CN116688151A - Mixed volatile oil inclusion compound and preparation method thereof - Google Patents
Mixed volatile oil inclusion compound and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 47
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- 238000002156 mixing Methods 0.000 claims abstract description 48
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 40
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 39
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 39
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 39
- 229960004853 betadex Drugs 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 238000000227 grinding Methods 0.000 claims abstract description 21
- 239000000084 colloidal system Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 16
- 239000007787 solid Substances 0.000 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 25
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- 235000001287 Guettarda speciosa Nutrition 0.000 claims description 13
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- 238000010298 pulverizing process Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 4
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- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- 206010027339 Menstruation irregular Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/232—Angelica
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/534—Mentha (mint)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/538—Schizonepeta
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The application discloses a mixed volatile oil inclusion compound and a preparation method thereof, comprising the following steps: beta-cyclodextrin and pure water are mixed according to the mass ratio of 1: uniformly mixing the components (1-3) in proportion to obtain a mixture A; mixing the volatile oil and ethanol according to the mass ratio of 1: uniformly mixing the components in the proportion of (3-5) to obtain a mixture B; uniformly mixing the mixture A and the mixture B, and then grinding the mixture A and the mixture B in a colloid mill for 10-30 min to obtain a ground substance; standing the ground material at 2-10 ℃ for 10-20 h, and centrifuging to obtain a semi-solid inclusion compound; drying and crushing the semi-solid inclusion compound to obtain the volatile oil beta-cyclodextrin inclusion compound. The application optimizes the concentration, the steps, the temperature, the time, the proportion of raw materials and the like of the included dispersing agent in the preparation process of the mixed volatile oil inclusion compound, thereby improving the inclusion rate and the utilization rate of the volatile oil inclusion compound and further improving the stability of the mixed volatile oil inclusion compound.
Description
Technical Field
The application relates to the technical field of volatile oil, in particular to a mixed volatile oil clathrate compound and a preparation method thereof.
Background
Volatile oil refers to the general term for readily flowable oily liquids which are distilled off with water vapor, are water-insoluble, and have a certain fragrance or special odor. Volatile oil has volatility and can volatilize by itself at normal temperature without leaving any trace. The volatile oil has low content in the traditional Chinese medicinal materials, is volatile and unstable, and has quite low actual yield in the preparation process. The method of increasing the dosage is not theoretically preferable either, because the dosage is increased, so that more other components in the medicinal materials are extracted, and the compatibility of the medicinal materials is affected. The volatile oil is a lipophilic substance, plays an important role in the curative effect of the medicine, if the volatile oil is added in a direct spraying mode in the preparation process of the medicine, the stability of the medicine in the storage process can be a certain problem due to the volatility of the volatile oil, meanwhile, the characteristics of part of medicine taking methods are considered, water is required to be uniformly dispersed, the solubility of the effective substance becomes a key point for exerting the biological activity of the effective substance, and the volatile oil has poor water solubility and low bioavailability, so that the clinical use is limited.
Disclosure of Invention
The application provides a mixed volatile oil inclusion compound for different densities and a preparation method thereof, which are used for solving the technical problems of limited clinical use of volatile oil and low inclusion rate of the mixed volatile oil.
According to one aspect of the application, there is provided a method of preparing a mixed volatile oil clathrate, comprising the steps of:
beta-cyclodextrin and pure water are mixed according to the mass ratio of 1: uniformly mixing the components (1-3) in proportion to obtain a mixture A;
mixing the volatile oil and ethanol according to the mass ratio of 1: uniformly mixing the components in the proportion of (3-5) to obtain a mixture B;
uniformly mixing the mixture A and the mixture B, and then grinding the mixture A and the mixture B in a colloid mill for 10-30 min to obtain a ground substance, wherein the mass ratio of the mixed volatile oil to the beta-cyclodextrin is 1: (6-8); the grinding temperature is 30-40 ℃; the grinding rotating speed is 2000-3000 rpm;
standing the ground material at 2-10 ℃ for 10-20 h, and centrifuging to obtain a semi-solid inclusion compound;
drying and crushing the semi-solid inclusion compound to obtain the volatile oil beta-cyclodextrin inclusion compound.
Further, the mixed volatile oil is composed of any two of angelica volatile oil, fingered citron volatile oil, mint volatile oil and schizonepeta volatile oil.
Further, the volatile oil comprises mixed volatile oil of angelica and fingered citron or mixed volatile oil of mint and schizonepeta.
Further, the preparation method of the angelica and fingered citron mixed volatile oil comprises the following steps: mixing the angelica and the fingered citron in a mass ratio of 1:0.5-1.5, and carrying out steam distillation extraction to obtain the mixed volatile oil of the angelica and the fingered citron.
Further, the preparation method of the mint-schizonepeta mixed volatile oil comprises the following steps: mixing mint and schizonepeta in the mass ratio of 1:0.5-1.5, and carrying out steam distillation extraction to obtain mint-schizonepeta mixed volatile oil.
Further, the mass percentage of the ethanol is 90-98%.
Further, the centrifugal treatment rotating speed is 1800-2000 rpm; the centrifugation time is 10-30 min.
Further, the drying temperature is 50-60 ℃; the drying time is 6-10 h.
Further, the crushing treatment further comprises sieving treatment.
According to another aspect of the application, there is also provided a mixed volatile oil clathrate prepared by the above preparation method of the mixed volatile oil clathrate.
The application has the following beneficial effects:
the preparation method of the mixed volatile oil clathrate compound provided by the application adopts ethanol with proper concentration as a dispersing agent, the volatile oil is diluted in advance, and then the volatile oil is clathrated by beta-cyclodextrin. In the preparation process, the inclusion step, the inclusion temperature, the inclusion time and the proportion of raw materials are optimized, so that proper inclusion conditions are obtained, the loss caused by volatile oil volatilization in the preparation process of the inclusion compound is reduced, the inclusion rate and the utilization rate of the mixed volatile oil inclusion compound are improved, and the stability of the volatile oil inclusion compound is further improved. The results of the examples show that the prepared inclusion compound of the mixed volatile oil is still stable in properties after being placed for 24 months at the temperature of 18+/-2 ℃ and the relative humidity of 60% +10%.
Detailed Description
In order to make the objects, technical solutions and advantageous technical effects of the present application clearer, the present application will be further described in detail with reference to examples. It should be understood that the examples described in this specification are for the purpose of illustrating the application only and are not intended to limit the application.
For simplicity, only a few numerical ranges are explicitly disclosed herein. However, any lower limit may be combined with any upper limit to form a range not explicitly recited; and any lower limit may be combined with any other lower limit to form a range not explicitly recited, and any upper limit may be combined with any other upper limit to form a range not explicitly recited. Furthermore, each point or individual value between the endpoints of the range is included within the range, although not explicitly recited. Thus, each point or individual value may be combined as a lower or upper limit on itself with any other point or individual value or with other lower or upper limit to form a range that is not explicitly recited.
In the description herein, unless otherwise indicated, "above" and "below" are intended to include the present number, "one or more" means two or more, and "one or more" means two or more.
According to one aspect of the application, there is provided a method of preparing a mixed volatile oil clathrate, comprising the steps of:
beta-cyclodextrin and pure water are mixed according to the mass ratio of 1: uniformly mixing the components (1-3) in proportion to obtain a mixture A;
mixing the volatile oil and ethanol according to the mass ratio of 1: uniformly mixing the components in the proportion of (3-5) to obtain a mixture B;
uniformly mixing the mixture A and the mixture B, and then grinding the mixture A and the mixture B in a colloid mill for 10-30 min to obtain a ground substance, wherein the mass ratio of the mixed volatile oil to the beta-cyclodextrin is 1: (6-8); the grinding temperature is 30-40 ℃; the grinding rotating speed is 2000-3000 rpm;
standing the ground material at 2-10 ℃ for 10-20 h, and centrifuging to obtain a semi-solid inclusion compound;
drying and crushing the semi-solid inclusion compound to obtain the volatile oil beta-cyclodextrin inclusion compound.
Inclusion refers to the technique in which one molecule is embedded within the hole structure of another molecule to form an inclusion compound. The inclusion compound is formed by adding two components of a host molecule and a guest molecule, wherein the host molecule has a larger cavity structure, which is enough for accommodating the guest molecule therein to form an ascone. After being included as guest molecules, the medicine has increased solubility and stability, and the liquid medicine can be powdered, so that volatile components can be prevented from volatilizing, bad smell or taste of the medicine can be covered, the medicine release speed can be regulated, the bioavailability of the medicine can be improved, the irritation and toxic and side effects of the medicine can be reduced, and the like.
The volatile oil is clathrated with beta-cyclodextrin, and the obtained volatile oil clathrate is added into the preparation, so that on one hand, the water solubility of the volatile oil can be improved, on the other hand, the volatile oil is prevented from volatilizing and oxidizing, and the stability of volatile components is enhanced, thereby ensuring the accuracy of the formula in the preparation and further ensuring the clinical curative effect of the medicine.
For inclusion of mixed volatile oil, because some volatile oil belongs to heavy oil, some volatile oil is light oil, the effective components in the traditional Chinese medicine compound preparation are often compositions, and the physicochemical properties and molecular structures of each composition have large differences, which are direct factors influencing the inclusion effect. The inclusion effect is only better if the physical and chemical properties, molecular size and shape of the guest are adapted to the space requirements provided by the host. The application adopts ethanol as dispersant to dilute the volatile oil in advance, and then uses beta-cyclodextrin to carry out inclusion. In the preparation process of the volatile oil inclusion compound, the inclusion step, the inclusion temperature, the inclusion time and the proportion of raw materials are optimized, so that proper inclusion conditions are obtained, the loss caused by volatile oil volatilization in the preparation process of the inclusion compound is reduced, the inclusion rate and the utilization rate of the volatile oil inclusion compound are improved, and the stability of the volatile oil inclusion compound is further improved.
In the embodiment of the application, the preparation method of the mixed volatile oil inclusion compound comprises the following steps:
taking beta-cyclodextrin with the mass of 6-8 times of the mixed volatile oil, adding purified water with the mass of 1-3 times of the beta-cyclodextrin, and uniformly mixing to obtain A; collecting volatile oil, and mixing the volatile oil with the volatile oil: adding 90% -98% ethanol in the ratio of 1:3-1:5, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 10-30 min (colloid mill rotating speed 2000-3000 rpm, temperature 30-40 deg.C), standing in cold storage (temperature: 2-10 deg.C) for 10-20 hr, high-speed centrifuging, rotating speed: centrifuging for 10-30 minutes at 1800-2000 rpm/50 hz, and collecting the obtained semi-solid inclusion compound; drying at 50-60 deg.c for 6-10 hr, crushing in universal crusher, sieving with 80 mesh sieve to obtain volatile oil beta-cyclodextrin clathrate. The clathrate yield (%) was calculated as follows:
the beta-cyclodextrin is uniformly mixed by purified water, so that beta-cyclodextrin molecules are fully dispersed, sufficient space is provided for an inclusion process, inclusion is more sufficient, and the volatile oil is dispersed by ethanol similarly, but different dispersing agents are selected according to different polarities of the beta-cyclodextrin molecules; the colloid mill is adopted for low-temperature grinding, so that small molecules of the volatile oil are fully embedded into holes of the beta-cyclodextrin, the volatile oil volatilization can be reduced in the process, the volatile oil inclusion rate is improved, the inclusion time can be obviously shortened by adopting the colloid mill, and the traditional method is that a magnetic stirrer is adopted, so that the inclusion time is long and the inclusion rate is low. The grinding speed is not too fast or too slow, and the inclusion is insufficient due to too slow; refrigerating is a process for fully fusing volatile oil small molecules and cyclodextrin; centrifuging, drying, and pulverizing to obtain clathrate, which can be directly added into granule without preparation process, thereby reducing volatile oil loss.
In some embodiments, the mixed volatile oil is composed of any two of angelica volatile oil, fingered citron volatile oil, mint volatile oil, and schizonepeta volatile oil.
The clathrate of the mixed volatile oil has very wide application, for example, the mixed volatile oil of mint and schizonepeta in the Ligusticum wallichii tea granule is a lipophilic substance, plays an important role in the curative effect of the medicine, and can not only disperse pathogenic wind, but also clear the head and eyes. The volatile oil of radix Angelicae sinensis has effects of preventing miscarriage, replenishing blood, promoting blood circulation, and relieving spasm. In addition, the angelica sinensis has the effects of enriching and activating blood, the angelica sinensis volatile oil can be properly taken when people suffer from anemia, so that the symptoms of anemia can be improved as soon as possible, and when people suffer from symptoms of blood stasis, the angelica sinensis volatile oil can be properly taken, so that the effect of improving blood circulation is achieved. The angelica volatile oil can also relieve some muscle spasms, such as dysmenorrhea occurring in women during menstrual period, and can be taken in proper amount during irregular menstruation, so as to effectively improve uncomfortable symptoms. Whereas the mixed volatile oil of Chinese angelica and fingered citron can be used as a gynecological preparation for tonifying qi and blood, stopping bleeding and regulating menstruation.
Examples
The present disclosure is more particularly described in the following examples that are intended as illustrations only, since various modifications and changes within the scope of the present disclosure will be apparent to those skilled in the art. Unless otherwise indicated, all parts, percentages, and ratios reported in the examples below are by weight, and all reagents used in the examples are commercially available or were obtained synthetically according to conventional methods and can be used directly without further treatment, as well as the instruments used in the examples.
Example 1
Extracting volatile oil: mixing herba Menthae and herba Schizonepetae at a mass ratio of 2:1, and steam distilling to obtain herba Menthae and herba Schizonepetae mixed volatile oil 6kg.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 20 min (colloid mill rotation speed 2800rpm, temperature 35 deg.C), standing in cold storage (temperature: 3-5 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 50-55 deg.c for 8 hr, crushing in universal crusher with main shaft rotation speed 3200rpm, sieving with 80 mesh sieve to obtain volatile oil beta-cyclodextrin clathrate of 53.66g and volatile oil clathrate yield of 99.4%.
Example 2
Extracting volatile oil: mixing radix Angelicae sinensis and fructus Citri Sarcodactylis at a mass ratio of 2:1, and steam distilling to obtain 2kg of mixed volatile oil of radix Angelicae sinensis and fructus Citri Sarcodactylis.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 20 min (colloid mill rotation speed 2800rpm, temperature 35 deg.C), standing in cold storage (temperature: 3-5 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 50-55deg.C for 10 hr, pulverizing with universal pulverizer (main shaft rotation speed 3200 rpm), sieving with 80 mesh sieve to obtain 17.85kg of volatile oil beta-cyclodextrin clathrate, and the yield of volatile oil clathrate is 99.2%.
Example 3
Extracting volatile oil: mixing radix Angelicae sinensis and fructus Citri Sarcodactylis at a mass ratio of 2:1, and steam distilling to obtain 2kg of mixed volatile oil of radix Angelicae sinensis and fructus Citri Sarcodactylis.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 18 min (colloid mill rotation speed 2500rpm, temperature 35 deg.C), standing in cold storage (temperature: 3-5 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 50-55 deg.c for 10 hr, crushing in universal crusher with main shaft rotation speed 3200rpm, sieving with 80 mesh sieve to obtain volatile oil beta-cyclodextrin clathrate 17.28kg with volatile oil clathrate yield of 98.0%.
Example 4
Extracting volatile oil: mixing herba Menthae and herba Schizonepetae at a mass ratio of 2:1, and steam distilling to obtain herba Menthae and herba Schizonepetae mixed volatile oil 6kg.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 20 min (colloid mill rotation speed 2800rpm, temperature 35 deg.C), standing in cold storage (temperature: 3-5 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 55-60deg.C for 6 hr, pulverizing with universal pulverizer (spindle rotation speed 3200 rpm), sieving with 80 mesh sieve to obtain volatile oil beta-cyclodextrin clathrate 52.64kg, and volatile oil clathrate yield 98.5%.
Comparative example 1
Extracting volatile oil: mixing herba Menthae and herba Schizonepetae at a mass ratio of 2:1, and steam distilling to obtain herba Menthae and herba Schizonepetae mixed volatile oil 6kg.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 20 min (colloid mill rotation speed 2800rpm, temperature 35 deg.C), standing in cold storage (temperature: 12-15 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 55-60deg.C for 6 hr, pulverizing with universal pulverizer (spindle rotation speed 3200 rpm), sieving with 80 mesh sieve to obtain volatile oil beta-cyclodextrin clathrate 30.44kg with a yield of 92.48%.
Comparative example 2
Extracting volatile oil: mixing radix Angelicae sinensis and fructus Citri Sarcodactylis at a mass ratio of 2:1, and steam distilling to obtain 2kg of mixed volatile oil of radix Angelicae sinensis and fructus Citri Sarcodactylis.
Taking 8 times of beta-cyclodextrin in the mixed volatile oil, adding 2 times of purified water of the beta-cyclodextrin, and uniformly mixing to obtain A; and adding 95% ethanol into the volatile oil according to the ratio of 1:4, and uniformly mixing to obtain B. Mixing A and B, pouring into colloid mill, circularly grinding for 40 min (colloid mill rotation speed 1800rpm, temperature 35 deg.C), standing in cold storage (temperature 3-5 deg.C) for 18 hr, centrifuging at high speed, and rotating: centrifugation at 1900 rpm/50 hz power for 20 min, and collecting the semi-solid clathrate; drying at 50-55deg.C for 10 hr, pulverizing with universal pulverizer (spindle rotation speed 3200 rpm), sieving with 80 mesh sieve to obtain 13.14kg of volatile oil beta-cyclodextrin clathrate, and the yield of volatile oil clathrate is 73.0%.
And (3) investigating the stability of the inclusion compound:
the stability of the prepared inclusion compound is greatly enhanced by adopting the inclusion process conditions. Stability test: the inclusion compound of example 2 and comparative example 1 was subjected to stability investigation and comparison study by adopting an acceleration test and a long-term test method with reference to the requirements under the stability test item of the traditional Chinese medicine of the new medicine approval method. The results show that the stability of the product of the application is obviously better than that of other comparative examples in the 6-month acceleration test and the 24-month long-term stability test.
1. Test method
Acceleration test: referring to the requirements under the stability test items, a sample retention observation method is adopted, a proper amount of inclusion compound (example 2 and comparative example 1) is taken, the inclusion compound is placed for 6 months under the conditions of the temperature of 40 ℃ plus or minus 2 ℃ and the relative humidity of 75% plusor minus 5%, and is inspected once a month of 1, 2, 3 and 6, and compared with the detection result of 0 month, and the result is shown in table 1.
Long-term test: referring to the requirements under the stability test item, adopting a sample retention observation method, taking a proper amount of the inclusion compound of the embodiment 2, placing the inclusion compound for 24 months under the conditions of 60% +10% of relative humidity and 3 rd, 6 th, 9 th, 12 th, 18 th and 24 th months for examination once monthly, wherein the temperature is 18+/-2 ℃ and the stability test is carried out under the conditions of selecting the cool preservation condition by taking the change of menthol thin layer chromatographic spots under the normal temperature preservation condition into consideration; and comparing with the detection result of 0 month.
2. Measurement method
Taking 0.1g of the inclusion compound of the example 1 or the comparative example 1, grinding, placing into a conical flask with a plug, adding 20ml of diethyl ether, sealing, shaking, performing ultrasonic treatment in an ice bath for 20 minutes, filtering, and volatilizing the filtrate to about 1ml to obtain a test solution. And adding ethanol into appropriate amount of menthol (i.e. menthol) reference substance to obtain solution containing 0.5mg per 1ml as reference substance solution. According to thin layer chromatography (appendix VI B of Chinese pharmacopoeia 2020 edition), 10 μl of each of the above two solutions was absorbed, respectively spotted on the same silica gel G thin layer plate, developed with toluene-ethyl acetate (17:3) as developing agent, taken out, air-dried, sprayed with 5% vanillin sulfuric acid solution, and baked at 105deg.C until the spot color is clear. Spots of the same color appear in the sample chromatogram at positions corresponding to those of the control chromatogram.
An appropriate amount of inclusion compound of example 2 or comparative example 2 was taken, and 1ml of ethanol was added thereto and shaken to dissolve the inclusion compound, thereby obtaining a sample solution. 1g of each of the Chinese angelica and the fingered citron reference medicinal materials is prepared into a medicinal material solution. According to the test of the thin-layer chromatography operation procedure, 10-20 μl of the sample solution is sucked, 5 μl of each of the angelica and fingered citron control medicinal material solutions is respectively spotted on the same silica gel G thin-layer plate, and n-hexane is used for preparing the sample solution: ethyl acetate (9:1) is used as a developing agent, developed, dried in the sun and inspected under an ultraviolet lamp (365 nm). In the chromatogram of the test sample, fluorescent spots with the same color appear at the positions corresponding to the chromatogram of the control medicinal material.
3. Test results
Acceleration test: example 2 was left for 6 months at a temperature of 40 ℃ plus 2 ℃ and a relative humidity of 75% ± 5%, spots of the same color were detected at positions corresponding to the chromatogram of the control for 0, 1, 2, 3, 6 months, indicating that the preparation was stable. The comparative example product showed spots of the same color at 0 and 1 month, but not at 2 months. The specific results are shown in the following table.
TABLE 1 stability test results
Long-term test: the same color spots were detected at the positions corresponding to the chromatogram of the control for 0, 3, 6, 9, 12, 18, and 24 months when the samples of example 1, example 2, and comparative example 2 were left at a temperature of 18.+ -. 2 ℃ and a relative humidity of 60% +10% for 24 months, indicating that the preparation was stable. The product of comparative example 1 was not detected at 6 months.
It can be seen that the standing temperature of the refrigerator mainly influences the stability of the mixed volatile oil inclusion compound, and the grinding condition mainly influences the inclusion rate of the mixed volatile oil inclusion compound.
While the application has been described with reference to a preferred embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the application, and in particular, the technical features set forth in the various embodiments may be combined in any manner so long as there is no structural conflict. The present application is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions falling within the scope of the claims.
Claims (10)
1. The preparation method of the mixed volatile oil clathrate compound is characterized by comprising the following steps:
beta-cyclodextrin and pure water are mixed according to the mass ratio of 1: uniformly mixing the components (1-3) in proportion to obtain a mixture A;
mixing the volatile oil and ethanol according to the mass ratio of 1: uniformly mixing the components in the proportion of (3-5) to obtain a mixture B;
uniformly mixing the mixture A and the mixture B, and then grinding the mixture A and the mixture B in a colloid mill for 10-30 min to obtain a ground substance, wherein the mass ratio of the mixed volatile oil to the beta-cyclodextrin is 1: (6-8); the grinding temperature is 30-40 ℃; the grinding rotating speed is 2000-3000 rpm;
standing the ground material at 2-10 ℃ for 10-20 h, and centrifuging to obtain a semi-solid inclusion compound;
drying and crushing the semi-solid inclusion compound to obtain the volatile oil beta-cyclodextrin inclusion compound.
2. The method for preparing the mixed volatile oil clathrate according to claim 1, wherein the mixed volatile oil is composed of any two of angelica volatile oil, fingered citron volatile oil, peppermint volatile oil, and schizonepeta volatile oil.
3. The method for preparing the mixed volatile oil clathrate according to claim 2, wherein the volatile oil comprises mixed volatile oil of angelica and fingered citron or mixed volatile oil of mint and schizonepeta.
4. The method for preparing the mixed volatile oil clathrate of claim 3, wherein the method for preparing the mixed volatile oil of angelica and fingered citron comprises the following steps: mixing the angelica and the fingered citron in a mass ratio of 1:0.5-1.5, and carrying out steam distillation extraction to obtain the mixed volatile oil of the angelica and the fingered citron.
5. The method for preparing the mixed volatile oil clathrate according to claim 3, wherein the method for preparing the mixed volatile oil of herba Menthae schizonepetae comprises the following steps: mixing mint and schizonepeta in the mass ratio of 1:0.5-1.5, and carrying out steam distillation extraction to obtain mint-schizonepeta mixed volatile oil.
6. The method for preparing the mixed volatile oil clathrate according to claim 1, wherein the mass percentage of the ethanol is 90-98%.
7. The method for preparing the mixed volatile oil clathrate according to claim 1, wherein the centrifugal processing rotation speed is 1800-2000 rpm; the centrifugation time is 10-30 min.
8. The method for preparing the mixed volatile oil clathrate according to claim 1, wherein the drying temperature is 50-60 ℃; the drying time is 6-10 h.
9. The method for preparing the clathrate of mixed volatile oil according to claim 1, wherein the pulverizing treatment further comprises sieving treatment.
10. A mixed volatile oil clathrate produced by the method for producing a mixed volatile oil clathrate according to any one of claims 1 to 9.
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