CN110151696B - Puerarin freeze-dried Pickering emulsion and preparation method thereof - Google Patents

Puerarin freeze-dried Pickering emulsion and preparation method thereof Download PDF

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CN110151696B
CN110151696B CN201910568549.3A CN201910568549A CN110151696B CN 110151696 B CN110151696 B CN 110151696B CN 201910568549 A CN201910568549 A CN 201910568549A CN 110151696 B CN110151696 B CN 110151696B
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CN110151696A (en
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张继芬
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Southwest University
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Abstract

The invention discloses a puerarin freeze-dried pickering emulsion and a preparation method thereof. The raw materials for preparing the puerarin freeze-dried Pickering emulsion comprise the following components in percentage by weight: puerarin: 0.1-5.0%, oil phase: 5-10% of a freeze-drying protective agent, 1-10% of water and the balance of water. Adding puerarin raw material into water phase, preparing primary puerarin suspension by using a high-speed shearing machine, and obtaining puerarin nanocrystalline suspension by using a high-pressure homogenizer. And adding the oil phase into the puerarin nanocrystal suspension, and preparing by using a high-pressure homogenizer to obtain the puerarin nanocrystal self-stabilizing Pickering emulsion. And then adding a freeze-drying protective agent, uniformly mixing, and freeze-drying to obtain the puerarin freeze-dried Pickering emulsion.

Description

Puerarin freeze-dried Pickering emulsion and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a puerarin freeze-dried pickering emulsion and a preparation method thereof.
Background
Puerarin is isoflavone derivative extracted from radix Puerariae with coronary dilating effect, and is present in root of Pueraria lobata (Willd.) Ohwi and Pueraria thomsonii (Willd.) Ohwi of Leguminosae. Puerarin has effects of relieving fever, tranquilizing, increasing coronary blood flow, and protecting acute myocardial hemorrhage caused by hypophysin, and is mainly used for treating coronary heart disease, angina pectoris, and hypertension. Puerarin is insoluble medicine and has low bioavailability. Above pH10, puerarin has poor stability and the core structure may be irreversibly damaged.
The pickering emulsion is a novel emulsion which is formed by stabilizing an emulsion system by solid particles instead of a surfactant. Compared with the traditional emulsion using the surfactant, the Pickering emulsion does not use the surfactant, and the emulsion is prepared by adding solid particles into oil water, wherein the solid particles are adsorbed on the surface of oil drops to form a layer of protective film, thereby preventing the liquid drops from polymerizing and stabilizing the emulsion; the concentration of the needed solid particles is far lower than that of the surfactant, so that the composite material has less harm to human bodies and the environment, higher safety, strong interface stability, low toxicity and the like, and has wide application prospect in the industries of cosmetics, food processing, biomedicine and the like.
The drug nanocrystal self-stabilizing Pickering emulsion is prepared by taking insoluble drug nanocrystals as solid particle stabilizers and not containing surfactants, silicon dioxide and other auxiliary materials such as heterogeneous solid particles and the like. The emulsion is only composed of 3 substances of water, oil and insoluble drugs, and the drug nanocrystals are adsorbed on the surface of oil drops to prevent merging of emulsion drops, stabilize the emulsion and improve the safety and drug-loading rate of the emulsion. However, the emulsion is a crude dispersion system, and has poor stability, and various unstable phenomena such as rancidity, mildew, delamination, sedimentation, flocculation, coalescence, combination and destruction, Ostwald ripening, phase transformation and the like may occur in the long-term storage process.
The freeze drying method is that the material is frozen to below the eutectic point temperature of the material at low temperature, the water in the completely frozen material is changed into solid ice, then the ice is directly sublimated into gas in a vacuum environment at low temperature and low pressure to be removed, and then partial bound water is removed through analysis and drying, thereby achieving the drying purpose. Packaging the medicinal liquid before freezing, with accurate dosage, and drying at low temperature and low pressure to prevent the heat-sensitive substances from denaturation, inactivation or oxidative decomposition; the dried product is loose and porous, has good rehydration property, and can quickly absorb water to restore the original character; the freeze-dried product is completely dehydrated, has strong stability, can be stored for a long time, and is used for drying and solidifying a plurality of emulsions. The freeze-dried powder of the emulsion prepared by freeze drying not only keeps the advantages of the emulsion, but also can remove water in the emulsion, increases the stability of the emulsion, is a good preparation form and is beneficial to the long-term storage of the emulsion. When in use, the specific loose porous structure of the freeze-dried preparation can be directly redispersed by a corresponding solvent, can also be prepared into tablets or capsules for use, and can also play a role in rapidly disintegrating tablets. According to the characteristics of the components in the emulsion, the quality of the product after the emulsion freeze-dried powder is redispersed is ensured through the conditions of a proper freeze-drying protective agent, freeze-drying conditions and the like.
Disclosure of Invention
The invention discloses a puerarin freeze-dried Pickering emulsion, which solves the problem that the puerarin nanocrystalline self-stabilizing Pickering emulsion is poor in long-term stability.
In order to achieve the purpose, the technical scheme of the invention is as follows:
1. prescription of the invention
The puerarin freeze-dried pickering emulsion comprises the following components in percentage by weight:
puerarin: 0.1-5.0%; oil phase: 5-15%; 1-15% of freeze-drying protective agent and the balance of water.
The lyophilized emulsion of puerarin according to claim 1, wherein the weight percentage of the raw materials is preferably: puerarin: 0.1-5.0%; oil phase: 5-10%; 4-12% of a freeze-drying protective agent; the balance of water.
The water phase is preferably sodium hydroxide water solution with the pH value of 11-12.
The oil phase is preferably mixture of rhizoma Ligustici Chuanxiong oil and 9:1 of polyethylene glycol oleate.
The freeze-drying protective agent comprises one or more of sucrose, mannitol, lactose, glucose, trehalose, maltose, PVP K30, HPMC K4M and HP- β -CYD, and preferably the trehalose or maltose with the mass ratio of 8:1 is compatible with PVP K30.
2. The forming process of the invention
The preparation method of the puerarin freeze-dried emulsion comprises the following steps:
(1) adding the puerarin raw material medicine into a sodium hydroxide aqueous solution with the pH value of 11-12, and shearing at a high speed to prepare a primary puerarin suspension.
(2) Homogenizing under high pressure to obtain puerarin nanocrystalline suspension.
(3) Adding rhizoma Ligustici Chuanxiong oil and polyethylene glycol glyceryl oleate (9:1) into puerarin nanocrystalline suspension, and homogenizing to obtain puerarin nanocrystalline self-stabilizing Pickering emulsion.
(4) Adding freeze-drying protective agent, mixing, and freeze-drying to obtain puerarin freeze-dried emulsion.
In the step (1), the high-speed shearing condition is preferably 19000rpm for 2 min.
In step (2), the homogenization conditions are preferably 800-1000bar for 3 min.
In step (3), the homogenization conditions are preferably 800-1000bar for 3 min.
In the step (4), the freeze-drying condition is preferably that the mixture is pre-frozen at 80 ℃ for 24 hours and sublimated at 10 ℃ for 15 hours under the condition that the vacuum degree is less than 5 Pa.
The invention is added with water to shake and redisperse, a dispersed sample forms uniform and stable emulsion, and the emulsion stabilizer is puerarin nanocrystalline.
Compared with the existing puerarin emulsion, self-emulsifying preparation and pickering emulsion, the puerarin emulsion has better stability, the puerarin cannot be influenced by high pH environment to cause the damage of mother nucleus, and is not easy to generate various unstable phenomena such as rancidity, mildewing, layering, sedimentation, flocculation, coalescence, combination and damage, ostwald curing, phase transformation and the like, and is easy to transport and store. Compared with other emulsion freeze-dried powder, the freeze-drying protective agent and the freeze-drying conditions which are more suitable for the puerarin pickering emulsion freeze-dried powder are selected, and the emulsion freeze-dried powder can obtain the pickering emulsion with stable quality after being dispersed.
Drawings
FIG. 1 shows puerarin lyophilized emulsion of Pickering prepared by different lyophilization processes, levo-trehalose; maltose right
FIG. 2 shows the appearance of the puerarin freeze-dried Pickering emulsion prepared by different freeze-drying processes after re-dispersion; maltose right
FIG. 3 shows the appearance of puerarin lyophilized Pickering emulsion prepared from lyophilized protectant with different compatibility, A, trehalose-HPMC, B, trehalose-HP- β -CYD, C, trehalose-PVPK 30, D, maltose-HPMC, E, maltose-HP- β -CYD, F, maltose-PVPK 30
FIG. 4 shows the appearance of the puerarin lyophilized Pickering emulsion after redispersion, prepared by different varieties of lyophilized protectant, A, trehalose-HPMC, B, trehalose-HP- β -CYD, C, trehalose-PVPK 30, D, maltose-HPMC, E, maltose-HP- β -CYD, F, maltose-PVPK 30
Fig. 5 shows puerarin freeze-dried pickering emulsion prepared by mixing trehalose (a) or maltose (B) with different dosages and PVPK30 according to different proportions, the dosage of the freeze-dried preparation: upper.4%, middle.8%, lower.12%; the compatibility proportion is as follows: 1.1:1,2.2:1,3.4:1,4.8:1,5.16:1
Fig. 6 shows the appearance of the puerarin freeze-dried pickering emulsion prepared by different dosages of trehalose (A) or maltose (B) and PVPK30 in different proportions after being redispersed. Upper.4%, middle.8%, lower.12%; the compatibility proportion is as follows: 1.1:1,2.2:1,3.4:1,4.8:1,5.16:1
Figure 7 is the appearance of a puerarin freeze-dried pickering emulsion during storage at 40 ℃ and 75% relative humidity for 3 months.
FIG. 8 is a graph showing the appearance of puerarin freeze-dried Pickering emulsion after redispersion during storage at 40 ℃ and 75% relative humidity for 3 months
Fig. 9 is a diagram showing the form of emulsion droplets after redispersion during storage of a puerarin lyophilized pickering emulsion at 40 ℃ and 75% relative humidity for 3 months, time: month A.0, month B.1, month C.2, month D.3; batch: 1.201810131,2.201810132,3.201810133
FIG. 10 is a fluorescence microscopic photograph of the emulsion droplets after the puerarin freeze-dried Pickering emulsion is redispersed.
The specific implementation mode is as follows:
the present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1:
350mg puerarin was weighed out and added to 63mL of aqueous phase (1 mol. L)-1Adjusting the pH value of a water phase with sodium hydroxide to 11.5), shearing at 19000rpm for 2min at high speed, homogenizing at 800bar under high pressure for 3min, measuring 7mL of an oil phase (Ligusticum wallichii oil: polyethylene glycol oleate ═ 9:1, v/v), adding into a high-pressure homogenizer, and continuously homogenizing at 80MPa for 3min to obtain the puerarin nanocrystalline self-stabilizing Pickering emulsion.
Adding 2mL of the puerarin nanocrystalline self-stabilizing Pickering emulsion into a penicillin bottle, adding 0.16g (8%) of freeze-drying protective agents (trehalose and maltose), uniformly mixing, and respectively processing according to the following process conditions to obtain the puerarin freeze-dried emulsion.
The process A comprises the following steps: prefreezing at-40 deg.C for 6h, and sublimation drying by the following procedure: 18h at-40 ℃, 6h at-15 ℃, 4h at 0 ℃ and 4h at 15 ℃ and the vacuum degree is lower than 5 Pa.
And a process B: prefreezing at-80 deg.C for 24h, and sublimation drying by the following procedure: 30 ℃ for 15h, and the vacuum degree is lower than 5 Pa.
And (4) a process C: prefreezing at-80 deg.C for 24h, and sublimation drying by the following procedure: 10 ℃ for 15h, and the vacuum degree is lower than 5 Pa.
TABLE 1 appearance of lyophilized emulsions of Puerarin prepared by different lyophilization processes
Figure GDA0002449610110000041
TABLE 2 redispersibility of lyophilized emulsions of puerarin prepared by different lyophilization processes
Figure GDA0002449610110000042
Example 2:
weighing 350mg puerarin, adding 63mL of water phase (the pH value of the water phase is adjusted to 11.5 by 1 mol. L-1 of sodium hydroxide), shearing at 19000rpm for 2min at high speed, homogenizing at 800bar under high pressure for 3min, weighing 7mL of oil phase (ligusticum wallichii oil: polyethylene glycol oleate ═ 9:1, v/v), adding into a high-pressure homogenizer, and continuously homogenizing at 80MPa for 3min to obtain puerarin nanocrystal self-stabilizing Pickering emulsion (puerarin nanocrystal self-stabilizing Pickering emulsion).
Adding 2mL of the puerarin nanocrystalline self-stabilizing Pickering emulsion into a penicillin bottle, adding different compatible freeze-drying protective agents, respectively matching trehalose and maltose with HPMC K4M, HP- β -CYD and PVP K30 according to a ratio of 1:1, uniformly mixing the trehalose and the maltose with the HPMC K4M, the HP- β -CYD and the PVP K30, carrying out pre-freezing at the temperature of-80 ℃ for 24h, carrying out sublimation drying at the temperature of 10 ℃ for 15h and the vacuum degree of less than 5Pa, and obtaining the puerarin freeze-dried emulsion.
TABLE 3 appearance of lyophilized emulsion of puerarin prepared by different varieties of lyophilized protectant
Figure GDA0002449610110000043
Figure GDA0002449610110000051
TABLE 4 redispersibility of lyophilized emulsion of puerarin prepared by different varieties of lyophilized protectant
Figure GDA0002449610110000052
Example 3:
weighing 350mg puerarin, adding 63mL of water phase (the pH value of the water phase is adjusted to 11.5 by 1 mol. L-1 of sodium hydroxide), shearing at 19000rpm for 2min at high speed, homogenizing at 800bar under high pressure for 3min, weighing 7mL of oil phase (ligusticum wallichii oil: polyethylene glycol oleate ═ 9:1, v/v), adding into a high-pressure homogenizer, and continuously homogenizing at 80MPa for 3min to obtain puerarin nanocrystal self-stabilizing Pickering emulsion (puerarin nanocrystal self-stabilizing Pickering emulsion).
Adding 2mL of the puerarin nanocrystalline self-stabilizing Pickering emulsion into a penicillin bottle, wherein the mass ratio of maltose, trehalose and PVP K30 is 1: 1. 2: 1. 4: 1. 8:1 and 16:1, adding the components according to the proportion of 4%, 8% and 12%, uniformly mixing, pre-freezing for 24h at-80 ℃, and carrying out sublimation drying according to the following procedures: and (3) obtaining the puerarin freeze-dried emulsion at 10 ℃ for 15h and under the vacuum degree of less than 5 Pa.
TABLE 5 appearance of lyophilized emulsion of puerarin prepared with different compatibility ratios and concentrations of protective agent
Figure GDA0002449610110000061
Figure GDA0002449610110000071
TABLE 6 redispersibility of lyophilized emulsion of puerarin prepared with different compatibility ratios and concentrations of protective agent
Figure GDA0002449610110000072
Figure GDA0002449610110000081
Example 4:
weighing 350mg puerarin, adding 63mL of water phase (the pH value of the water phase is adjusted to 11.5 by 1 mol. L-1 of sodium hydroxide), shearing at 19000rpm for 2min at high speed, homogenizing at 800bar under high pressure for 3min, weighing 7mL of oil phase (ligusticum wallichii oil: polyethylene glycol oleate ═ 9:1, v/v), adding into a high-pressure homogenizer, and continuously homogenizing at 80MPa for 3min to obtain puerarin nanocrystal self-stabilizing Pickering emulsion (puerarin nanocrystal self-stabilizing Pickering emulsion).
Adding 2mL of puerarin nanocrystalline self-stabilizing Pickering emulsion into a penicillin bottle, respectively mixing trehalose and maltose with PVP K30 at a ratio of 8:1 as a freeze-drying protective agent, uniformly mixing the freeze-drying protective agent with the use amount of 4%, pre-freezing for 24h at-80 ℃, and carrying out sublimation drying according to the following procedures: and (3) obtaining the puerarin freeze-dried emulsion at 10 ℃ for 15h and under the vacuum degree of less than 5 Pa.
Example 5:
the lyophilized emulsion of puerarin obtained in example 4 was sealed with a sealing film, and placed in a constant temperature and humidity chamber (40 ℃, 75% relative humidity), and the following quality evaluations were performed at 0, 1, 2, and 3 months.
(1) Appearance of the product
And observing whether the appearance of the Pickering emulsion freeze-dried powder is full, collapse, shrinkage and the like.
(2) Redispersibility
Taking 1 count of Pickering emulsion freeze-dried powder, adding 2mL of water, shaking to redisperse the emulsion freeze-dried powder, and observing whether the redispersed sample is uniform emulsion or not and whether an oil phase is separated out or not.
(3) Emulsion droplet form
And taking the redispersion liquid to observe the shape and the quantity of emulsion droplets under a microscope.
(4) Particle size
And (3) measuring the particle size of emulsion droplets of the Pickering emulsion freeze-dried powder after redispersion by using a laser particle size distribution instrument.
(5) Drug content
Taking 1 count of Pickering emulsion freeze-dried powder, adding 2mL of water, shaking and redispersing, immediately taking 100 mu L of emulsion layer, dissolving with 500 mu L of methanol-chloroform (1:2), adding a proper amount of methanol, carrying out ultrasonic treatment for 10min, fixing the volume to 10mL with methanol, filtering with a 0.45 mu m microporous filter membrane, and measuring the puerarin content by HPLC (high performance liquid chromatography). the chromatographic conditions are that a chromatographic column is a SilGreenGH0525046C18A chromatographic column (4.6mm × 250mm, 5m), the flow rate is 1mL/min, the column temperature is 30 ℃, the mobile phase is water-acetonitrile (15: 85), and the detection wavelength is 250 nm.
TABLE 7 accelerated stability test for puerarin freeze-dried emulsion
Time of day Appearance of the product Redispersibility Emulsion droplet form Particle size (. mu.m) Drug content (mg/ml)
0 month Good effect Uniform without precipitation Good effect 1.362 4.05
1 month Good effect Uniform without precipitation Good effect 2.504 4.12
2 month Good effect Uniform without precipitation Good effect 4.321 4.18
3 month Good effect Uniform without precipitation Good effect 3.184 4.18
The puerarin lyophilized emulsion is stored for 3 months at 40 deg.C and 75% humidity. The appearance has no obvious change within 3 months, and is always full, has no shrinkage, no bubble, no crack, no layering and uniform color; the redispersibility is good, no oil phase is separated out after dispersion, the oil phase can be dissolved in 60s, and the emulsion is uniform and has good emulsibility after dissolution; the emulsion droplet has no obvious change in shape, is smooth all the time and is uniformly dispersed; the particle size of the emulsion drops is slightly increased but is not greatly changed; the puerarin drug content is kept at about 4 mg/ml.

Claims (2)

1. A puerarin freeze-dried pickering emulsion is characterized in that the raw materials comprise the following components in percentage by weight:
0.1-5.0% of puerarin, 5-10% of a mixture of ligusticum wallichii oil and oleic acid polyethylene glycol glyceride in a volume ratio of 9:1, 8% of freeze-drying protective agent and the balance of sodium hydroxide aqueous solution with the pH value of 11-12; the freeze-drying protective agent is a mixture of trehalose or maltose and PVP K30 in a mass ratio of 8: 1;
the preparation method comprises the following steps:
(1) adding the puerarin raw material medicine into a sodium hydroxide aqueous solution with the pH value of 11-12, and shearing at a high speed of 19000rpm for 2min to prepare a primary puerarin suspension;
(2) homogenizing at 800-1200 bar to obtain puerarin nanocrystal suspension;
(3) adding a mixture of ligusticum wallichii oil and oleic acid polyethylene glycol glyceride in a volume ratio of 9:1 into the puerarin nanocrystalline suspension, and homogenizing at 800-1200 bar to obtain puerarin nanocrystalline self-stabilizing Pickering emulsion;
(4) adding the freeze-drying protective agent into the emulsion, uniformly mixing, pre-freezing at-80 ℃ for 12-24h, and sublimating at 10 ℃ for 15-24h under the condition that the vacuum degree is less than 5Pa to obtain the puerarin freeze-dried Pickering emulsion.
2. The lyophilized emulsion of puerarin according to claim 1, wherein the lyophilized emulsion of puerarin is added with water and then shaken for redispersion, and the dispersed sample forms a uniform and stable emulsion, and the emulsion stabilizer is puerarin nano-crystal.
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