an appropriate amount of anhydrous ethanol was added. The mixture was stirred until completely dissolved to form a homogeneous and transparent mixed solution. The remaining steps were the same as in Example 1 to obtain a solid dispersion.

[0029] Example 5 Based on Example 4, 1.0 g of L-proline (accounting for 1.0% of the total solid mass) was added to step S1, and the remaining steps were the same.

[0030] Example 6 Preparation of Seabuckthorn Flavonoid Solid Dispersion Weigh out 10 g of sea buckthorn flavonoids, 30 g of PVP K30, 20 g of Pluronic F68, and 1.0 g of L-proline; Dissolve in 100 mL of anhydrous ethanol and sonicate for 15 min to obtain a clear solution; With stirring, the solution was added dropwise to 500 mL of deionized water pre-cooled to 4°C at a rate of 1.5 mL / min; Continue stirring for 30 minutes, and a white flocculent precipitate will form. Reduced pressure filtration and collect the precipitate; The wet precipitate was dispensed into freeze-drying trays, pre-frozen at -50℃ for 4 h, and then freeze-dried at ≤10 Pa pressure for 24 h to obtain a loose porous powder.

[0031] Example 7 The difference from Example 6 is that citric acid is used instead of L-proline.

[0032] Comparative Example 1 Commercially available sea buckthorn flavonoid powder was used directly as a control, without any formulation treatment.

[0033] The solubility and stability of the solid dispersions obtained in the examples and comparative examples were determined. The determination methods and results are as follows: 1. Solubility determination Accurately weigh appropriate amounts of the solid dispersions prepared in Examples 1-7 and the active pharmaceutical ingredient in Comparative Example 1. Under constant temperature conditions of 37°C, use pH 1.2 hydrochloric acid buffer (simulating gastric juice), pH 6.8 phosphate buffer (simulating intestinal juice), and purified water as dissolution media, respectively, and place them in a constant temperature shaker for 24 hours to allow the system to reach dissolution equilibrium.

[0034] Samples were taken and immediately filtered through a 0.45 μm microporous membrane. An appropriate amount of the filtrate was diluted with the corresponding solvent, and the absorbance was measured at a wavelength of 430 nm using ultraviolet-visible spectrophotometry (UV method). The saturated solubility of each sample in each medium was calculated based on the pre-established standard curve of sea buckthorn flavonoids.

[0035] Boost factor = Sample solubility / Comparative Example 1 solubility (pH 1.2 hydrochloric acid buffer) Table 1. Solubility test results of different solid dispersants 2. Stability determination The solid dispersions prepared in Examples 1-7 and the active pharmaceutical ingredient of Comparative Example 1 were stored at 25°C / 60% RH for 90 days. A sample equivalent to 10 mg of sea buckthorn flavonoids was placed in 900 mL of pH 1.2 buffer solution and stirred at 37°C and 50 rpm. Samples of 5 mL were taken at 5, 10, 15, and 30 min (with simultaneous replenishment of the buffer). After filtration, the absorbance was measured, and the cumulative dissolution percentage was calculated to determine the dissolution rate (using the 30-min dissolution rate as the key evaluation indicator). Dissolution retention rate (%) = (90-day dissolution rate / initial dissolution rate) × 100%.

[0036] Table 2. Stability test results of different solid dispersants The data in Tables 1 and 2 show that, compared with Comparative Example 1 of sea buckthorn flavonoid powder, Examples 1–3 all significantly improved the solubility of sea buckthorn flavonoids (43–56 times). Among them, Example 2 is the optimal balance point, with a moderate amount of excipients and a solubility of 1.78 mg / mL, which meets the clinical high-dose requirements.

[0037] Example 4 showed that, with the same total carrier dosage, the solubility was better than that of a single carrier material (1.85 vs 1.78 mg / mL), indicating that Pluronic F68 can further promote dissolution by improving wettability and interfacial adsorption.

[0038] Example 5 showed only a slight increase in solubility (1.87 mg / mL), indicating that the main function of L-proline is not solubilization, but rather inhibition of recrystallization (see stability data).

[0039] Examples 6 and 7 used antisolvent precipitation and freeze drying to obtain nanoscale amorphous particles with a solubility exceeding 2.3 mg / mL (a 68-fold increase), far surpassing the samples prepared by rotary evaporation.

Claims

1. A solid dispersion of sea buckthorn flavonoids, characterized in that, It contains seabuckthorn flavonoids and a carrier material, wherein the mass ratio of seabuckthorn flavonoids to the hydrophilic carrier material is 1:4 to 1:7, and the carrier material is polyvinylpyrrolidone.

2. The sea buckthorn flavonoid solid dispersion according to claim 1, characterized in that, The carrier material is a composite carrier of povidone and poloxamer, and the mass ratio of sea buckthorn flavonoid:povidone:poloxamer is 1:(2–4):(1–3).

3. The sea buckthorn flavonoid solid dispersion according to claim 1, characterized in that, It also contains a crystal form inhibitor, which is selected from L-proline or citric acid.

4. The sea buckthorn flavonoid solid dispersion according to claim 3, characterized in that, Its dosage is 0.5–2% of the total solid mass.

5. The sea buckthorn flavonoid solid dispersion according to claim 3, characterized in that, The crystal form inhibitor is L-proline, used in an amount of 1.0 wt%.

6. A method for preparing the sea buckthorn flavonoid solid dispersion as described in any one of claims 1-5, characterized in that, Includes the following steps: Seabuckthorn flavonoids and carrier materials were added to anhydrous ethanol in a certain proportion to completely dissolve them and form a homogeneous solution. The resulting solution was subjected to rotary evaporation to remove most of the solvent, yielding a viscous substance. Vacuum dry the viscous substance at 40–60°C to completely remove residual solvent; After drying, the material is crushed and sieved to obtain a solid dispersion.

7. The method according to claim 6, characterized in that, The rotary evaporation temperature is 50–60°C, and the vacuum drying temperature is 40°C.

8. A method for preparing the sea buckthorn flavonoid solid dispersion as described in any one of claims 1-5, characterized in that, The method further includes the following steps: Seabuckthorn flavonoids and carrier materials were added to anhydrous ethanol in a certain proportion to completely dissolve them and form a homogeneous mixed solution. The dissolved mixture was slowly added dropwise to pre-cooled deionized water at 4°C with stirring. The volume of the antisolvent was 5–10 times that of the ethanol, causing the complex to precipitate. After collecting the precipitate by filtration, the precipitate is then freeze-dried under vacuum.

9. A pharmaceutical composition, characterized in that, It comprises the sea buckthorn flavonoid solid dispersion as described in any one of claims 1–5, and pharmaceutically acceptable excipients.

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