A solid dispersion of poorly soluble drugs and preparation method thereof

Abstract

The present invention discloses a solid dispersion of a poorly soluble drug and a preparation method thereof. The solid dispersion comprises any one of vinyl pyrrolidone-vinyl acetate copolymer, methacrylic acid-ethyl acrylate copolymer, fatty acid polyoxyethylene esters, and fatty alcohol polyoxyethylene ethers, and white rutaecarpa as a composite carrier in a mass ratio of 1:0.1-10. The mass ratio of the filler ethyl cellulose is 25%-55%, and the mass ratio of the poorly soluble drug is 10%-30%. Using a solvent rotary evaporation method, the cumulative dissolution rates of rutin solid dispersions using #imgabs0#VA64 and white rutaecarpa as composite carriers, curcumin solid dispersions using methacrylic acid copolymer type C and white rutaecarpa as composite carriers, avermectin solid dispersions using #imgabs1#S100 polyoxyethylene stearate and white rutaecarpa as composite carriers, and monensin solid dispersions using lauryl alcohol polyoxyethylene ether and white rutaecarpa as composite carriers in water over 15 minutes all exceed 80%, significantly improving their saturation solubility compared to solid dispersions of poorly soluble drugs using a single carrier.

Description

Technical Field

[0001] The invention relates to a solid dispersion of a poorly soluble drug and a preparation method thereof, which improves the saturation solubility and dissolution rate of the poorly soluble drug. Background Art

[0002] Poorly soluble drugs have low solubility in water, which prevents them from fully exerting their efficacy and leads to poor bioavailability. The pharmaceutical industry has developed a variety of dosage forms, including liposomes, emulsions, microneedles, solid dispersions, and micelles. Solid dispersion technology, in particular, involves highly uniformly dispersing poorly soluble drugs in a carrier in molecular, colloidal, or microcrystalline forms, thereby improving their solubility, dissolution rate, and bioavailability. Its preparation industry is becoming increasingly mature and sophisticated, and its application in industrialized pharmaceutical production is expected to be even broader. Li Yuwei et al. used a hot-melt extrusion process to prepare a berberine hydrochloride solid dispersion with a ratio of berberine hydrochloride: carrier: crystallization inhibitor of 1:(2-5):(2-4). This study not only improved the thermal stability of the berberine hydrochloride solid dispersion, but also enhanced its solubility and dissolution rate, masked its unpleasant odor, and improved palatability. It also addressed storage aging issues, enhanced bioavailability, and facilitated precise control of drug release during the formulation process. (Li Yuwei, Wang Xiaoli, Zhu Lifei, et al. A berberine hydrochloride solid dispersion, preparation process, and application: China, 202010837025.2 [P]. 2020-08-19.) Sun Changhai et al. disclosed an ursolic acid solid dispersion and its preparation method, which comprises ursolic acid, a surfactant, and a pH regulator. The invented ursolic acid solid dispersion can improve the solubility of ursolic acid. The addition of the acid regulator facilitates drug absorption in the intestine, promoting the surfactant's solubility-enhancing effect, thereby further improving the dissolution rate and bioavailability of ursolic acid. (Sun Changhai, Yang Yuting, Fang Hongzhuang, et al. Ursolic acid solid dispersion and its preparation method: China, 201610508093.8 [P]. 2016-11-16.)

[0003] The process conditions for the above-mentioned small-scale trials and industrial amplifications of solid dispersion technology cannot be completely consistent, and the industrial production of many drugs is restricted. Whether the solid dispersion carrier of oral drugs will remain in the body or produce toxic and side effects is a factor that needs to be considered. Compared with the solid dispersion of common carriers, the present invention has a wide range of applications for poorly soluble drugs, and the saturated solubility and dissolution rate of the solid dispersion prepared are significantly improved. White rue is a natural resin, also known as liquidambar, which is a traumatic secretion flowing out from the trunk of the liquidambar. Solid liquidambar is light yellow, transparent, has an aromatic smell, and has a crisp texture. Generally, liquidambar trees with an age of more than 20 years are selected to collect liquidambar. In July and August of each year, the bark of the liquidambar is peeled off, and a hole is dug at intervals of approximately 20 cm from the root. The resin that flows out naturally between the beginning of winter and March of the following year is harvested and dried. White rue contains a variety of chemical components, the highest content of which is pentacyclic triterpenoids, which have the skeletal structures of oleanane, ursane, and lupane. The pentacyclic triterpenoids in Rutaecarpa form hydrogen bonds with vinylpyrrolidone-vinyl acetate copolymer, methacrylic acid-ethyl acrylate copolymer, polyoxyethylene fatty acid esters, and polyoxyethylene fatty alcohol ethers. This complex combines the lipophilic and hydrophilic structures of Rutaecarpa, acting as an emulsifier. Rutaecarpa also exhibits excellent antibacterial activity and is non-toxic, making it suitable for development and application in related pharmaceutical and food products. The oral solid dispersion formed by this carrier is safe and non-toxic, significantly increasing the wettability and solubility of poorly soluble drugs in water, inhibiting their crystallization, and improving their bioavailability. Summary of the Invention

[0004] The purpose of the present invention is to provide a solid dispersion technology for poorly soluble drugs to obtain a solid dispersion with a wide range of applications. This composite carrier can inhibit the crystallization of the raw material drug and make the raw material drug distributed in the carrier in an amorphous state.

[0005] For this reason, the technical solution adopted in the present invention is as follows:

[0006] A solid dispersion of a poorly soluble drug comprises the following effective components, calculated by mass percentage: any one of vinyl pyrrolidone-vinyl acetate copolymer, methacrylic acid-ethyl acrylate copolymer, fatty acid polyoxyethylene ester, and fatty alcohol polyoxyethylene ether and white rutaecarpa as a composite carrier, the mass ratio of the two being 1:0.1-10, the mass ratio of filler ethyl cellulose being 25-55%, and the content of the raw material drug being 10%-30%.

[0007] The present invention also adopts the following technical solution:

[0008] A solid dispersion of a poorly soluble drug is prepared by weighing each component according to a set ratio, dissolving the composite carrier, the API, and ethyl cellulose in a certain ratio in a solvent such as methanol, ethanol, or ethyl acetate, and stirring at 40-60°C and 100 r·min.-1 After stirring at a speed of 10-30 minutes, the solvent was removed by rotary evaporation, and the obtained solid was finally dried in an oven at 40°C for 36 hours.

[0009] Compared with existing technologies, the present invention's beneficial effects are primarily reflected in the following: the pentacyclic triterpenoid compounds in Rutaecarpa odorata form hydrogen bonds with vinyl pyrrolidone-vinyl acetate copolymer, methacrylic acid-ethyl acrylate copolymer, fatty acid polyoxyethylene esters, and fatty alcohol polyoxyethylene ethers. This complex combines both the lipophilic and hydrophilic structures of Rutaecarpa odorata, acting as an emulsifier. Furthermore, Rutaecarpa odorata exhibits excellent antibacterial activity and is non-toxic, making it suitable for development and application in related pharmaceutical and food products. The oral solid dispersion formed by this carrier is safe and non-toxic, significantly increasing the wettability and solubility of poorly soluble drugs in water, inhibiting crystallization of poorly soluble drugs, and improving drug bioavailability. DETAILED DESCRIPTION

[0010] The present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto:

[0011] It should be understood that these embodiments are preferred embodiments of the present invention and are for illustrative purposes only. Based on the above discussion and these embodiments, those skilled in the art can determine the essential features of the present invention and, without departing from the spirit and technical scope of the present invention, can make various changes and modifications to the present invention to adapt it to various uses and conditions.

[0012] “r·min -1 " represents "speed", "nm" represents the wavelength unit "nanometer"; "min" represents the time unit "minute"; "℃" represents the temperature "degrees Celsius"; "mg / L" represents the "concentration unit"; " "VA64" is "vinyl pyrrolidone-vinyl acetate copolymer from BASF, Germany"; "methacrylic acid copolymer type C" means "methacrylic acid and ethyl acrylate are copolymerized in a ratio of 1:1, and the average molecular weight of the copolymer is 250,000"; "lauryl polyoxyethylene ether" was purchased from "Shanghai Myrel Chemical Technology Co., Ltd."

[0013] Example 1

[0014] With 12% rutin content and 30% ethyl cellulose content, VA64 powder and white rutaecarpa were used as composite carriers to prepare rutin solid dispersion. VA64 powder and white rutaecarpa were dissolved in anhydrous ethanol at a mass ratio of 1:3, 1:2, 1:1, 2:1, and 3:1, rutin, and ethyl cellulose, and the mixture was heated at 40 °C and 100 r·min. -1After stirring at a speed of 15 minutes, the ethanol was removed by rotary evaporation under reduced pressure, and the resulting solid was dried in an oven at 40°C for 36 hours. The optimal preparation process was determined by comparing the dissolution rate of rutin solid dispersions after 10 minutes.

[0015] Table 1 The dissolution rate of rutin solid dispersions with different mass ratios of VA64 and white rutin in 10 min

[0016]

[0017] Saturation solubility determination

[0018] Weigh out excess rutin raw material, VA64 as a carrier of rutin solid dispersion, The solid dispersion of rutin with VA64 and white rutin in a mass ratio of 1:1 as a composite carrier was placed in a 250mL beaker and dissolved in 100mL of distilled water. The solution was allowed to stand for 48 hours to saturate the solution. The upper suspension was centrifuged for 10 minutes and the supernatant was taken to measure its saturated solubility in water. The results showed that the saturated solubility of rutin raw material in water was 194.6mg / L. The saturated solubility of rutin solid dispersion with VA64 as carrier in water is 306.4 mg / L. The saturated solubility of rutin solid dispersion with VA64 and white rutaecarpa as composite carrier in water is 8640.7 mg / L. The saturated solubility of rutin solid dispersion with composite carrier prepared in this experiment is 44.4 times that of rutin raw material, which is 2720.1% higher than that of rutin solid dispersion with single carrier. The rutin solid dispersion with VA64 and white rutaecarpa as the composite carrier significantly improved the solubility of rutin.

[0019] Determination of cumulative dissolution rate

[0020] At 37±0.5℃ and a rotation speed of 100r / min, add 1000mL of ultrasonically degassed distilled water into the dissolution cup, and accurately weigh an appropriate amount of VA64 as a carrier of rutin solid dispersion, The rutin solid dispersion with the optimal ratio of VA64 and white rue as the composite carrier was placed in a dissolution cup. 10 mL of the dissolution solution was extracted with a syringe at 5 minutes, 10 minutes, 20 minutes, 40 minutes, and 60 minutes respectively. After extraction, isothermal distilled water was immediately added to make up to 1000 mL. The sample solution was filtered through a 0.45 μm microporous filter membrane, and the filtrate was taken to calculate the cumulative dissolution rate of the sample. The results showed that the cumulative dissolution rate of the rutin solid dispersion prepared with the composite carrier was 96% in 15 minutes, while the cumulative dissolution rate of the solid dispersion prepared with the composite carrier was 96%. The cumulative dissolution rate of the rutin solid dispersion with VA64 as the carrier was 34% in 15 minutes.

[0021] Example 2

[0022] A curcumin solid dispersion was prepared using a curcumin content of 11%, an ethyl cellulose content of 50%, methacrylic acid copolymer type C, and white rutaecarpa as composite carriers. The optimal preparation process was determined using the same preparation process as in Example 1.

[0023] Table 2 Dissolution rate of curcumin solid dispersions containing different mass ratios of methacrylic acid copolymer type C and white rutaecarpa in 10 min

[0024] Serial number Methacrylic acid copolymer type C: white rue Dissolution rate in 10 minutes (%) 1 1∶3 60.9 2 1∶2 72.3 3 1∶1 88.3 4 2∶1 76.3 5 3∶1 64.5

[0025] Saturation solubility

[0026] The same operation as in Example 1 was performed. The results showed that the saturated solubility of the curcumin API in water was 11 ng / mL, the saturated solubility of the curcumin solid dispersion using methacrylic acid copolymer type C as a carrier in water was 106.4 ng / mL, and the saturated solubility of the curcumin solid dispersion using methacrylic acid copolymer type C and white rutaecarpa as a composite carrier in water was 1640.7 ng / mL. The results showed that the saturated solubility of the curcumin solid dispersion using methacrylic acid copolymer type C and white rutaecarpa as a composite carrier in water was 149.2 times that of the curcumin API, an increase of 1442.0% over the curcumin solid dispersion using methacrylic acid copolymer type C as a carrier. The experimental results show that the saturated solubility of the curcumin solid dispersion using methacrylic acid copolymer type C and white rutaecarpa as a composite carrier prepared in this experiment is significantly improved.

[0027] Determination of cumulative dissolution rate

[0028] The cumulative dissolution rate operation was performed in the same manner as in Example 1. The results showed that the cumulative dissolution rate of the curcumin solid dispersion prepared with the composite carrier was 94% in 15 minutes, while the cumulative dissolution rate of the curcumin solid dispersion with methacrylic acid copolymer type C as the carrier was 27% in 15 minutes.

[0029] Example 3

[0030] by S 100 polyoxyethylene stearate and white rutaecarpa were used as composite carriers. The same method as in Example 2 was used to compare the 10 min dissolution rate of monensin solid dispersion and determine its optimal preparation process.

[0031] Table 3 Dissolution rate of monensin solid dispersions with different mass ratios of S 100 polyoxyethylene stearate and white rutaecarpa in 10 min

[0032]

[0033] Saturation solubility

[0034] The same operation as in Example 1 was performed. The saturated solubility of monensin solid dispersion in water with S 100 polyoxyethylene stearate as carrier is 15.3 μg / mL. The saturated solubility of the lutein solid dispersion with S 100 polyoxyethylene stearate and white rue as composite carriers in water is 670.3 μg / mL. The solid dispersion of monensin with S 100 polyoxyethylene stearate and white rutaecarpa as carriers was better than that with The solid dispersion of monensin with S100 polyoxyethylene stearate as carrier increased by 4281.0%. The solubility of monensin solid dispersion in the composite carrier of S 100 polyoxyethylene stearate and white rutaecarpa was significantly improved.

[0035] Determination of cumulative dissolution rate

[0036] The cumulative dissolution rate of the monensin solid dispersion prepared by the composite carrier was 92% in 15 minutes, while the cumulative dissolution rate of the monensin solid dispersion prepared by the composite carrier was 92% in 15 minutes. The cumulative dissolution rate of the monensin solid dispersion using S 100 polyoxyethylene stearate as a carrier was only 15% within 15 minutes.

[0037] Example 4

[0038] Using lauryl alcohol polyoxyethylene ether and white rutaecarpa as composite carriers, the optimal preparation process was determined by comparing the 10 min dissolution rate of avermectin solid dispersions in the same manner as in Example 2.

[0039] Table 4 Dissolution rate of avermectin solid dispersions with different mass ratios of lauryl alcohol polyoxyethylene ether and white rutaecarpa in 10 min

[0040] Serial number Lauryl polyoxyethylene ether: Rutaecarpa Dissolution rate in 10 minutes (%) 1 1∶3 69.1 2 1∶2 78.2 3 1∶1 85.4 4 2∶1 64.6 5 3∶1 52.5

[0041] Saturation solubility

[0042] The same operation as in Example 1 was performed. As a result, the saturated solubility of the avermectin solid dispersion in water using lauryl alcohol polyoxyethylene ether as a carrier was 12.3 mg / mL, and the saturated solubility of the avermectin solid dispersion in water using lauryl alcohol polyoxyethylene ether and white rue as a composite carrier was 374.1 mg / mL. It was found that the saturated solubility of the avermectin solid dispersion in water using lauryl alcohol polyoxyethylene ether as a carrier increased by 2941.5% compared to the avermectin solid dispersion using lauryl alcohol polyoxyethylene ether as a carrier. The experimental results show that the avermectin solid dispersion of the lauryl alcohol polyoxyethylene ether-white rue composite carrier prepared in this experiment significantly improves the solubility.

[0043] Determination of cumulative dissolution rate

[0044] The cumulative dissolution rate operation was performed in the same manner as in Example 1. The results showed that the cumulative dissolution rate of the avermectin solid dispersion prepared with the composite carrier was 95% in 15 minutes, while the cumulative dissolution rate of the avermectin solid dispersion with lauryl alcohol polyoxyethylene ether as the carrier was 39% in 15 minutes.

[0045] The solid dispersion formed by the carrier prepared by the present invention has a simple preparation method, can significantly increase the wettability of the poorly soluble drug, increase the solubility in water, inhibit the crystallization of the poorly soluble drug, and significantly improve the dissolution rate of the poorly soluble drug.

[0046] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, replacements and improvements based on the principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A solid dispersion of a poorly soluble drug, characterized in that: Vinyl pyrrolidone-vinyl acetate copolymer and maple balsam resin were used as composite carriers in a mass ratio of 1:

1. A solid dispersion of the poorly soluble drug rutin was prepared by solvent rotary evaporation. The solid dispersion contained 12% of the poorly soluble drug rutin, 30% of the filler ethyl cellulose, and the remainder of the composite carrier. Alternatively, methacrylic acid copolymer type C and maple resin are used as composite carriers in a mass ratio of 1:1, and a solvent rotary evaporation method is used to prepare a solid dispersion of the poorly soluble drug curcumin, wherein the content of the poorly soluble drug curcumin is 11%, the content of the filler ethyl cellulose is 50%, and the rest is the composite carrier.

2. The method for preparing a solid dispersion of a poorly soluble drug according to claim 1, wherein: The composite carrier, the raw material drug and ethyl cellulose were dissolved in an organic solvent in a certain proportion, stirred at 40-60°C at a speed of 100 r·min-1 for 10-30 minutes, and then the organic solvent was removed by rotary evaporation. Finally, the obtained solid was dried in an oven at 40°C for 36 hours.

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