CN116650421A - Rosemary solid dispersing agent and preparation method and application thereof - Google Patents

Rosemary solid dispersing agent and preparation method and application thereof Download PDF

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CN116650421A
CN116650421A CN202310657328.XA CN202310657328A CN116650421A CN 116650421 A CN116650421 A CN 116650421A CN 202310657328 A CN202310657328 A CN 202310657328A CN 116650421 A CN116650421 A CN 116650421A
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solid
rosemary extract
carrier
polyvinylpyrrolidone
dispersing agent
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罗伟
曹文豪
伍勇
宋诗雨
孙志良
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Hunan Xianwei Sunshine Biotechnology Co ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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Abstract

The invention provides a rosemary solid dispersing agent, a preparation method and application thereof. The solid dispersing agent comprises rosemary extract and a carrier, wherein the rosemary extract comprises ursolic acid and oleanolic acid. According to the invention, the dissolution rate of the ursolic acid and oleanolic acid in the rosemary extract is improved by a melting method or a solvent method solid dispersion technology, so that the oxidation resistance of rosemary is improved.

Description

Rosemary solid dispersing agent and preparation method and application thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to a rosemary solid dispersing agent and a preparation method and application thereof.
Background
Rosemary is a shrub plant of Rosmarinus of Labiatae, has antioxidant, blood sugar and blood lipid reducing effects, and can be used for maintaining organism oxidation balance, and preventing and treating high sugar and high lipid diseases caused by obesity. The antioxidant effect of rosemary mainly comes from phenolic acid substances contained in the rosemary body, and mainly comprises the following components: ursolic acid, oleanolic acid, carnosic acid, rosmarinic acid, chlorogenic acid, caffeic acid, etc. Wherein oleanolic acid and ursolic acid are isomers of each other, often exist in natural plants at the same time, and are main effective components of rosemary extract. Because of its excellent liver protecting ability, oleanolic acid was registered as a liver protecting agent in China 40 years ago, and in addition, oleanolic acid has the effects of resisting bacteria, resisting tumors, resisting diabetes, regulating blood lipid and the like, and the pharmacological effects of ursolic acid are approximately the same as that of oleanolic acid. However, oleanolic acid and ursolic acid are insoluble in water, so that the bioavailability is extremely low, and the large-scale popularization and application of rosemary are seriously affected.
Therefore, there is a need to improve the bioavailability and drug dissolution of rosemary to facilitate its clinical use.
Disclosure of Invention
In order to solve one of the technical problems in the prior art, the rosemary extract solid dispersing agent with high dissolution and excellent oxidation resistance is obtained by selecting a proper carrier through a solid dispersing technology.
In a first aspect, the present invention provides a solid dispersion comprising a rosemary extract and a carrier, wherein the rosemary extract comprises ursolic acid and oleanolic acid.
In some embodiments, the carrier comprises at least one of polyethylene glycol, polyvinylpyrrolidone, citric acid, tartaric acid, sucrose, mannitol, sorbitol, xylitol, poloxamer, and leucine, preferably comprises polyethylene glycol and/or polyvinylpyrrolidone.
In some embodiments, the polyethylene glycol has an average molecular weight greater than 1000. In some embodiments, the polyethylene glycol has an average molecular weight of 2000 or greater. In some embodiments, the polyethylene glycol has an average molecular weight of 2000 to 10000. In some embodiments, the polyethylene glycol has an average molecular weight of 4000 to 8000. In some embodiments, the polyethylene glycol is at least one of PEG-2000, PEG-4000, and PEG-6000.
In some preferred embodiments, the carrier is PEG-6000.
In some embodiments, the polyvinylpyrrolidone has an average molecular weight of 20000 to 50000. In some embodiments, the polyvinylpyrrolidone has an average molecular weight of 25000 to 45000. Preferably, the polyvinylpyrrolidone is polyvinylpyrrolidone K30 or polyvinylpyrrolidone K40.
In some preferred embodiments, the carrier is polyvinylpyrrolidone K30.
In some embodiments, the mass ratio of rosemary extract to carrier is 1 (1-20), e.g., 1:1, 1:3, 1:5, 1:8, 1:10, 1:12, 1:15, 1:18, 1:20, or any value therebetween, preferably 1 (3-10).
In some embodiments, the ursolic acid is present in an amount of 20-40wt%, e.g., 20wt%, 22wt%, 25wt%, 28wt%, 30wt%, 32wt%, 35wt%, 38wt%, 40wt%, or any value therebetween, based on the total mass of the rosemary extract.
In some embodiments, the oleanolic acid is present in an amount of 10-20wt%, such as 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, 20wt%, or any value therebetween, based on the total mass of the rosemary extract.
In a second aspect, the present invention provides a method of preparing a solid dispersant according to the first aspect.
The rosemary extract solid dispersing agent is prepared by a solid dispersing technology. The solid dispersion technique may be either a melt method or a solvent method. The key point of the preparation of the solid dispersing agent by the fusion method is that the solid dispersing agent is rapidly cooled at high temperature to reach a supersaturated state, so that colloidal crystal nuclei are rapidly formed to obtain highly dispersed medicines, and the solid dispersing agent is suitable for medicines with high thermal stability. The solvent method is to dissolve the drug and the carrier together in an organic reagent, and then evaporate the organic solvent to separate out the drug and the carrier.
In the present invention, the method for preparing the solid dispersing agent comprises the steps of:
step a: and (3) heating and melting the carrier, mixing the carrier with the rosemary extract, cooling, solidifying and drying to obtain the solid dispersing agent.
In some embodiments, in step a, the temperature of the heating is 60-100 ℃, e.g., 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, or any value therebetween.
In some embodiments, in step a, the cooled temperature is-30 to-10 ℃, such as-30 ℃, -28 ℃, -25 ℃, -22 ℃, -20 ℃, -18 ℃, -15 ℃, -12 ℃, -10 ℃, or any value in between.
In some embodiments, in step a, the carrier is polyethylene glycol. Preferably, the polyethylene glycol has an average molecular weight of greater than 1000, preferably 2000-10000, more preferably 4000-8000, even more preferably 5000-7000. Preferably, the polyethylene glycol is at least one of PEG-2000, PEG-4000 and PEG-6000, more preferably PEG-6000. Polyethylene glycol (PEG) is a polyether carrier, can obviously improve the dissolution rate and bioavailability of the drug, and is more suitable for being used as a carrier in a solid dispersing agent prepared by a melting method because of lower melting point.
In some embodiments, the method of preparing the solid dispersant comprises the steps of:
step b: mixing the carrier, the rosemary extract and a solvent, removing the solvent, and drying to obtain the solid dispersing agent.
In some embodiments, in step b, the solvent is a volatile organic solvent, preferably ethanol.
In some embodiments, in step b, the carrier is polyvinylpyrrolidone. Preferably, the polyvinylpyrrolidone has an average molecular weight of 20000 to 50000, preferably 25000 to 45000, more preferably 30000 to 40000. Preferably, the polyvinylpyrrolidone is polyvinylpyrrolidone K30 or polyvinylpyrrolidone K40, more preferably polyvinylpyrrolidone K30. Polyvinylpyrrolidone (PVP) has good thermal stability, can form hydrogen bonds with the drugs, and inhibit the formation and growth of drug crystal nuclei so as to maintain the amorphous form or the highly dispersed state of the drugs, so that the polyvinylpyrrolidone (PVP) is more suitable for being used as a carrier in a solvent method for preparing solid dispersing agents.
Preferably, in the step a and the step b, the solid dispersing agent is obtained by further crushing and sieving, preferably an 80-mesh pharmacopoeia sieve, after drying.
In a third aspect, the present invention provides a pharmaceutical formulation comprising a solid dispersion according to the first aspect and a pharmaceutically acceptable adjuvant.
In some embodiments, the excipients include at least one of microcrystalline cellulose, lactose, starch, croscarmellose sodium, magnesium stearate.
In some embodiments, the formulation is in the form of a tablet, powder, pill, or capsule.
In a fourth aspect, the present invention provides the use of the solid dispersion according to the first aspect for the manufacture of an antioxidant or hypoglycemic agent or hypolipidemic agent.
The medicaments of the present invention include, but are not limited to, veterinary medicaments.
Compared with the prior art, the invention has the beneficial effects that:
1. the rosemary extract is prepared into the solid dispersing agent by adopting the solid dispersing technology, so that the in-vitro dissolution rate of the ursolic acid and the oleanolic acid is remarkably improved, and a preparation foundation is provided for development and utilization of the rosemary extract.
2. The rosemary extract solid dispersing agent disclosed by the invention has excellent antioxidation capability, and provides a data basis for application of rosemary in the field of pharmacy.
3. The rosemary extract solid dispersing agent can also improve the growth performance of animals, and is safe and free of toxic and side effects.
Drawings
Fig. 1 shows the cumulative dissolution rates of oleanolic acid and ursolic acid in the solid dispersions of examples 1-3.
Fig. 2 shows the cumulative dissolution rates of oleanolic acid and ursolic acid in the solid dispersions of examples 4-6.
Fig. 3 shows the cumulative dissolution rates of oleanolic acid and ursolic acid in the solid dispersions of comparative examples 1-2.
FIG. 4 shows serum T-AOC content, GSH-PX content, SOD content and MDA content of mice from both the blank group and the test group.
Fig. 5 shows liver T-AOC content, GSH-PX content, SOD content and MDA content of mice in the blank group and the test group.
Figure 6 shows the T-AOC content, GSH-PX content, SOD content and MDA content of mice in both the blank and test groups.
Detailed Description
The present invention will be described in further detail with reference to the following examples and the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way.
As used herein, the term "Oleanolic Acid (OA)" has the formula C 30 H 48 O 3 Is a 5-ring triterpene compound, white needle point crystal (ethanol), odorless, unstable to acid and alkali, insoluble in water, and soluble in organic reagents such as chloroform, methanol, ethanol, etc.
The term "Ursolic Acid" (UA) as used herein has the formula C 30 H 48 O 3 The oleanolic acid is an isomer with oleanolic acid, has glossy prismatic crystal (absolute ethyl alcohol) or capillary needle tip (diluted ethyl alcohol), is insoluble in water and petroleum ether, and is easily dissolved in organic reagents such as methanol, ethanol and the like.
The lot numbers and manufacturer information of the reagents used below are shown in Table 1.
TABLE 1
Example 1: preparation of rosemary solid dispersing agent by fusion method
PEG-6000 was stirred to the molten state in a water bath at 80deg.C, following rosemary extract: adding herba Rosmarini officinalis extract at a mass ratio of 1:3, stirring, pouring onto ice cooled stainless steel plate, coating into sheet, solidifying completely, placing into a refrigerator at-20deg.C for solidifying for 3 hr, drying in a dryer for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract melt solid dispersing agent.
Example 2: preparation of rosemary solid dispersing agent by fusion method
PEG-6000 was stirred to the molten state in a water bath at 80deg.C, following rosemary extract: adding herba Rosmarini officinalis extract at a mass ratio of 1:5, stirring, pouring onto ice cooled stainless steel plate, coating into sheet, solidifying completely, placing into a refrigerator at-20deg.C for solidifying for 3 hr, drying in a dryer for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract melt solid dispersing agent.
Example 3: preparation of rosemary solid dispersing agent by fusion method
PEG-6000 was stirred to the molten state in a water bath at 80deg.C, following rosemary extract: adding herba Rosmarini officinalis extract at a mass ratio of 1:10, stirring, pouring onto ice cooled stainless steel plate, coating into sheet, solidifying completely, placing into a refrigerator at-20deg.C for solidifying for 3 hr, drying in a dryer for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract melt solid dispersing agent.
Example 4: solvent method for preparing rosemary solid dispersing agent
Mixing PVP-K30 and herba Rosmarini officinalis extract (with mass ratio of herba Rosmarini officinalis extract to PVP-K30=1:3), dissolving with absolute ethanol, removing ethanol in rotary evaporator at 60deg.C, drying in a drier for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract solvent solid dispersing agent.
Example 5: solvent method for preparing rosemary solid dispersing agent
Mixing PVP-K30 and herba Rosmarini officinalis extract (with mass ratio of herba Rosmarini officinalis extract to PVP-K30=1:5), dissolving with absolute ethanol, removing ethanol in rotary evaporator at 60deg.C, drying in a drier for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract solvent solid dispersing agent.
Example 6: solvent method for preparing rosemary solid dispersing agent
Mixing PVP-K30 and herba Rosmarini officinalis extract (with mass ratio of herba Rosmarini officinalis extract to PVP-K30=1:10), dissolving with absolute ethanol, removing ethanol in rotary evaporator at 60deg.C, drying in a drier for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain herba Rosmarini officinalis extract solvent solid dispersing agent.
Comparative example 1: physical mixing
According to rosemary extract: mixing PEG-6000 and herba Rosmarini officinalis extract at a mass ratio of 1:5, drying in a dryer for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain physical mixture of PEG-6000 and herba Rosmarini officinalis extract.
Comparative example 2: physical mixing
According to rosemary extract: mixing PVP-K30 and herba Rosmarini officinalis extract at a mass ratio of 1:5, drying in a dryer for 24 hr, pulverizing, and sieving with 80 mesh pharmacopoeia sieve to obtain physical mixture of PVP-K30 and herba Rosmarini officinalis extract.
And (3) effect test: in vitro dissolution test
The in vitro dissolution rate of ursolic acid and oleanolic acid in the rosemary extract solid dispersing agent is determined by adopting a second method in the dissolution rate and release rate of 2020 edition of Chinese animal pharmacopoeia. The specific test method is as follows:
25mg of rosemary extract, 150mg of PEG-6000-rosemary extract physical mixture prepared in comparative example 1 (equivalent to 25mg of rosemary extract), 150mg of PVP-K30-rosemary extract physical mixture prepared in comparative example 2, 100mg of solid dispersant prepared in example 1, 150mg of solid dispersant prepared in example 2, 275mg of solid dispersant prepared in example 3, 100mg of solid dispersant prepared in example 4, 150mg of solid dispersant prepared in example 5 and 275mg of solid dispersant prepared in example 6, respectively, were taken.
Taking 900mL of 0.5% sodium dodecyl sulfate solution (SDS) of a dissolution medium, degassing, recording at the temperature of 37+/-0.5 ℃ and the rotation speed of 100r/min, taking 5mL of the dissolution medium as a sample to be tested when the medicine is in contact with the dissolution medium and starting to record at 15, 30, 60 and 120min, timely supplementing an equivalent blank dissolution medium with the temperature of 37 ℃, centrifuging the sample to be tested for 5min at 12000r/min, transferring the supernatant, taking 20 mu L of sample volume according to high performance liquid chromatography, recording a chromatogram, and respectively measuring the in vitro dissolution rate of the rosemary extract, the physical mixture and the solid dispersing agent.
In examples 1 to 3, the cumulative dissolution rates of oleanolic acid and ursolic acid in the solid dispersion prepared by the melting method are shown in FIG. 1. As can be seen from fig. 1, in example 1, the mass ratio of rosemary extract to carrier PEG-6000 is 1:3, the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 21.36%, 37.84% and 42.32%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 18.68%, 45.95% and 44.44%. In the example 2, the mass ratio of the bulk drug to the carrier is 1:5, the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 20.76%, 28.77% and 55.70%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 27.69%, 30.52% and 54.30%. In example 3, the mass ratio of the bulk drug to the carrier is 1: the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 20.37%, 34.83% and 49.30%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 17.69%, 31.17% and 42.07%.
The in vitro dissolution rates of oleanolic acid and ursolic acid in the solid dispersions prepared in examples 4-6 using the solvent method are shown in FIG. 2. As can be seen from fig. 2, in example 4, the mass ratio of rosemary extract to PVP-K30 carrier is 1:3, the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 42.69%, 48.22%, 58.68% and 69.38%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 50.21%, 50.88%, 79.70% and 81.96%.
In the example 5, the mass ratio of the bulk drug to the carrier PVP-K30 is 1:5, the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 48.36%, 55.27%, 56.98% and 78.59%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 47.00%, 59.04%, 75.93% and 81.69%. In the example 6, the mass ratio of the bulk drug to the carrier PVP-K30 is 1: the cumulative dissolution rates of oleanolic acid in the solid dispersing agent at 0.25h, 0.5h, 1.0h and 2.0h are 47.76%, 71.79%, 70.88% and 95.40%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 62.92%, 87.90%, 78.08% and 92.78%.
Rosemary extract, physical mixture prepared in comparative examples 1-2 and material ratio 1: the cumulative dissolution of oleanolic acid and ursolic acid in the solid dispersing agent is shown in figure 3. As can be seen from fig. 3, the cumulative dissolution rates of oleanolic acid in rosemary extract at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 4.87%, 6.95% and 11.24%, and the cumulative dissolution rates of ursolic acid at 0.25h, 0.5h, 1.0h and 2.0h are 0.00%, 5.53%, 7.94% and 10.09%. The cumulative dissolution rates of oleanolic acid in the physical mixture of PEG-6000 and rosemary extract in comparative example 1 were 0.00%, 7.18%, 10.76% and 15.78% at 0.25h, 0.5h, 1.0h and 2.0h, and the cumulative dissolution rates of ursolic acid were 0.00%, 8.65%, 12.67% and 20.99% at 0.25h, 0.5h, 1.0h and 2.0 h. The cumulative dissolution rates of oleanolic acid in the physical mixtures of PVP-K30 and rosemary extract of comparative example 2 were 0.00%, 11.03%, 9.13% and 18.21% at 0.25h, 0.5h, 1.0h and 2.0h, and the cumulative dissolution rates of ursolic acid were 0.00%, 18.21%, 19.40% and 33.10% at 0.25h, 0.5h, 1.0h and 2.0 h.
Conclusion:
dissolution is an important functional parameter for evaluating solid formulations and is also an important tool for screening formulation formulations. The solid dispersing agent prepared by the melting method in the embodiment 1-3 and the solid dispersing agent prepared by the solvent method in the embodiment 4-6 in the invention have the cumulative dissolution rate which is obviously higher than that of the rosemary extract and the physical mixture of the raw material and the carrier in the comparative example 1-2 at four time points, wherein when the solid dispersing agent is prepared by the melting method, the mass ratio of the raw material and the carrier in the embodiment 2 is 1:5, the dissolution rate is highest; in the case of the solvent-based solid dispersing agent, the mass ratio of the bulk drug to the carrier in example 6 is 1: at 10, the dissolution rate was highest.
In addition, the solid dispersants prepared by the solvent method in examples 4 to 6 were higher in cumulative dissolution at four time points than the solid dispersants prepared by the melt method in examples 1 to 3. In addition, the cumulative dissolution rate of the solvent-based solid dispersing agent in examples 4 to 6 increased gradually between 1.0h and 2.0h, while the cumulative dissolution rate of the melt-based solid dispersing agent in examples 1 to 3 increased significantly between 1.0h and 2.0h, indicating that the solvent-based solid dispersing agent not only had a higher dissolution rate than the melt-based solid dispersing agent, but also had a faster dissolution rate than the melt-based solid dispersing agent.
In addition to the dissolution rate of the prepared drug, the carrier used in the preparation process is an important factor affecting the dissolution rate. In the present invention, the physical mixture of comparative example 2 has slightly higher cumulative dissolution rate than the physical mixture of comparative example 1 at four time points, which indicates that the dissolution rate of PVP-K30 medium in rosemary extract is better than that in PEG-6000, which may be one of the reasons why the overall dissolution effect of the solvent-based solid dispersant is significantly higher than that of the melt-based solid dispersant.
And II, effect test: effect of rosemary extract solid dispersant on antioxidant Properties of rats
1. Test animals
80 SPF-grade SD rats, male, weighing 140+ -10 g, were purchased from Gekko Biotechnology Inc. Feeding conditions: temperature 25+ -1deg.C, humidity 60+ -10%, 8:00-20:00 light. The pad is replaced once in 2 days, and the food and water can be taken freely.
2. Dosing regimen
The 80 SD male rats were fed adaptively for 3 days before the test, and were uniformly divided into 8 groups according to body weight, namely, group a (blank group), group B (rosemary extract group), group C (low-dose melt solid dispersant group), group D (medium-dose melt solid dispersant group), group E (high-dose melt solid dispersant group), group F (low-dose solvent solid dispersant group), group G (medium-dose solvent solid dispersant group), and group H (high-dose solvent solid dispersant group). Rosemary extract and formulation were made into suspension (ready to use), 9 per day: 00 is orally administered by gastric lavage for 28 days. The gastric lavage doses are shown in table 2.
Table 2 dosing regimen and dosage
3. Sample collection
(1) Blood sample
On the 29 th day of the test, the test animals are subjected to blood sampling, fasted for 12 hours before blood sampling, free drinking water, blood sampling is carried out by using capillary vessels in retrobulbar veins, and after standing for 0.5-1.0h, the test animals are centrifuged for 10 minutes at 12000 rpm, and serum is obtained through separation and is used for detecting antioxidant indexes.
(2) Organ sample
After the test animals were collected on day 29, the test animals were sacrificed, hearts, livers, spleens, lungs, kidneys and testes were collected, cleaned with physiological saline, blotted dry with filter paper, weighed, data recorded and individual organ indexes were calculated from individual organ weights/body weights.
(3) Muscle sample
2cm of the left leg muscle is taken at the same position 3 Left and right muscle tissues for measuring an antioxidant index.
4. Test index
The measurement of oxidation index comprises four items of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-PX), and is detected by adopting a Nanjing building kit. The experiment totally determines four indexes of T-AOC, GSH-PX, SOD and MDA in rat serum, liver and leg muscle.
5. Test results
(1) Index of serum oxidation
The results of the effect of rosemary extract and rosemary extract solid dispersant on the oxidation index in rat serum are shown in figure 4. The medium-dose melt-process, medium-dose solvent-process and serum levels of T-AOC were elevated (p < 0.05) compared to the blank, and the other formulation groups were compared to each other and to the blank without differences (p > 0.05). The GSH-PX content in the serum of the high-dose solvent-based group was elevated compared to the blank (p < 0.05), and the other formulation groups were compared to each other and to the blank (p > 0.05). The SOD content in serum of the low-dose melting method group and the solvent method group is reduced compared with that of the blank group (p < 0.05), and the other preparation group and the rosemary extract group are not different from that of the blank group (p > 0.05). MDA levels in serum were reduced in the medium-dose solvent-based group compared to the blank (p < 0.05), and the other formulation groups were compared to each other and to the blank (p > 0.05).
Note that: as Zhang Tuzhong, all letters are not identical (p < 0.05) and represent significant differences (p > 0.05), as follows.
(2) Index of liver oxidation
The effect of rosemary extract and rosemary extract solid dispersion on the oxidation index in rat liver is shown in figure 5. The high dose solvent based group had elevated T-AOC levels in the liver (p < 0.05) compared to the blank, and the other formulation groups were compared to each other and to the blank without differences (p > 0.05). The GSH-PX content in the liver of the high-dose solvent-based group was elevated compared to the low-dose melt-based group (p < 0.05), and the other formulation groups were compared to each other and to the blank group (p > 0.05). SOD levels in the livers of the medium and low solvent melting groups were elevated compared to the blank (p < 0.05), and the other formulation groups were compared to each other and to the blank (p > 0.05). In addition to the medium-dose melting method, the MDA content in the liver of the preparation group is reduced (p < 0.05) compared with that of the blank group, the MDA content in the liver of the preparation group is lower than that of the rosemary extract group (p < 0.05), and the MDA content in the liver of the medium-dose melting method group is higher than that of other preparation groups (p < 0.05).
(3) Index of leg muscle oxidation
The results of the effect of rosemary extract and rosemary extract solid dispersion on the oxidation index in rat leg muscle are shown in fig. 6. The T-AOC content in the leg muscle was elevated in the high-dose solvent-treated group compared to the high-dose and low-dose solvent-treated groups (p < 0.05), and there was no difference between the other formulation groups compared to each other and to the blank group (p > 0.05). The GSH-PX content in the leg muscles of the medium and high dose fusion groups was elevated (p < 0.05) compared to the blank, rosemary extract groups, and the other formulation groups were compared to each other and to the blank without differences (p > 0.05). The SOD content in the leg muscle of the test group was increased compared to the blank group (p < 0.05), and the other formulation groups were compared to each other and to the blank group without difference (p > 0.05). MDA levels in leg muscles were reduced in the medium and high dose fusion and solvent sets compared to the blank, rosemary extract and low dose fusion sets (p < 0.05), and MDA levels in leg muscles were reduced in the high dose and solvent sets compared to the medium dose fusion sets (p < 0.05).
Conclusion:
the rosemary extract solid dispersing agent changes various oxidation indexes in rats, the serum GSH-PX content, liver T-AOC, SOD content, leg muscle T-AOC, GSH-PX and SOD content of a high-dose solvent method group are increased (p < 0.05) compared with a blank group, and MDA content in the liver and leg muscle is reduced (p < 0.05). Serum T-AOC content, liver SOD content, leg muscle SOD content were increased (p < 0.05) compared to the blank group and leg muscle MDA content was decreased (p < 0.05) in the medium dose fusion group. Serum T-AOC content, leg muscle GSH-PX content were increased (p < 0.05), and MDA content of serum, liver and leg muscle was decreased (p < 0.05) in the medium dose solvent method group. Overall, the high-dose solvent method produces the strongest solid dispersant in terms of antioxidant capacity, the medium-dose solid dispersant is superior to rosemary extract, and the low-dose solid dispersant is partially superior to rosemary extract, which may be related to the solid dispersant improving the dissolution of oleanolic acid and ursolic acid in rosemary extract.
In addition, the invention also researches the influence of the rosemary extract solid dispersing agent on the growth and oxidation resistance of rats, and respectively determines the data of the growth performance, biochemical index, intestinal villus height, crypt depth, organ index and the like of the rats. The results show that the conversion rate of the rat feed is reduced in the medium-high dose melting method group and the high dose solvent method group, the AST, ALT and Cre contents of all preparation groups are reduced (p < 0.05), the jejunum villus height of the low-medium dose group and the medium dose group is increased (p < 0.05), and the rosemary extract solid dispersing agent can protect the liver and improve the glomerular filtration rate to a certain extent, and can also improve the growth performance by improving the villus morphology. The heart, liver, spleen, lung, kidney and testis indexes of the blank group and the test group are all not different (p < 0.05), and no obvious lesions are found in liver and kidney slices, which indicates that the rosemary extract and the solid dispersing agent thereof have no toxic or side effect on main organs such as heart, liver, spleen, lung, kidney and the like under the test dose.
The technical scheme of the invention is not limited to the specific embodiment, and all technical modifications made according to the technical scheme of the invention fall within the protection scope of the invention.

Claims (10)

1. A rosemary solid dispersion comprising a rosemary extract and a carrier, wherein the rosemary extract comprises ursolic acid and oleanolic acid.
2. The solid dispersant according to claim 1, wherein the carrier comprises at least one of polyethylene glycol, polyvinylpyrrolidone, citric acid, tartaric acid, sucrose, mannitol, sorbitol, xylitol, poloxamer and leucine, preferably comprises polyethylene glycol and/or polyvinylpyrrolidone.
3. A solid dispersant according to claim 2, wherein the polyethylene glycol has an average molecular weight of more than 1000, preferably 2000-10000, more preferably 4000-8000; further preferably, the polyethylene glycol is selected from at least one of PEG-2000, PEG-4000, and PEG-6000; and/or the number of the groups of groups,
the average molecular weight of the polyvinylpyrrolidone is 20000-50000, preferably 25000-45000; more preferably, the polyvinylpyrrolidone is selected from polyvinylpyrrolidone K30 and/or polyvinylpyrrolidone K40.
4. A solid dispersion according to any one of claims 1 to 3, characterized in that the mass ratio of rosemary extract to carrier is 1 (1-20), preferably 1 (3-10).
5. The solid dispersion according to any one of claims 1 to 4, wherein the content of ursolic acid is 20 to 40wt% and/or the content of oleanolic acid is 10 to 20wt% based on the total mass of the rosemary extract.
6. A method of preparing the solid dispersant of any one of claims 1 to 5, comprising the steps of:
step a: heating and melting the carrier, mixing with rosemary extract, cooling, solidifying and drying to obtain the solid dispersing agent; or alternatively
Step b: mixing the carrier, rosemary extract and solvent, removing the solvent and drying to obtain the solid dispersing agent.
7. The method according to claim 6, wherein in step a, the heating temperature is 60-100 ℃ and/or the cooling temperature is-30 to-10 ℃;
preferably, in step a, the carrier is polyethylene glycol, more preferably PEG-6000;
preferably, in step b, the solvent is a volatile organic solvent, preferably ethanol;
preferably, in step b, the carrier is polyvinylpyrrolidone, more preferably polyvinylpyrrolidone K30.
8. A pharmaceutical formulation comprising the solid dispersion of any one of claims 1-5 and a pharmaceutically acceptable adjuvant.
9. The formulation of claim 8, wherein the excipients comprise at least one of microcrystalline cellulose, lactose, starch, croscarmellose sodium, magnesium stearate;
preferably, the formulation is in the form of a tablet, powder, pill or capsule.
10. Use of the solid dispersion according to any one of claims 1 to 5 for the preparation of an antioxidant or hypoglycemic agent or hypolipidemic agent.
CN202310657328.XA 2023-06-05 2023-06-05 Rosemary solid dispersing agent and preparation method and application thereof Pending CN116650421A (en)

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