CN115671169A - Composition with sleep improving effect - Google Patents
Composition with sleep improving effect Download PDFInfo
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- CN115671169A CN115671169A CN202211413126.2A CN202211413126A CN115671169A CN 115671169 A CN115671169 A CN 115671169A CN 202211413126 A CN202211413126 A CN 202211413126A CN 115671169 A CN115671169 A CN 115671169A
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a composition with a sleep improving effect, which is prepared from the following raw materials in parts by weight: 1 to 5 parts of peony seed oil, 1 to 5 parts of acer truncatum buge oil and 0.5 to 2.5 parts of vitamin E. Animal experiments prove that the compound obtained by mixing high-purity peony seed oil containing high-purity alpha-linolenic acid and linoleic acid, high-purity arachidonic acid and acer truncatum oil containing nervonic acid and vitamin E in a specific proportion has the effect of improving sleep, and is specifically characterized in that the awakening activity and the total awakening time are reduced, and the relative expression level of mtnr1aa and gabra1 genes is up-regulated. Compared with the single peony seed oil, acer truncatum buge oil and VE, the composition has better efficacy in the aspect of improving sleep, and has practical popularization and application values.
Description
Technical Field
The invention particularly relates to a composition with the effect of improving sleep.
Background
Sleep is an essential element of survival and inadequate sleep can lead to various dysfunctions. According to the world health organization statistics, 27% of people worldwide are suffering from insomnia, and this value is rising. Currently, the sleep problem has become one of the issues of common medical concern. Although the chemical medicine for treating insomnia has been developed rapidly in the last years, the treatment effect is poor due to toxic and side effects and possible dependence effects, for example, melatonin, and the long-term administration not only causes the effect of treating insomnia to be poor, but also causes the sleep rhythm disorder to be aggravated, and even then, neurasthenia can be caused. Therefore, it is very important to develop a pure natural medicine without toxic and side effects and capable of improving sleep quality.
The plant essential oil is a general name of a volatile oily liquid substance with fragrance and/or aroma, which is extracted from flowers, roots, stems, leaves, branches, stems, barks, fruits or secretions of aromatic plants by processes of distillation, dry distillation, extraction, squeezing, adsorption or absorption and the like. The natural plant essential oil contains 696 kinds, such as herba Menthae essential oil, fructus Litseae essential oil, lavender essential oil, and herba Pogostemonis essential oil. The plant essential oil has small molecular weight and certain bioactivity, and can contribute to relieving sleep disorder. Researches prove that the lavender essential oil, the lemon essential oil, the jasmine essential oil, the peony seed oil, the acer truncatum buge oil and the like have good sedative effect, have certain regulating capacity on a nervous system, can relieve the stress and the uneasy symptoms of a body, keep the organism in a relaxed state and improve the sleep, but have poor effect.
At present, no report on the combination of peony seed oil, acer truncatum buge oil and vitamins for improving sleep quality exists.
Disclosure of Invention
In order to solve the problems, the invention provides a composition with the effect of improving sleep, which is prepared from the following raw materials in parts by weight:
1 to 5 parts of peony seed oil, 1 to 5 parts of acer truncatum buge oil and 0.5 to 2.5 parts of vitamin E.
Further, the medicine is prepared from the following raw materials in parts by weight:
1 part of peony seed oil, 1 part of acer truncatum buge oil and 0.5 part of vitamin E.
Furthermore, the relative content of linoleic acid in the peony seed oil is greater than 17%, and the relative content of alpha-linolenic acid is greater than 58%.
Furthermore, the relative content of linoleic acid, arachidonic acid and nervonic acid in the acer truncatum buge oil is more than 30%, 12% and 4%.
Furthermore, the preparation is prepared by taking peony seed oil, acer truncatum buge oil and vitamin E as active ingredients and adding pharmaceutically acceptable auxiliary materials.
Further, the preparation is an external preparation.
Further, the external preparation is a solution, an emulsion, a gel, an aerosol, a coating agent and a emplastrum.
The invention also provides a preparation method of the composition, which comprises the following steps:
1) Weighing the raw materials according to the proportion;
2) Mixing the raw materials, and adding pharmaceutically acceptable adjuvants.
The invention finally provides the use of the aforementioned composition for the preparation of a medicament for improving sleep.
The composition for improving the sleep is prepared by mixing peony seed oil containing high-purity alpha-linolenic acid and linoleic acid, high-purity arachidonic acid and acer truncatum oil containing nervonic acid with vitamin E in a specific proportion, and animal experiments prove that the composition has a remarkable effect of improving the sleep, and is specifically characterized in that the wakefulness activity and the total wakefulness time are both reduced, and the relative expression level of mtnr1aa and gabra1 genes is up-regulated. Compared with the single peony seed oil, the acer truncatum buge oil and VE, the composition has better effect on improving sleep, and has practical popularization and application values.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a typical diagram of the motion trail of zebra fish after sample treatment
FIG. 2 Zebra fish wake activity after sample treatment
FIG. 3 Total time to wake-up of Zebra fish after sample treatment
FIG. 4 relative expression level of mtnr1aa Gene
FIG. 5 relative expression levels of the gabra1 Gene
Detailed Description
Raw materials and equipment used in the specific implementation mode of the invention are known products and are obtained by purchasing commercially available products, wherein the peony seed oil and the acer truncatum oil are obtained by physically squeezing peony seeds and acer truncatum kernels, or performing a supercritical fluid extraction method or a subcritical fluid extraction method to obtain crude peony seed oil and acer truncatum oil, and then performing one or more combined purification and separation methods such as column chromatography, low-temperature crystallization, molecular distillation and the like to obtain high-purity peony seed oil containing alpha-linolenic acid and linoleic acid and acer truncatum oil containing high-content arachidonic acid and nervonic acid. The preparation method comprises the following steps:
preparing peony seed oil:
(1) Drying fresh, clean, mildew-free and insect-free peony seeds at 50-60 ℃, crushing, sieving (40-100 mesh sieve), rolling (20-40 min), drying again (50-60 ℃) for 4-5h, mixing the obtained peony seed powder with an extracting agent n-butane according to a proportion of 1:5, performing subcritical fluid extraction according to the material solute volume ratio (g/mL) to obtain a peony seed-skin extract;
(2) Separating the extract by heating under reduced pressure at 60-70 deg.C under 0.5-1.5Mpa to obtain oily extractive solution, and standing at room temperature for 50-60min to obtain peony seed oil;
(3) Performing primary purification on the peony seed oil after saponification reaction to obtain a saponification reactant (wherein the saponification reaction temperature is 35-55 ℃, and the saponification reaction time is 45-120 min);
(4) Removing ethanol in the saponification reactant by reduced pressure distillation, and then mixing the saponification reactant after alcohol removal with the solvent according to a volume ratio of 1: 2-5, adding a sulfuric acid aqueous solution (with the mass percentage concentration of 4% -8%) to mix and stir, separating an oil phase, washing with water to be neutral, and drying with anhydrous sodium sulfate to obtain mixed fatty acid;
(5) And (2) carrying out melt crystallization on the mixed fatty acid solution to obtain high-purity alpha-linolenic acid, wherein the temperature, the cooling time and the maintaining time of an inner layer and an outer layer in a melt layer crystallizer with a double-layer jacket need to be controlled so as to facilitate the crystallization of the melt layer: controlling the temperature of the outer layer jacket to be reduced to-10 to-35 ℃ within 100-150min, and the temperature of the inner layer jacket to be reduced to-12 to-35 ℃ within 100-150min, and maintaining for 3-6h; collecting mother liquor crystallized in the melting layer to obtain the peony seed oil containing high-purity alpha-linolenic acid and linoleic acid.
Preparation of acer truncatum oil:
(1) Drying fresh, clean, mildew-free and insect-free acer truncatum bunge seed kernels at 50-60 ℃, crushing, sieving (40-100 mesh sieve), rolling (30-40 min), drying again (55-60 ℃) for 3-4h to obtain acer truncatum bunge seed kernel powder and an extracting agent n-butane according to the weight ratio of 1:6, performing subcritical fluid extraction according to the material solute volume ratio (g/mL) to obtain acer truncatum seed extract;
(2) Separating the extract by heating under reduced pressure at 60-75 deg.C under 0.5-1.5Mpa to obtain oily extractive solution, and standing at room temperature for 55-60min to obtain Acer Truncatum Bunge oil;
(3) Mixing Acer truncatum oil according to the weight ratio of 1:2 (g/mL) of potassium hydroxide ethanol solution with the concentration of 2M, uniformly mixing, carrying out water bath reaction at 80 ℃ for 90min, sequentially adding pure water with the volume of 1 time of the product and n-hexane with the volume of 1 time of the product into the product, slightly shaking, standing for layering, removing an upper organic phase, and separating to obtain a lower layer; adding 3M hydrochloric acid solution into the lower layer solution to adjust pH to 1-2, and adding n-hexane 2 times the volume of the lower layer solution for extraction for 2 times. Combining organic phases, washing the organic phases to be neutral by using a small amount of pure water, drying and filtering the organic phases by using anhydrous sodium sulfate, and removing n-hexane by rotary evaporation at the temperature of 45 ℃ to obtain mixed fatty acid;
(4) Mixing the mixed fatty acid solution with ethanol according to a mass volume ratio of 1:3 (g/mL), crystallizing at the low temperature of-40 ℃ for 4-5h, performing suction filtration to obtain crystals, and mixing with the filtrate obtained by removing the ethanol solvent through rotary evaporation to obtain the acer truncatum oil with high content of arachidonic acid and nervonic acid.
The GC-MS analysis results of the fatty acids of the peony seed oil and the acer truncatum buge oil prepared by the process are as follows:
note: the relative fatty acid content is the ratio of the peak area of the fatty acid to the sum of the peak areas of all the components in the GC-MS spectrum.
Example 1 compositions according to the invention
And (3) uniformly mixing 1 part of peony seed oil, 1 part of acer truncatum buge oil and 0.5 part of vitamin E to obtain the compound feed.
Example 2 compositions of the invention
And (3) uniformly mixing 2 parts of peony seed oil, 2 parts of acer truncatum buge oil and 2 parts of vitamin E.
Example 3 compositions of the invention
And (3) uniformly mixing 5 parts of peony seed oil, 5 parts of acer truncatum buge oil and 1.5 parts of vitamin E to obtain the compound feed.
The advantageous effects of the present invention are further illustrated by the following test examples
Test example 1 evaluation of sleep improvement efficacy
Evaluation of sleep improvement efficacy of the invention
The previous animal preliminary test shows that the volume ratio of 2:2: the compound of 1 part of peony seed oil, 1 part of acer truncatum buge oil and 0.5 part of vitamin E is obviously higher than the compound of other dosage proportions in the aspects of the reduction degree of the awakening activity and the awakening total time (P is less than 0.05), so the sleep improvement effect evaluation is carried out by using the composition of 1 part of peony seed oil, 1 part of acer truncatum buge oil and 0.5 part of vitamin E.
1. Detection material
1.1. Sample preparation information
Peony Oil (prepared as in example 1) was heated and then prepared into a 100 μ L/mL stock solution using 10% dmso, and was ready for use.
Positive control: melatonin, white powder, lot No. F1804064, shanghai alatin biochemistry science & technology limited, stored in shade and in the dark. 12.5mg/mL of stock solution was prepared in DMSO and stored at-20 ℃.
1.2. Laboratory animal
The zebra fish are all raised in water for fish culture at 28 ℃ (water quality: 200mg of instant sea salt is added into per 1L of reverse osmosis water, the conductivity is 450-550 mu S/cm, the pH is 6.5-8.5, and the hardness is 50-100 mg/LCaCO 3 ) The fish culture center of the company breeds and provides the fish culture, and the license number for experimental animals is as follows: SYXK (Zhe) 2022-0004, and the feeding management meets the requirements of international AAALAC certification (certification number: 001458).
Wild type AB strain zebrafish, in a natural mated breeding mode. Zebrafish aged 5 days (5 dpf) after fertilization were used for sleep improvement efficacy Maximum Test Concentration (MTC) determination and efficacy evaluation.
1.3. Instruments, consumables and reagents
Dissecting microscopy (SZX 7, OLYMPUS, japan); a CCD camera (VertA 1, shanghai, geosenson vision science and technology ltd, china); precision electronic balances (CP 214, OHAUS, USA); zebrafish behavioral analysis system (Zebra Lab 3.22.3.31, viewpoint, france); general PCR amplification apparatus (T100, BIO-RAD, singapore); fluorescent quantitative PCR instrument (CFX Connect, BIO-RAD, singapore); ultraviolet-visible spectrophotometer (Nanodrop 2000, thermo, USA); microplate mini-centrifuges (BE-6100, china, leibeibel instruments manufacture Co., ltd., haiman); low skirt 96-well plates (clear) (HSP 9601, bio-rad, USA); 6-well plates (Nest Biotech, china); optically adhesive seal B (MSB 1001, bio-rad, USA).
Pentylenetetrazole (PTZ, batch No. A27O8L46880, shanghai-derived PhylloBiotech Co., ltd., china); dimethyl sulfoxide (DMSO, lot No. BCCD8942, sigma, switzerland); absolute ethanol (batch No. 20210107, national chemical group, ltd., china); powerUp TM SYBR TM GreenMasterMix (batch No. 01145665, siemer heyere technologies (china), lithuania); fastKing cDNA first strand synthesis kit (genome removal) (batch No. W0008, tiangen Biochemical technology (Beijing) Ltd., china); RNA-Quick Purification Kit (RNA Rapid extraction Kit) (batch No. 20220101, YIShan Biotech, china).
2. Detection method
2.1.MTC assay
5dpf wild-type AB strain zebrafish were randomly selected in 6-well plates, and 30 fish were treated per well (experimental group). Peony Oil (concentration see table 1) was dosed in water, while a normal control and a model control were set with a volume of 3mL per well. After the treatment is carried out for 24 hours at the temperature of 28 ℃, all experimental groups except a normal control group are dissolved in water and are given PTZ to establish a zebra fish insomnia model. After further treatment at 28 ℃ for 1h, the MTC of the Peony Oil on the model zebra fish was determined.
2.2. Evaluation of sleep improvement efficacy (phenotypic evaluation)
Randomly selecting 5dpf wild type AB strain zebra fish in a 6-well plate with 30 tails per well. Peony Oil (see table 2 for concentration) was administered in water, and a positive control melatonin concentration of 125. Mu.g/mL was added, while a normal control group and a model control group were set, each well having a volume of 3mL. After 24h of treatment at 28 ℃, 10 zebra fish were randomly selected from each experimental group and transferred to a 96-well plate at 1 tail/200 μ L/well. Except for the normal control group, all the other experimental groups are dissolved in water and are given to PTZ to establish a zebra fish insomnia model. Measuring the awakening activity amount and the awakening total time of the zebra fish within 1h by using a behavior analyzer, and evaluating the sleep improvement effect of the Peony Oil according to the statistical analysis result of the indexes; wherein, the waking activity amount refers to the sum of the fast moving distance of the zebra fish within 1h (the low speed is less than 4mm/s, the medium speed is 4-20mm/s, and the fast speed is more than 20 mm/s), and the waking activity time refers to the sum of the fast moving time of the zebra fish within 1 h. Statistical treatment results are expressed as mean ± SE. Statistical analysis was performed using SPSS26.0 software and p <0.05 indicated that the differences were statistically significant. The concentrations of the Peony seed Oil, acer truncatum Oil and VE administered respectively were the same as those of the Peony seed Oil composition (Peony Oil), as follows.
2.3. Evaluation of sleep improving efficacy (Gene)
5dpf wild type AB strain zebrafish was randomly selected in 6-well plates, 30 tails per well. Peony Oil (see table 3 for concentration) was administered in water, and melatonin as a positive control was used at a concentration of 125. Mu.g/mL, while a normal control group and a model control group were set to have a volume of 3mL per well. After the treatment is carried out for 24 hours at the temperature of 28 ℃, all experimental groups except a normal control group are dissolved in water and are given PTZ to establish a zebra fish insomnia model. After the treatment is continued for 1h at the temperature of 28 ℃, the total RNA of each group of zebra fish is extracted by using the RNA rapid extraction kit, and the concentration and the purity of the total RNA are measured by using an ultraviolet-visible spectrophotometer. And (3) taking 2.00 mu g of zebrafish sample total RNA, synthesizing 20.0 mu L of cDNA according to the operation of the cDNA first strand synthesis kit, and detecting the expression of beta-actin, mtnr1aa and gabra1 genes by q-PCR. The relative RNA expression levels of the mtnr1aa and gabra1 genes were calculated using β -actin as an internal control for gene expression. Statistical treatment results are expressed as mean ± SE. Statistical analysis was performed using SPSS26.0 software and p <0.05 indicated that the differences were statistically significant.
3. The result of the detection
3.1.MTC
Under the present experimental conditions, the MTC of the Peony Oil on the model zebrafish was 0.078. Mu.L/mL. See table 1 for details.
Table 1 concentration of sample for improving sleep results (n = 30)
3.2. Evaluation of sleep improvement efficacy (phenotypic evaluation)
In this experimental condition, peony Oil had the effect of improving sleep, as evidenced by a reduction in both the amount of wakefulness activity and the total time of wakefulness. See table 2, fig. 1, fig. 2 and fig. 3 for details.
TABLE 2 sample evaluation of efficacy in improving sleep (n = 10)
P <0.01, p <0.001, compared to model control group
3.3 RNA extraction results and primer sequence information
At the end of the experiment, total RNA of the zebra fish is extracted, the concentration of the RNA and the ratio A260/A280 (table 3) are measured by an ultraviolet-visible spectrophotometer, and the ratio A260/A280 is 1.8-2.2, which shows that the extracted total RNA of the zebra fish has better quality and can be used for the subsequent q-PCR experiment. The primer sequences are shown in Table 4.
TABLE 3 concentration of total RNA and A260/A280 ratio (n = 30)
TABLE 4 primer sequence information
3.4. Evaluation of sleep improving efficacy (Gene)
Under the experimental condition, the Peony Oil has the efficacy of improving sleep, and is specifically characterized in that the relative expression quantity of mtnr1aa and gabra1 genes is up-regulated. See table 5, fig. 4 and fig. 5 for details.
TABLE 5 sample evaluation of efficacy in improving sleep (n = 3)
P <0.05, p <0.01, compared to model control group
(II) evaluation of sleep improvement efficacy of single application of peony seed oil, acer truncatum oil and VE
1. Detection material
1.1. Sample preparation information
The peony seed oil, acer Truncatum Bunge oil and VE were heated respectively and then mixed with 10% DMSO to make 100. Mu.L/mL of mother liquor, which was used as it is.
Positive control: melatonin, white powder, lot No. F1804064, shanghai alatin biochemistry science & technology limited, stored in shade and in the dark. 12.5mg/mL stock solutions were prepared in DMSO and stored at-20 ℃.
1.2 test animals
Same item 1.2, experimental animals "
1.3 instruments, consumables and reagents
In same item 1.3 instruments, consumables and reagents "
2. Detection method
2.1.MTC assay
The specific measurement method was the same as "(2.1. MTC measurement under item (I)"). Under the experimental condition, the MTC of the peony seed oil, the acer truncatum buge oil and the VE is 0.078 mu L/mL respectively. See table 6 for details.
TABLE 6 concentration of sample for improving sleep results (n = 30)
2.2. Evaluation of sleep improvement efficacy (phenotypic evaluation)
The specific measurement method was the same as "(one) item 2.2. Evaluation of sleep improvement efficacy (phenotypic evaluation)". Under the experimental condition, the peony seed oil, the acer truncatum buge oil and the VE all have certain sleep improvement effects, and are particularly characterized in that the wakefulness activity and the total wakefulness time are reduced; however, at the same concentration, they all had less sleep improvement than the Peony seed Oil composition (Peony Oil). See table 7 for details.
TABLE 7 evaluation of efficacy of sample in improving sleep (n = 10)
As compared to model control group, <0.01, <0.001 · p
2.3. Evaluation of sleep improving efficacy (Gene)
The measurement method was the same as "(item 2.3. Evaluation of sleep improvement efficacy (Gene)"). At the end of the experiment, total RNA of the zebra fish is extracted, and the ratio of RNA A260/A280 measured by an ultraviolet-visible spectrophotometer is between 1.8 and 2.2, which shows that the extracted total RNA of the zebra fish has better quality and can be used for the subsequent q-PCR experiment.
Under the experimental condition, the peony seed oil, the acer truncatum buge oil and the VE all have certain sleep improvement effects, and are specifically expressed by up-regulating the relative expression quantity of mtnr1aa genes; however, under the same concentration, the effect of improving sleep is lower than that of a Peony seed Oil composition (Peony Oil), and the relative expression amount of the gabra1 gene is not significantly influenced. See table 8 for details.
TABLE 8 sample evaluation of efficacy in improving sleep (n = 3)
P <0.05, p <0.01, compared to model control group
In conclusion, in the aspect of improving the sleep effect, the effect of independently and respectively administering the Peony seed Oil, the acer truncatum buge Oil and the VE is lower than that of the Peony seed Oil composition (Peony Oil) under the same dosage.
The animal experiment proves that: the Peony seed Oil composition (Peony Oil) has the effect of improving sleep, and is specifically characterized in that the awakening activity and the awakening total time are both reduced, the relative expression quantity of mtnr1aa and gabra1 genes is up-regulated, and the Peony seed Oil composition has better effect in the aspect of improving sleep compared with single Peony seed Oil, acer truncatum buge Oil and VE, and has practical popularization and application values.
Claims (9)
1. A composition having sleep improving effects, characterized in that: the traditional Chinese medicine is prepared from the following raw materials in parts by weight:
1 to 5 parts of peony seed oil, 1 to 5 parts of acer truncatum buge oil and 0.5 to 2.5 parts of vitamin E.
2. The composition of claim 1, wherein: the traditional Chinese medicine is prepared from the following raw materials in parts by weight:
1 part of peony seed oil, 1 part of acer truncatum buge oil and 0.5 part of vitamin E.
3. The composition of claim 1, wherein: the peony seed oil contains more than 17% of linoleic acid and more than 58% of alpha-linolenic acid.
4. The composition of claim 1, wherein: the acer truncatum buge oil contains linoleic acid in relative content higher than 30%, arachidonic acid in relative content higher than 12%, and nervonic acid in relative content higher than 4%.
5. The composition according to any one of claims 1 to 4, characterized in that: the preparation is prepared by taking peony seed oil, acer truncatum buge oil and vitamin E as active ingredients and adding pharmaceutically acceptable auxiliary materials.
6. The composition of claim 5, wherein: the preparation is an external preparation.
7. The composition of claim 6, wherein: the external preparation is solution, emulsion, gel, aerosol, film coating agent and emplastrum.
8. A method of preparing a composition according to any one of claims 1 to 7, wherein: it comprises the following steps:
1) Weighing the raw materials according to the proportion;
2) Mixing the raw materials, and adding pharmaceutically acceptable adjuvants.
9. Use of a composition according to any one of claims 1 to 7 in the manufacture of a medicament for improving sleep.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626227A (en) * | 2012-04-23 | 2012-08-08 | 昆明海之灵生物科技开发有限公司 | Acer truncatum flavone and acer truncatum nervonic acid soft capsules and preparation method thereof |
| CN105994691A (en) * | 2016-05-20 | 2016-10-12 | 洛阳泽达慧康医药科技有限公司 | Method for manufacturing blend oil with peony seed oil and acer truncatum oil |
| CN112386630A (en) * | 2019-08-19 | 2021-02-23 | 淄博鲁祥生物科技有限公司 | Brain-strengthening and intelligence-improving composition and preparation method and medical application thereof |
| CN113577228A (en) * | 2021-07-27 | 2021-11-02 | 株式会社健康事业资讯 | Composition for improving sleep and memory and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102626227A (en) * | 2012-04-23 | 2012-08-08 | 昆明海之灵生物科技开发有限公司 | Acer truncatum flavone and acer truncatum nervonic acid soft capsules and preparation method thereof |
| CN105994691A (en) * | 2016-05-20 | 2016-10-12 | 洛阳泽达慧康医药科技有限公司 | Method for manufacturing blend oil with peony seed oil and acer truncatum oil |
| CN112386630A (en) * | 2019-08-19 | 2021-02-23 | 淄博鲁祥生物科技有限公司 | Brain-strengthening and intelligence-improving composition and preparation method and medical application thereof |
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