CN112870167A - Oryzanol solid dispersion and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a oryzanol solid dispersion and a preparation method and application thereof, wherein the oryzanol solid dispersion comprises oryzanol and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier material, the mass ratio of the oryzanol to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 1-1: 4, the equilibrium solubility of the oryzanol solid dispersion is more than 6.5 mg/ml, and the solubility of the oryzanol and the stability of a high-humidity environment are improved. The oryzanol solid dispersion is further prepared into tablets, so that the long-term stability of the oryzanol solid dispersion is enhanced, and the content and the dissolution rate can be kept above 95%; compared with the commercially available oryzanol tablets, the dissolution rate and the dissolution rate are remarkably improved, and the bioavailability in rats is also remarkably improved and is 2.67 times that of the commercially available oryzanol tablets.
Description
Technical Field
The invention relates to an oryzanol oral preparation, in particular to a oryzanol solid dispersion and a preparation method and application thereof.
Background
Oryzanol is mainly present in rice bran and is a kind of combined lipid of ferulic acid and phytosterol. Has effects in resisting lipid peroxidation, reducing blood lipid and blood glucose, preventing cardiovascular diseases, and relieving inflammation. Oryzanol is a natural substance with high safety, but simultaneously is a fat-soluble medicine, is dissolved in acetone, is slightly soluble in ethanol and n-heptane, is insoluble in water, is poorly absorbed in vivo, is easily metabolized and degraded, has low bioavailability, and has limited application.
In order to improve the solubility and bioavailability of oryzanol, oryzanol is prepared into an injection preparation in the prior art. For example, CN1338255A discloses an oily oryzanol injection, which is prepared by dissolving high-purity oryzanol powder in refined vegetable oil, but the oryzanol powder is easy to cause muscle agglomeration when intramuscular injection is carried out, and the compliance is poor. Few oral formulation techniques have been reported to improve the solubility and bioavailability of oryzanol.
CN102058537A discloses a oryzanol solid dispersion composition and its preparation, wherein the oryzanol solid dispersion composition comprises oryzanol and povidone K30, and is prepared by dissolving the oryzanol and povidone K30 in an organic solvent, recovering the organic solvent and drying, and mixing with pharmaceutical excipients to prepare an oral preparation. Compared with other carrier materials, the dissolution rate of the prepared solid dispersion and the bioavailability of the tablet are remarkably improved by taking the povidone K30 as the carrier material. However, the present inventors have found that a solid dispersion consisting of oryzanol and povidone K30 has stability problems, especially under high humidity environment. Therefore, there is a need to select a new oryzanol solid dispersion carrier material, which simultaneously meets the requirements of increasing the solubility, oral bioavailability and stability of oryzanol.
Disclosure of Invention
The invention aims to provide a oryzanol solid dispersion and a preparation method and application thereof.
The purpose of the invention is realized by the following technical scheme: a oryzanol solid dispersion is characterized by comprising oryzanol and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier material; the mass ratio of the oryzanol to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 1-1: 4; the oryzanol solid dispersion has an equilibrium solubility of more than 6.5 mg/ml.
Preferably, the mass ratio of the oryzanol to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 3.
A preparation method of a oryzanol solid dispersion comprises the following steps:
step 1: the oryzanol and the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer are uniformly mixed and then added into a feeding hopper of a hot melt extruder.
Step 2: setting the frequency of a main machine to be 2.5-4 Hz, the feeding frequency to be 1.5-3.5 Hz and the temperature to be 120-180 ℃ to prepare the solid dispersion.
And step 3: and (3) collecting the extrudate obtained in the step (2), cooling, crushing and sieving to obtain the oryzanol solid dispersion powder.
Preferably, the frequency of the main machine in the step 2 is 4Hz, the feeding frequency is 3.5Hz, and the temperature is 160 ℃.
An oral oryzanol preparation comprises the oryzanol solid dispersion and pharmaceutically acceptable auxiliary materials.
Preferably, the oral dosage form is a tablet.
Preferably, the pharmaceutically acceptable auxiliary materials are one or more of lactose, microcrystalline cellulose, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate.
Compared with the prior art, the invention has the beneficial effects that:
1) the invention takes the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as the carrier of the oryzanol solid dispersion, and the solubilization effect of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer on the oryzanol is obvious. The equilibrium solubility of the oryzanol solid dispersion reaches 8.9mg/ml when the drug loading ratio is 1:3, is equivalent to the solubilization effect of povidone K30 as a carrier material, and is 1.4-1.9 times of that of other carrier materials such as PEG, poloxamer and the like. The oryzanol solid dispersion is further prepared into tablets, compared with the commercially available oryzanol tablets, the dissolution rate is remarkably improved, the 10min cumulative dissolution percentage is higher than 40%, and the 45min cumulative dissolution percentage is higher than 95%; the bioavailability in rats is also obviously improved and is 2.67 times of that of the commercially available oryzanol tablets.
2) The oryzanol solid dispersion taking the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as the carrier material overcomes the unstable phenomena of property change, content reduction, dissolution reduction and the like of the oryzanol solid dispersion taking povidone K30 as the carrier material in a high-humidity environment. The oryzanol solid dispersion is further prepared into tablets, so that the long-term stability of the oryzanol solid dispersion is enhanced, and the content and the dissolution rate of the oryzanol solid dispersion after 6 months of accelerated stability test can be kept above 95%.
3) The oryzanol solid dispersion is prepared by adopting a melting method, the preparation process avoids using an organic solvent, and the preparation process is simple and has controllable conditions.
Drawings
FIG. 1 is the in vitro dissolution results of a commercially available oryzanol tablet in example 17 and a oryzanol solid dispersion tablet of the present invention;
fig. 2 is a graph showing the in vivo administration time of rats of the commercially available oryzanol tablet in example 19 and the oryzanol solid dispersion tablet of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples and the accompanying drawings.
Examples 1-4 screening of oryzanol solid Dispersion Carrier Material
The oryzanol and a carrier material (PEG 4000, PEG6000, poloxamer 188, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus, BASF)) are weighed according to the mass shown in Table 1, uniformly mixed, added into a feeding hopper of a hot melt extruder (Pharma Mini HME, Sammerful pharmaceutical) and set the host frequency of 4Hz and the feeding frequency of 3.5Hz and the temperature of 160 ℃ to prepare a solid dispersion, the extrudate is collected, cooled, crushed and sieved by a 120-mesh sieve to obtain oryzanol solid dispersion powder, the solid dispersion powder is dissolved in an aqueous solution, and the equilibrium solubility at room temperature (25 ℃) is measured, and the result is shown in Table 1.
The results in table 1 show that the solid dispersion prepared from oryzanol and the carrier material by the hot-melt extrusion method can effectively improve the solubility of the oryzanol. The solubilizing effect of Soluplus on oryzanol is most remarkable, and the equilibrium solubility of the oryzanol solid dispersion at the drug loading ratio of 1/3 is 8.9mg/ml, 4.24 times of the oryzanol and 1.4-1.9 times of the oryzanol solid dispersion formed by carrier materials such as PEG, poloxamer and the like.
Example 5-8 screening of drug Loading ratio of oryzanol solid Dispersion
Oryzanol and a carrier material (Soluplus) are weighed according to the mass shown in Table 2, mixed uniformly and added into a feeding hopper of a hot melt extruder, the frequency of a main machine is set to be 4Hz, the feeding frequency is set to be 3.5Hz, and the temperature is set to be 160 ℃, so that the solid dispersion is prepared. And collecting the extrudate, cooling, crushing, and sieving by a 120-mesh sieve to obtain the oryzanol solid dispersion powder. The solid dispersion powder was dissolved in an aqueous solution, and the equilibrium solubility at room temperature (25 ℃ C.) was measured, and the results are shown in Table 2.
The results in table 2 show that the drug loading ratio of oryzanol to Soluplus is in the range of 1-1/4, and the solubilizing effect of the carrier on oryzanol is enhanced as the drug loading ratio is reduced, but the drug loading rate is reduced, so that the ratio of oryzanol to Soluplus is preferably 1: 3.
Examples 9-11 Effect of the preparation Process of oryzanol solid Dispersion
Oryzanol and Soluplus in a mass ratio of 1:3 are uniformly mixed and added into a feeding hopper of a hot-melt extruder, and the host frequency, the feeding frequency and the temperature are set as shown in Table 3 to prepare the solid dispersion. And collecting the extrudate, cooling, crushing, and sieving by a 120-mesh sieve to obtain the oryzanol solid dispersion powder. The equilibrium solubility at room temperature (25 ℃) and the dissolution rate at 45min were measured, and the measurement results are shown in Table 3.
Table 3 the results show that during the preparation of the oryzanol solid dispersion, the hot-melt extruder sets the parameter ranges: the frequency of a host is 2.5-4 Hz, the feeding frequency is 1.5-3.5 Hz, the temperature is 120-180 ℃, the solubility and 45min dissolution rate of the oryzanol dispersion have no obvious difference, and the requirements of improving the solubility and completely dissolving out can be met.
Example 12 oryzanol solid Dispersion influencing factor experiment
Comparative example 2: weighing 3030 g of povidone K and 10 g of oryzanol, uniformly mixing, adding into a feeding hopper of a hot-melt extruder, setting the host frequency to be 2.5Hz, the feeding frequency to be 2Hz and the temperature to be 140 ℃, preparing a solid dispersion, collecting, cooling and crushing extrudate, and sieving with a 120-mesh sieve.
Comparative example 3: measuring 100 ml of 95% ethanol, adding 2 ml of propylene glycol, adding 3030 g of povidone K, fully shaking for dissolving, adding 10 g of oryzanol, heating and stirring at 80 ℃ for about 10min, pouring the obtained solution into a rotary evaporator, completely evaporating the organic solvent at 37 ℃, putting the organic solvent into a vacuum drying oven, drying at 25 ℃ overnight, taking out, and sieving with a 120-mesh sieve.
The oryzanol solid dispersion powders obtained in example 7 and comparative examples 2 and 3 were placed under high temperature (60. + -. 2 ℃ C.), high humidity (90. + -. 5% RH) and light (4500. + -. 500 Lux) conditions, and samples were taken for 0 day and 10 days to measure properties, contents and moisture-induced weight gain, and the results are shown in Table 4.
Table 4 the results show that oryzanol solid dispersion with povidone K30 as carrier material, whether prepared by the melt process (comparative example 2) or by the solvent process (comparative example 3), produces an unstable phenomenon in high humidity environment: change of properties, increase of weight by inducing dampness, decrease of drug content, and decrease of 45min dissolution rate. The oryzanol solid dispersion (example 7) using Soluplus as a carrier material has no obvious changes in properties and contents under high temperature, high humidity and illumination conditions, and has almost no hygroscopicity. Therefore, compared with povidone K30, the carrier material Soluplus overcomes the problem of hygroscopicity, and makes the oryzanol solid dispersion powder more stable.
EXAMPLE 13 preparation of oryzanol oral tablets
Weighing 40 g of oryzanol solid dispersion powder prepared in example 7, 40 g of lactose, 15 g of microcrystalline cellulose and 4 g of carboxymethyl starch sodium, uniformly mixing, adding 1 g of magnesium stearate, uniformly mixing, and tabletting, wherein the weight of the tablet is 100 mg, the hardness is 4-6 kg, and each tablet contains 10mg of oryzanol.
EXAMPLE 14 preparation of oryzanol oral tablets
Weighing 40 g of oryzanol solid dispersion powder prepared in example 7, 22 g of lactose, 35 g of microcrystalline cellulose and 2 g of crospovidone, uniformly mixing, adding 1 g of magnesium stearate, uniformly mixing, and tabletting, wherein the weight of each tablet is 100 mg, the hardness is 4-6 kg, and each tablet contains 10mg of oryzanol.
EXAMPLE 15 preparation of oryzanol oral tablets
Weighing 40 g of oryzanol solid dispersion powder prepared in example 7, 54 g of lactose and 5 g of low-substituted hydroxypropylcellulose, uniformly mixing, adding 1 g of magnesium stearate, uniformly mixing and tabletting to obtain the tablet. The tablet has a weight of 100 mg and hardness of 6-8 kg, and each tablet contains oryzanol 10 mg.
EXAMPLE 16 preparation of oryzanol oral tablets
Weighing 40 g of oryzanol solid dispersion powder prepared in example 7, 15 g of lactose, 36g of microcrystalline cellulose and 8 g of croscarmellose sodium, uniformly mixing, adding 1 g of magnesium stearate, uniformly mixing, and tabletting, wherein the weight of each tablet is 100 mg, the hardness is 2-4 kg, and each tablet contains 10mg of oryzanol.
Example 17 dissolution test of oryzanol oral tablets in vitro
A commercially available oryzanol tablet (Shanghai Pukang pharmaceutical Co., Ltd., 10 mg/tablet) and a oryzanol solid dispersion tablet obtained in example 13 were used as samples. Referring to the second method (slurry method) of 0931 dissolution and release rate determination method of the general rule of the four departments in the 2020 edition of Chinese pharmacopoeia, 500 ml of phosphate buffer solution (pH6.8) containing 0.3% Tween 80 is used as a medium, an in vitro dissolution curve is determined at the temperature (37 +/-0.5 ℃) and the rotating speed of 100rpm, 5 ml of samples are respectively sampled at 10min, 30 min, 45min and 60min, and isothermal fresh dissolution medium is supplemented at the same time. The sample was filtered through a 0.45 μm filter and the cumulative percent dissolution was measured and calculated as shown in FIG. 1.
The results in fig. 1 show that the 60min cumulative dissolution percentage of the commercially available oryzanol tablets is lower than 20%, while the 10min cumulative dissolution percentage of the oryzanol solid dispersion tablets is higher than 40%, and the 45min cumulative dissolution percentage is higher than 95%.
EXAMPLE 18 accelerated stability test
The oryzanol solid dispersion powder obtained in example 7 and the oryzanol solid dispersion tablet obtained in example 13 were used as samples, and the samples were stored in a 40 ℃ and RH75% incubator for 6 months, respectively, and sampled at 0 month, 1 month, 2 months, 3 months, and 6 months, respectively, to measure the properties, the content, and the 45min dissolution rate, and the results are shown in table 5.
The results in table 5 show that the oryzanol solid dispersion powder (example 7) and the tablet thereof (example 13) of the present invention have substantially no change in properties and content under accelerated test conditions, but the dissolution rate of the solid dispersion powder slightly decreases with the increase in the storage time, and the tablet prepared from the powder can suppress the tendency of dissolution rate decrease, thereby enhancing the stability.
Example 19 in vivo pharmacokinetic experiments in rats
A commercially available oryzanol tablet (Shanghai Pukang pharmaceutical Co., Ltd., 10 mg/tablet) and a oryzanol solid dispersion tablet obtained in example 13 were used as samples. Healthy SD adult rats 18 (250 +/-20) g are taken, the weight is randomly divided into 2 groups, 9 rats in each group are fasted overnight, the rats are intragastrically administered according to the dose of 1 mg/100g, 0.5 mL of tail vein blood is taken at 1, 5, 15, 30, 60, 90, 120, 150, 180, 240, 360 and 720 min, the rats are centrifuged at 3000rpm and 4 ℃ for 20min, supernatant liquid is taken, and the blood concentration is measured, wherein the time curve of the drug is shown in figure 2.
The results in fig. 2 show that the oryzanol solid dispersion tablet can obviously improve the maximum blood concentration and bioavailability of the oryzanol, and the bioavailability of the oryzanol solid dispersion tablet is calculated to be 2.67 times that of the commercially available oryzanol tablet.
Claims (7)
1. A oryzanol solid dispersion is characterized by comprising oryzanol and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as a carrier material; the mass ratio of the oryzanol to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 1-1: 4; the oryzanol solid dispersion has an equilibrium solubility of more than 6.5 mg/ml.
2. The oryzanol solid dispersion according to claim 1, wherein the weight ratio of the oryzanol to the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is 1: 3.
3. The method for producing a oryzanol solid dispersion as claimed in claim 1, comprising the steps of:
step 1: uniformly mixing oryzanol and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and adding the mixture into a feeding hopper of a hot-melt extruder;
step 2: setting the frequency of a host machine to be 2.5-4 Hz, the feeding frequency to be 1.5-3.5 Hz and the temperature to be 120-180 ℃ to prepare a solid dispersion;
and step 3: and (3) collecting the extrudate obtained in the step (2), cooling, crushing and sieving to obtain the oryzanol solid dispersion powder.
4. The method for preparing oryzanol solid dispersion as claimed in claim 3, wherein the host frequency in step 2 is 4Hz, the feeding frequency is 3.5Hz, and the temperature is 160 ℃.
5. An oral formulation of oryzanol, comprising the oryzanol solid dispersion of claim 1 and a pharmaceutically acceptable excipient.
6. The oryzanol oral preparation as claimed in claim 6, wherein the dosage form of the oral preparation is a tablet.
7. The oryzanol oral formulation of claim 6, wherein the pharmaceutically acceptable excipient is one or more of lactose, microcrystalline cellulose, sodium carboxymethyl starch, crospovidone, low substituted hydroxypropylcellulose, croscarmellose sodium, and magnesium stearate.
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| CN112843006A (en) * | 2021-01-28 | 2021-05-28 | 上海嘉申医药研发有限公司 | Oryzanol phospholipid complex and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058537A (en) * | 2009-11-18 | 2011-05-18 | 北京世纪博康医药科技有限公司 | Oryzanol solid dispersion composition and preparation thereof |
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| CN102058537A (en) * | 2009-11-18 | 2011-05-18 | 北京世纪博康医药科技有限公司 | Oryzanol solid dispersion composition and preparation thereof |
Non-Patent Citations (2)
| Title |
|---|
| 吴慧敏等: "Soluplus在药物制剂中的应用", 《中国医药工业杂志》 * |
| 朱甜等: "超临界CO2抗溶剂法制备谷维素/PVP-K30固体分散体", 《今日药学》 * |
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| CN112843006A (en) * | 2021-01-28 | 2021-05-28 | 上海嘉申医药研发有限公司 | Oryzanol phospholipid complex and preparation method and application thereof |
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