CN114533667A - Silybin nanosuspension, freeze-dried preparation and preparation method thereof - Google Patents

Silybin nanosuspension, freeze-dried preparation and preparation method thereof Download PDF

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CN114533667A
CN114533667A CN202210252432.6A CN202210252432A CN114533667A CN 114533667 A CN114533667 A CN 114533667A CN 202210252432 A CN202210252432 A CN 202210252432A CN 114533667 A CN114533667 A CN 114533667A
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silybin
stabilizer
nanosuspension
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freeze
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刘喜纲
张领
程佳慧
常金花
刘沛
王汝兴
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Chengde Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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

Abstract

The invention relates to a silybin nano suspension, a freeze-dried preparation and a preparation method thereof, wherein the silybin nano suspension comprises silybin, a stabilizer and water, the mass ratio of the silybin to the stabilizer is 1-10: 1, the stabilizer is a composition of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and sodium dodecyl sulfate, and the mass ratio of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer to the sodium dodecyl sulfate is 1-5: 1-5. The invention optimizes the particle size of the nano-medicament by adjusting the composition, the preparation method and the parameters of the stabilizer, and the finally prepared silybin nano-suspension obviously improves the dissolution rate and the bioavailability of the insoluble bulk drug silybin.

Description

Silybin nanometer suspension, freeze-dried preparation thereof and preparation method
Technical Field
The invention belongs to the technical field of silybin pharmaceutical preparations, and particularly relates to a silybin nano suspension, a freeze-dried preparation and a preparation method thereof.
Background
Silibinin (Sy) is extracted and separated from Silybum marianum fruit of Compositae, belongs to flavone lignin compounds, and has effects of promoting recovery of damaged cell membrane, protecting normal liver cell, etc., and has low toxicity and slight adverse reaction. The liver protection mechanism is that a layer of protective film is formed on liver cells to block toxic substances, reduce the chance that the liver cells are damaged by free radicals, stimulate the synthesis of protein to promote the repair of the liver cells and promote the regeneration of the cells, and the like.
Silybin belongs to BBS II medicines, has poor water solubility and low bioavailability, and greatly limits the application of the Silybin. The slightly soluble drug can increase the surface area of the drug by reducing the particle size of the drug, thereby increasing the dissolution rate. Nanosuspension (NS) is a solution in which a small amount of surfactant is added and the drug particles are stabilized in a dispersion formed by suitable techniques. In the preparation of NS, it is necessary to use a proper amount of a stabilizer to reduce the aggregation speed of particles and to select a suitable preparation method. In addition, the nanosuspension needs to be solidified after being prepared, the nanosuspension is generally solidified by adopting a freeze drying method, and a freeze-drying protective agent needs to be added in order to prevent the silybin nanosuspension from agglomerating in the freeze drying process. Different stabilizer compositions, different preparation methods and freeze-drying protective agents have great influence on the stability, the medicine dissolution and the bioavailability of the nano-medicine. Therefore, the search for suitable stabilizers, preparation methods and lyoprotectants is crucial for the preparation of silybin nanosuspensions with good clinical application prospects.
Disclosure of Invention
The first purpose of the invention is to provide a silybin nanosuspension, which is prepared by adopting a specific ionic stabilizer combined with a non-ionic stabilizer as a stabilizer in a proper weight ratio, wherein the stabilizer can be adsorbed on the surface of a drug nanocrystal, and can effectively prevent particles from aggregating by providing the combined action of sufficient steric hindrance and electrostatic repulsive force, so that the silybin nanosuspension has better stability.
The silybin nano suspension comprises silybin, a stabilizer and water, wherein the mass ratio of the silybin to the stabilizer is 1-10: 1, the stabilizer is a composition of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus) and Sodium Dodecyl Sulfate (SDS), and the mass ratio of the soluplus to the SDS is 1-5: 1-5. Preferably, the mass ratio of the silybin to the stabilizer is 10:1, and the mass ratio of the soluplus to the SDS is 1: 5.
The second purpose of the invention is to provide a preparation method of the silybin nanosuspension. The preparation method is an anti-solvent precipitation method.
The method for preparing the silybin nanosuspension by the anti-solvent precipitation method comprises the following steps: (1) dissolving a stabilizer in water to obtain a water phase; dissolving silybin in an organic solvent to obtain an organic phase; (2) under the action of ultrasonic pulverization, organic phase is dropped into water phase, and after the organic phase is completed, the organic solvent is removed, so that the silybin nano suspension is obtained. Preferably, in the step (1), the organic solvent is absolute ethyl alcohol, and the volume ratio of the absolute ethyl alcohol to the water is 1: 7-10; in the step (2), a cell ultrasonic crusher is adopted for ultrasonic crushing, the ultrasonic power is 65-260w, and the ultrasonic time is 7-31 min.
The third purpose of the invention is to provide a freeze-dried preparation prepared by the silybin nanosuspension. The freeze-dried preparation is prepared by the following method: adding a freeze-drying protective agent into the silybin nano suspension, and freeze-drying to obtain the silybin nano suspension. The freeze-drying protective agent is preferably mannitol, and the addition amount of the mannitol is 5% of the weight of the silybin nanosuspension.
The invention has the beneficial effects that:
1. according to the silybin nanosuspension, the soluplus and the SDS are used as stabilizers in a specific ratio, wherein the soluplus is used as a nonionic surfactant, and the soluplus occupies growth sites of crystals to inhibit the crystal growth so as to provide a space stabilizing effect for preparing the silybin nanosuspension. SDS is ionic surfactant, its toxicity and irritation are lower than cationic surfactant, it is easy to dissolve in water, and it is good in compatibility with non-ionic surfactant, and can form electrostatic layer on the surface of medicine, and can prevent medicine molecule from aggregating and settling by means of electrostatic repulsion, and when it is used together with sodium sulfate, it can better inhibit Ostwald ripening phenomenon, and can make sample grain size smaller and more stable.
2. The preparation method of the silybin nanosuspension is simple and easy to operate, has good reproducibility, and further improves the dissolution rate and bioavailability of the raw material medicine. Early tests show that the dissolution rate of the silybin nanosuspension prepared by the preparation method is 1.3-2 times of that of a silybin bulk drug, and the bioavailability is 4.47 times of that of the bulk drug.
3. The freeze-dried preparation prepared from the silybin nanosuspension improves the chemical and physical stability of the silybin nanosuspension, optimizes the type and dosage proportion of the freeze-drying protective agent in the preparation process of the freeze-dried preparation, and ensures that the particle size change before and after freeze-drying is small, and the prepared nano freeze-dried powder has good appearance and shape, high drug content and good re-solubility.
Drawings
FIG. 1 is a blood concentration-time curve of silibinin;
FIG. 2 is a graph showing the cumulative dissolution profile of Sy-NS in a pH4.5 aqueous solution containing 0.2% SDS;
FIG. 3 is a graph of the cumulative dissolution profile of Sy-NS in an aqueous solution containing 0.2% SDS;
fig. 4 shows the effect of different lyoprotectants on particle size (x ± s, n ═ 3);
fig. 5 shows the effect of different lyoprotectants on PDI (x ± s, n ═ 3).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
The apparatus and the materials involved in the following examples and experiments were as follows: ultrasonic cell crusher (Ningbo Xinzhi Biotechnology Co., Ltd.), FSH-2 high-speed dispersion homogenizer (Vician instruments manufacturing Co., Ltd., Changzhou), HJ-6 multi-head magnetic stirrer (Jiangsu Ke analysis instruments Co., Ltd.), RB806 dissolution tester (Tiandakuchen technology Co., Ltd.), ZEN3690 Malvern particle size analyzer (Malvern, UK), LGJ-220 type freeze dryer (Beijing Tekko instruments Co., Ltd.), AH-2010 high-pressure homogenizer (AST Industrial systems Co., Ltd.), Agilent1260 type high-performance liquid chromatograph (Agilen, USA). Silibinin bulk drug (Ginko, Kingtai area Kerui instrument Cantor part, batch number: HS236834198), Silibinin reference substance (Dode Philippine Biotechnology Co., Ltd., batch number: 170503), Soluplus (BASF, Germany), SDS (St. Suzuki chemical research institute), glucose (Tekken chemical Co., Ltd., Tianjin Co., Mimi), mannitol (Tekken Biotechnology Co., Ltd.), methanol (chromatographic purity, Fisher Technology Inc, USA), and glacial acetic acid (chromatographic purity, Fisher Technology Inc, USA).
Example 1
Weighing 10mg of silybin bulk drug (Sy), adding 1mL of absolute ethyl alcohol, and ultrasonically dissolving to obtain a silybin absolute ethyl alcohol solution; weighing 1.00mg of stabilizer (soluplus: SDS ═ 1:5) and dissolving in 7mL of pure water to obtain a stabilizer solution, dropwise adding the silybin absolute ethanol solution into the stabilizer solution under the action of a cell ultrasonic pulverizer (65w ultrasonic for 31min) to uniformly disperse, and performing rotary evaporation on the obtained suspension in a rotary evaporator until no alcohol smell exists to obtain the silybin nano suspension. Adding 5% mannitol into the silybin nanometer suspension, and freeze-drying for 48h to obtain silybin nanometer freeze-dried powder.
Example 2
Weighing 10mg of silybin bulk drug (Sy), adding 1mL of absolute ethyl alcohol, and ultrasonically dissolving to obtain a silybin absolute ethyl alcohol solution; weighing 2.00mg of stabilizer (soluplus: SDS ═ 1:5) and dissolving in 10mL of pure water to obtain a stabilizer solution, dropwise adding the silybin absolute ethanol solution into the stabilizer solution under the action of a cell ultrasonic pulverizer (65w ultrasonic for 31min) to uniformly disperse, and performing rotary evaporation on the obtained suspension in a rotary evaporator until no alcohol smell exists to obtain the silybin nano suspension. Adding 5% mannitol into the silybin nanometer suspension, and freeze-drying for 48h to obtain silybin nanometer freeze-dried powder.
The silybin nano-suspension and the silybin nano-freeze-dried powder prepared in the embodiment 1-2 are respectively taken to measure the particle size and PDI. The results are shown in the following table.
Table 1 silybin nanosuspensions (x ± s, n ═ 3)
Figure BDA0003547303990000041
Figure BDA0003547303990000051
TABLE 2 Silybin nanometer lyophilized powder (x + -s, n ═ 3)
Figure BDA0003547303990000052
Test example 1 screening of stabilizer
1.1 preparation of Silibinin nanometer suspension (Sy-NS-G) by high-pressure homogenization method, putting 60ml purified water into 100ml beaker, precisely weighing a certain amount of stabilizer, adding into the beaker, stirring with magnetic stirrer until dissolved, then adding a certain amount of Silibinin, continuing stirring to mix Silibinin and stabilizer thoroughly, pre-dispersing for 20min at 6000r/min in high-speed dispersion homogenizer, placing the obtained mixture into high-pressure homogenizer, homogenizing under a certain pressure for a certain time, controlling the temperature of cold trap at-18 deg.C to obtain Sy-NS-G.
1.2 preparation of Silybin nanometer suspension (Sy-NS-F) by anti-solvent precipitation method, 10mg of Silybin (Sy) raw material drug is weighed and put into an EP tube, 1ml of absolute ethyl alcohol is added for ultrasonic dissolution to be used as an organic phase, a formula amount of stabilizer is weighed and dissolved in pure water to be used as a water phase, the organic phase is dropped into the water phase under the action of a cell ultrasonic crusher, suspension obtained by ultrasonic treatment at a certain power for a certain time is subjected to rotary evaporation on a rotary evaporator until no alcohol smell exists, and the Sy-NS-F is obtained.
1.3 screening of spatial type stabilizer poloxamer 407, HPMBE5, TPGS, soluplus and PVPVA64 are respectively selected as the stabilizer, 0.60g of silybin bulk drug is precisely weighed, and the ratio of the silybin bulk drug to the stabilizer is respectively 1:1, 5:1 and 10: 1. Sy-NS-G was prepared according to the method under "1.1", and the particle size and PDI were measured, and the results are shown in Table 3.
TABLE 3 particle size and PDI for different stabilizers and ratios Sy-NS-G
Figure BDA0003547303990000053
Figure BDA0003547303990000061
As can be seen from Table 3, different stabilizers and different ratios (drug-adjuvant ratios) of the silybin bulk drug to the stabilizer have different influences on the particle size of Sy-NS-G. The particle sizes and PDI values of different stabilizers in the optimal proportion are also obviously different, and the Sy-NS-G particle size obtained by the stabilizer TPGS (drug-adjuvant ratio 1:1) and the soluplus (drug-adjuvant ratio 10:1) is the smallest. Though the PDI of Sy-NS-G obtained by using TPGS as a stabilizer is smaller than that of soluplus. However, in experiments, the obvious drug precipitation phenomenon of the suspension occurs in the process of preparing Sy-NS-G by using TPGS as a stabilizer, so that soluplus is selected as a spatial stabilizer, and the ratio of the silybin bulk drug to the stabilizer is 10: 1.
1.4 composite stabilizer ratio screening
The soluplus belongs to a space stable stabilizer, while the ionic stabilizer can play a stabilizing role through electrostatic repulsion, and the combination of the two types of stabilizers can ensure that the NS has better stability. And (3) screening the proportion of the stabilizer by using the soluplus and the ionic surfactant SDS as a composite stabilizer.
Sy-NS-G was prepared in a drug-adjuvant ratio of 5:1 and a soluplus SDS (adjuvant ratio) ratio of 1:5, 1:2, 2:1, 5:1, according to the method under the section "1.1", and the particle size and PDI were measured, and the results are shown in Table 4.
TABLE 4 Sy-NS-G particle size and PDI for different ratios between adjuvants
Figure BDA0003547303990000062
As can be seen from Table 4, when the ratio of soluplus to SDS was 1:2 and 1:5, the particle size of Sy-NS-G was small.
Experimental example 2 preparation process optimization by high-pressure homogenization method
2.1 examination of the homogenization pressure
Accurately weighing 0.30g of silybin bulk drug, fixing homogenization time for 4min, and examining the influence of homogenization pressure (20, 50, 80 and 110MPa) on particle size and PDI according to the optimal result screened by 'test 1' under other conditions.
Table 5 homogeneous pressure study (x ± s, n ═ 3)
Figure BDA0003547303990000071
The particle size and PDI were measured under different pressure conditions for homogenization, and as a result, the homogenization pressure was selected to be 110MPa because the particle size decreased as a result of increasing the homogenization pressure.
2.2 examination of homogenization time
Accurately weighing 0.30g of Sy raw material medicine, and inspecting the influence of homogenization time (4, 8, 10 and 12min) on particle size and PDI according to the optimal result of 2.1 screening under other conditions.
Table 6 homogeneity time study (x ± s, n ═ 3)
Figure BDA0003547303990000072
The particle size and PDI were measured under different time conditions for homogenization, and as a result, the particle size decreased with an extended period of homogenization, and thus 12min was selected.
Experimental example 3 anti-solvent precipitation method preparation process optimization
3.1 solvent to antisolvent ratio investigation
In order to compare the influence of the preparation method on the in-vivo and in-vitro behaviors of the silybin, the prescription compositions and the dosage of the two nanosuspensions are kept consistent. The mass ratio of the silybin bulk drug to the stabilizer (soluplus: SDS-1: 2) is fixed to be 10:1, ultrasonic treatment is carried out for a certain time under certain ultrasonic power, the preparation is carried out according to the preparation method under the item of 1.2, and the influence of the ratio of the solvent (absolute ethyl alcohol) to the anti-solvent (pure water) on the particle size and PDI is examined, which is shown in the following table.
TABLE 7 solvent to antisolvent ratio examination
Figure BDA0003547303990000081
As can be seen from the table, the particle size obtained was the smallest when the ratio of solvent to anti-solvent was 1: 7.
3.2 ultrasonic Power and time Observation
The preparation method is characterized in that the mass ratio of the silybin bulk drug to the stabilizer (soluplus: SDS-1: 2) is fixed to be 10:1, the volume ratio of absolute ethyl alcohol to water is 1:7, the preparation method is carried out according to the item 1.2, and the influence of ultrasonic power and time on particle size and PDI is examined, and the table below shows.
TABLE 8 ultrasonic Power and time review
Figure BDA0003547303990000082
According to the particle size results in the table, the ultrasonic power is 65W and the time is 31 min.
3.3 screening of lyoprotectants
According to the preparation method of '1.2', freeze-drying protective agents with different concentrations (1%, 2%, 2.5%, 3%, 4%, 5%) and different types (maltose, sucrose, mannitol) are respectively added to carry out screening of types and concentrations of the Sy-NS-F freeze-drying protective agents.
The results of particle size and PDI of the Sy-NS freeze-dried powder after redissolution are shown in figures 4 and 5, the morphology of the Sy-NS freeze-dried powder is shown in Table 9, and the 5% mannitol freeze-drying protection effect is best after comprehensive consideration of the particle size, the PDI, the appearance morphology and the state after redissolution.
Table 9 effect of different lyoprotectants on morphology (x ± s, n ═ 3)
Figure BDA0003547303990000091
Test example 4
4.1 dissolution determination
According to the determination method of dissolution rate, slurry method, rotation speed of 100r/min, temperature (37 +/-0.5) DEG C, dissolution medium of pH4.5 containing 0.2% SDS and 900ml of aqueous solution respectively, respectively taking Sy-NS-G (prepared according to the preparation method under the item '1.1' and the optimal process condition of screening), Sy-NS-F (silybin nano freeze-dried powder of example 1), PM (physical mixture) and Sy bulk drug (all equivalent to 10mg silybin) to be placed in a dissolution cup, respectively sampling at 5, 10, 15, 30, 45, 60, 90 and 120min, performing dissolution rate determination, and drawing an accumulated dissolution curve, as shown in figures 2 and 3.
As can be seen from the figure, the cumulative dissolution rates of the Sy bulk drug, the Sy-NS-G, Sy-NS-F freeze-dried powder and the physical mixture 2h in the dissolution medium with the pH value of 4.5 (0.2% SDS) are respectively 38.80%, 46.77%, 53.54% and 35.58%, and the cumulative dissolution rates of the Sy bulk drug, the Sy-NS-G, Sy-NS-F freeze-dried powder and the physical mixture 2h in the dissolution medium with the 0.2% SDS aqueous solution are respectively 52.13%, 68.18%, 68.68% and 41.46%. The 2h cumulative dissolution rate of the silybin nano freeze-dried powder Sy-NS-G, Sy-NS-F in different pH (pH 4.5, water) aqueous solutions of 0.2% SDS is obviously higher than that of a silybin physical mixture and a silybin bulk drug, and the 2h cumulative dissolution rate of the silybin nano freeze-dried powder Sy-NS-F in 0.2% SDSpH 4.5 aqueous solution is higher than that of Sy-NS-G.
4.2 pharmacokinetic protocol and plasma sample Collection
18 SD rats are randomly divided into 3 groups and 6 rats in each group, after fasting for 12h, the Sy bulk drug (mixed with 0.5% sodium carboxymethyl cellulose) and Sy-NS-G, Sy-NS-F are respectively filled with stomach Sy bulk drug (mixed with 0.5% sodium carboxymethyl cellulose) and 0.3ml orbital blood is taken to EP tubes containing heparin sodium after administration for 0.0833, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 and 24h, and 5000 r.min-1Centrifuging for 10min, collecting supernatant, and storing at-80 deg.C.
And (4) processing the collected blood sample, analyzing, calculating to obtain the blood concentration, and drawing a pharmaceutical time curve. Pharmacokinetic parameters were calculated for each rat in a non-compartmental model by DAS 3.2.8 software, relative bioavailability was calculated from the AUB values, and statistically analyzed, see figure 1. Sy bulk drug, T of Sy-NS-G, Sy-NS-Fmax0.5h, 0.25h, 0.75h, B of Sy-NS-G, Sy-NS-FmaxIs 1.006 times and 3.5 times of that of Sy bulk drug, and the relative bioavailability of Sy-NS-G, Sy-NS-F is 64.56 percent and 447.72 percent respectively. The Sy-NS-F has greater advantages in improving bioavailability, and the anti-solvent precipitation method is more suitable for preparing the Sy-NS.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (9)

1. The silybin nanosuspension is characterized by comprising silybin, a stabilizer and water, wherein the mass ratio of the silybin to the stabilizer is 1-10: 1, the stabilizer is a composition of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and sodium dodecyl sulfate, and the mass ratio of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer to the sodium dodecyl sulfate is 1-5: 1-5.
2. The silybin nanosuspension according to claim 1, wherein the mass ratio of silybin to stabilizer is 10: 1.
3. The silybin nanosuspension of claim 1, wherein the mass ratio of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer to the sodium dodecyl sulfate is 1: 5.
4. A process for the preparation of a silybin nanosuspension according to any of claims 1 to 3, characterized in that the process is an anti-solvent precipitation process.
5. The process for preparing a silybin nanosuspension by an antisolvent precipitation method according to claim 4, comprising the steps of:
(1) dissolving a stabilizer in water to obtain a water phase; dissolving silybin in an organic solvent to obtain an organic phase;
(2) under the action of ultrasonic pulverization, organic phase is dropped into water phase, and after the organic phase is completed, the organic solvent is removed, so that the silybin nano suspension is obtained.
6. The method for preparing silybin nanosuspension by an anti-solvent precipitation method according to claim 5, wherein in the step (1), the organic solvent is absolute ethanol, and the volume ratio of the absolute ethanol to the water is 1: 7-10.
7. The method for preparing silybin nanosuspension by an antisolvent precipitation method according to claim 5, wherein in the step (2), the ultrasonic pulverization is carried out by using a cell ultrasonic pulverizer, the ultrasonic power is 65-260w, and the ultrasonic time is 7-31 min.
8. A lyophilized formulation prepared from a silybin nanosuspension according to any of claims 1 to 3, wherein the lyophilized formulation is prepared by: adding a freeze-drying protective agent into the silybin nano suspension, and freeze-drying to obtain the silybin nano suspension.
9. The lyophilized formulation according to claim 8, wherein the lyoprotectant is mannitol, and the amount of mannitol added is 5% by weight of the silybin nanosuspension.
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* Cited by examiner, † Cited by third party
Title
张领等: "水飞蓟宾纳米混悬剂的制备与体外评价", 《中国医药工业杂志》 *
赵晓宇等: "水飞蓟素纳米混悬剂冻干粉的制备及表征", 《中国中药杂志》 *

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