CN114099475A - One-step method for preparing interfacial porous active controlled release membrane and application thereof - Google Patents
One-step method for preparing interfacial porous active controlled release membrane and application thereof Download PDFInfo
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Abstract
The invention discloses an interfacial porous active controlled release membrane prepared by a one-step method and application thereof. The interfacial porous active controlled release membrane is prepared by mixing the gliadin and the active substance to prepare a membrane stock solution and carrying out anti-solvent titration, and is based on the gliadin interfacial membrane one-step method loading and controlled release of the active substance, and the micro-porous structure of the interfacial membrane, including the porosity and the aperture, is changed by regulating and controlling the technological parameters of the anti-solvent titration process, including the gliadin concentration, the active substance concentration, the anti-solvent and the like, so that the loading rate and the controlled release characteristic of the active substance are regulated and controlled. The preparation process can realize the forming of the interface film and the synchronous loading of the active matter within 5 seconds, the loading rate of the active matter is as high as 60-90 percent, the formed porous structure can intercept the active matter, the controlled release of the active matter is realized, a novel selection scheme is provided for the preparation of the active controlled release film, and the prepared active interface film can be used in the fields of functional foods, cosmetics, medicines and the like.
Description
Technical Field
The invention belongs to the technical field of preparation of active controlled release membranes, and particularly relates to an interfacial porous active controlled release membrane prepared by a one-step method and application thereof.
Background
Transdermal administration, as a new route of administration, has significant advantages over traditional intravenous and oral administration. In many transdermal drug delivery systems, the diffusional release of the drug is controlled by a controlled release membrane, which therefore has a critical role in transdermal drug delivery systems. The preparation method of the active controlled release membrane mainly comprises a tape casting method and an electrostatic spinning method at present, but the preparation time is long, the controllability of the membrane structure is poor, and the application of the active controlled release membrane is limited because the high load rate and the sustained and controlled release of the active substance cannot be achieved. The development of active controlled release films with rapid film formation and strong membrane structure regulation and base materials has been a hot research point in transdermal drug delivery systems.
Patent CN202110025707.8 provides a degradable drug-loaded skin wound dressing with high air permeability, which comprises a dressing inner layer, a dressing outer layer and a repair adhesive layer; the repair adhesive layer is positioned between the dressing inner layer and the dressing outer layer; the dressing inner layer is obtained by performing electrostatic spinning on the inner layer spinning solution, the dressing outer layer is obtained by performing electrostatic spinning on the outer layer spinning solution, the adhesive layer is made of natural protein materials, but various polymers are added to promote film formation, multi-step preparation is required, the film forming speed is low, the operation is complex, the controllability of the repaired adhesive layer structure is poor, and the controlled release regulation of active substances is limited.
Therefore, there is a need to develop a novel active controlled release film with simple preparation, fast film formation and controllable structure to meet the requirements of the field of controlled release delivery of active substances.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a one-step method for preparing an interfacial porous active controlled-release membrane and application thereof, the preparation efficiency of the prolamin active controlled-release membrane is greatly improved by a self-assembly membrane forming technology of cereal prolamin at a gas-liquid interface and loading an active substance with high efficiency by the one-step method, and the porous structure of the prolamin self-assembly interfacial membrane is further accurately regulated and controlled by regulating and controlling the self-assembly process, so that the controlled release of the loaded active ingredient is realized.
The invention aims to provide a one-step method for preparing an interfacial porous active controlled-release membrane and application thereof.
The invention further aims to provide application of the prolamin interface porous active controlled-release membrane in preparation of an active substance controlled-release product.
The above purpose of the invention is realized by the following technical scheme:
the invention firstly provides a prolamin interface porous active controlled-release membrane, which is prepared by dissolving prolamin and an active substance in a good solvent to obtain an active membrane stock solution with the prolamin concentration of 10-30 wt%, and then dripping the membrane stock solution into an anti-solvent with the temperature of 25-40 ℃ for one-step preparation.
The cereal prolamin is a main storage protein in the cereals, comprises zein, kafirin, Setarin, rice prolamin, wheat prolamin, hordein, highland barley prolamin and the like, and has biodegradability and biocompatibility. The high content of hydrophobic amino acids and the unique amino acid arrangement order of the zein make it have unique solubility, amphiphilicity and self-assembly properties. Amphiphilicity is a driving force for self-assembly of the prolamine, and when the polarity of the prolamine in a good solvent is changed, the prolamine molecules self-assemble under the action of non-covalent bonds (disulfide bonds, hydrogen bonds, hydrophobic interactions, van der waals forces) to form aggregates with certain structures and functions, so that the individual structural characteristics of the individual prolamine molecules become a substrate of a dominant delivery system.
According to the research, when the concentration of the cereal prolamin in a good solvent reaches a certain value, a continuous film can be quickly formed on a gas-liquid interface by an anti-solvent titration method, one-step high-efficiency loading and slow controlled release can be realized on natural active substances, the interaction force among protein molecules can be regulated and controlled by regulating and controlling the concentration of the cereal prolamin, and when the concentration of the protein is too low, the hydrophobic interaction force among the protein molecules in a film liquid storage solution is small, so that the loading rate of the interface film on the active substances is influenced; when the concentration of the protein is too high, the protein in the membrane stock solution is more, the collision probability is increased, the hydrophobic interaction force among protein molecules is increased, the solution is not easy to diffuse at the interface, the surface micro-pore diameter of the formed film is not easy to form, and the sustained and controlled release effect of the active substance cannot be achieved; the difference of the concentration of the prolamin can affect the self-aggregation of the protein at the interface and the diffusion of the solvent, so that the morphological structures of the upper surface and the lower surface of the interface membrane, such as a porous structure and hydrophilicity and hydrophobicity, are changed, and the loading and controlled release of the active substances are regulated. The grain alcohol soluble protein and the active matter are dissolved in a good protein solvent to prepare a grain alcohol soluble protein porous active controlled release membrane stock solution, and then the grain alcohol soluble protein membrane stock solution is quickly gathered and diffused on an anti-solvent interface to form a film with a porous micro interface structure through anti-solvent titration, and the active matter is loaded in one step while the film is quickly formed on the interface. The self-assembly and diffusion processes of the prolamin on the gas-liquid interface can be regulated and controlled by regulating the concentration of the cereal prolamin, the temperature, the pH value and the ionic strength of the anti-solvent, so that interface films with different microstructures are obtained, the load rate and the distribution condition of an active substance in the interface films are influenced, and the controlled release of the active substance is realized.
The interfacial porous active controlled-release membrane prepared by the one-step method is particularly suitable for meeting the design requirement of a specific structure in the field of contact type active substance controlled-release, is applied to the field of active substance controlled-release delivery, has unique technical advantages in similar products based on the advantages of green preparation process, natural and degradable products and controllable release of active substances, and provides another innovative solution for high-value utilization of cereal protein.
Preferably, the prolamin, active dissolution is stirring, sonication to complete dissolution.
Preferably, the pH of the antisolvent is 3.0-10.0, the ionic strength is 0-700 mM, and the gel strength is 0-100 pa.
The inventor has conducted a targeted study, and the result shows that when the pH of the anti-solvent is too low, protein molecules can be rapidly self-assembled, and the formed film cannot form microscopic pores and cannot achieve the slow release of the active substance; when the pH value of the anti-solvent is too high, the solubility of protein molecules in the anti-solvent is increased, the diffusion time of the protein molecules is prolonged, the micro-pore diameter of the formed film is larger, and the load rate of the formed film on active matters is reduced.
When the ionic strength of the anti-solvent is too low, the added ions compete for a hydration layer on the outer layer of the protein, so that the interaction force among protein molecules is increased, and the self-aggregation degree of the protein is increased; when the ionic strength of the anti-solvent is too high, salt ions can be combined with carboxyl and amino on the protein, so that the charge quantity of the protein molecules is reduced, and the self-aggregation degree of the protein molecules is reduced; the micro-pore size of the formed film is too large or too small, and the high-efficiency loading and sustained and controlled release of active substances cannot be realized.
In addition, the research result of the invention also shows that the gel strength of the anti-solvent can influence the loading rate of the active substance, and when the gel strength is properly improved, the loading rate of the active substance in the interface porous membrane can be improved due to the reduction of the dissolution and the dispersibility of the active substance in the gel; however, when the gel strength is too high, the diffusion performance of the interfacial film at the gel interface is poor, and the formed film cannot form microscopic pores and cannot achieve the slow release of the active substances.
Preferably, the pH of the antisolvent according to the present invention may be adjusted with sodium hydroxide and/or hydrogen chloride, and the ionic strength of the antisolvent may be adjusted with sodium chloride. Further preferably, the pH of the antisolvent is 3.0 to 9.0, and the ionic strength is 50 to 500 mM.
The control of the gel strength can be controlled by adding varying amounts of gelling agents (e.g., gelatin, alginate, low-fat pectin, agar, etc.) to the anti-solvent.
Preferably, the prolamin includes any one of zein, kafirin, Setarin, Rice gliadin, Triticum, hordein, and highland barley gliadin, but is not limited to the above.
Preferably, the active is a lipid soluble active, including but not limited to antibacterial, anti-inflammatory, growth promoting, analgesic actives such as curcumin, capsaicin, allicin, chamomile essential oil, vitamin E, growth factors, and the like, that are sufficiently soluble in a good solvent for the prolamine.
Preferably, the good solvent includes any one of an ethanol aqueous solution, a methanol aqueous solution, an acetic acid aqueous solution, and an acetone aqueous solution.
More preferably, the good solvent includes any one of a 60% to 95% (v/v) ethanol aqueous solution, a 60% to 90% (v/v) methanol aqueous solution, an 80% to 100% (v/v) acetic acid aqueous solution, and a 70% to 80% (v/v) acetone aqueous solution.
Preferably, the anti-solvent includes any one of water, an aqueous ethanol solution, an aqueous methanol solution, an aqueous acetic acid solution, and an aqueous acetone solution.
More preferably, the anti-solvent comprises any one of water, 0.1-50% (v/v) ethanol aqueous solution, 0.1-60% (v/v) methanol aqueous solution, 0.1-60% (v/v) acetic acid aqueous solution, and 0.1-70% (v/v) acetone aqueous solution; furthermore, the volume fraction of the ethanol aqueous solution is 10-30%, the volume fraction of the methanol aqueous solution is 10-30%, the volume fraction of the acetic acid aqueous solution is 10-30%, and the volume fraction of the acetone aqueous solution is 10-40%.
Preferably, the dropping of the membrane stock solution into the anti-solvent at the temperature of 25-40 ℃ is a single titration, and the volume ratio of the prolamin membrane stock solution to the anti-solvent during titration is 1: 500-10000; most preferably 1: 1000. when the dosage of the anti-solvent is too small, the diffusion of the good solvent in the membrane stock solution in the anti-solvent in the titration process can influence the aggregation and diffusion of the interfacial membrane; when the amount of the anti-solvent is too high, the cost of the product increases. The mold can be used in the anti-solvent titration process to prepare the interface self-assembly active controlled release membrane with the shape consistent with that of the mold.
According to the invention, by regulating and controlling the preparation process, the aperture of the obtained porous active controlled-release membrane can be controlled to be 1-10 μm, the porosity is 5-80%, the active substance loading rate is 60-90%, and the active substance loading rate can be regulated and controlled by the solubility difference of the active substance in the membrane stock solution and the anti-solvent; the distribution of the active in the membrane and its corresponding release characteristics can be regulated by the concentration of prolamin in the membrane stock solution, the type and concentration of good solvent, and the pH value, ionic strength, and gel strength in the anti-solvent. Therefore, the specific process can realize the precise regulation and control of the microstructure of the prolamin film, the loading rate of the active substance in the interfacial film and the controlled-release behavior.
Therefore, the invention also claims the application of the prolamin interface porous active controlled release film in the preparation of active controlled release products. Including but not limited to preparing pox patch, band-aid, products for healing wound after clinical operation and film products for tissue nerve analgesia.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a preparation method of a grain alcohol soluble protein porous active controlled-release membrane interface one-step loaded active substance, the process is simple, compared with the traditional solvent volatilization method for preparing a protein membrane (the average time is 4 hours), the preparation method is completed within 5 seconds, the process efficiency is improved by 2880 times, and the process efficiency is greatly improved.
(2) The grain alcohol soluble protein porous active controlled release membrane provided by the invention can accurately regulate and control the diameter, porosity and hydrophilic-hydrophobic property of the grain alcohol soluble protein membrane by regulating and controlling the process parameters of an anti-solvent titration process, including the concentration of the grain alcohol soluble protein, the concentration of an active substance, anti-solvent parameters (ethanol concentration, pH value, ionic strength, gel strength) and the like, so as to regulate and control the load rate and controlled release behavior of the active substance in an interface membrane, provides a production technology of the protein-based active controlled release membrane with higher efficiency, adjustable structure and controlled release performance compared with the traditional active membrane, and can be applied to the fields of functional foods, medicines and skin care products by loading different active substances.
Drawings
FIG. 1 is a flow chart of prolamin interfacial porous active controlled release membrane preparation;
fig. 2 is a microscopic topography of the prolamin curcumin-loaded interfacial porous active controlled release film prepared in example 1 under a scanning electron microscope;
FIG. 3 is a microscopic topography of the prolamin interfacial porous active controlled release film prepared in example 2 under a scanning electron microscope;
FIG. 4 is a microscopic topography of the prolamin interfacial porous active controlled release film prepared in example 3 under a scanning electron microscope;
FIG. 5 is a microscopic morphology of the prolamin interfacial porous active controlled release film obtained under the anti-solvent condition of different temperatures in the scanning electron microscope of example 5;
FIG. 6 is a macro-contrast of the prolamin interfacial porous active controlled release film prepared in example 6 with different concentrations of ethanol aqueous solution as good solvent for zein;
FIG. 7 is a graph of loading rate and controlled release for prolamin interfacial porous active controlled release films prepared with anti-solvents of example 7 at various pH;
FIG. 8 is a macroscopic comparison of prolamin interfacial porous active controlled release films prepared with anti-solvents of different ionic strengths from example 8;
FIG. 9 is a macroscopic comparison of prolamin interfacial porous active controlled release films prepared under different antisolvent gel conditions in example 9;
fig. 10 is a graph of the loading rate of the prolamin porous active controlled release membrane on allicin prepared in example 10 under the conditions of deionized water as anti-solvent, ionic strength I200 mM, and pH7, respectively.
Detailed Description
The invention will be further described with reference to the drawings and the detailed description, which are not intended to limit the invention in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.
The method for testing the pore diameter of the interface membrane comprises the following steps: scanning the micro appearance of the interface membrane by a Scanning Electron Microscope (SEM) under the conditions that the voltage is 10.00KV and the magnification is 5.00KX, measuring the pore diameters of SEM pictures of different parts of the membrane by imageJ software, firstly setting a scale, turning the pictures into grey white, measuring the pore diameter size, sampling at five points, and calculating the average value of a plurality of pore diameters;
the method for testing the interfacial film porosity comprises the following steps: porosity is defined as the ratio of the area of the pores to the total area of the material, between 0 and 100%. The porosity of the material directly reflects the degree of compaction of the material. The porosity of the SEM image is measured through imageJ software, firstly, a scale is set, the image is converted into grey white, the part except the scale in the SEM image is selected out, a threshold value is adjusted, the porosity is selected, and the porosity can be measured through click measurement (Measure).
The method for testing the active substance loading rate in the active controlled release film comprises the following steps: completely dissolving the film in a good solvent, and measuring the content of the active substances under the characteristic wavelength of the active substances by an ultraviolet spectrophotometer and a fluorescence spectrometer; if the selected active coincides with the protein wavelength, the active can be extracted with an organic solvent and then diluted for determination.
Active release test in active controlled release films: and immersing the active interface film in a PBS (phosphate buffer solution) with the pH value of 7.2-7.4, sampling at fixed points, and measuring the release content of the active substances at different time points by an ultraviolet spectrophotometer and a fluorescence spectrometer under the characteristic wavelength of the active substances.
Fig. 1 is a flow chart of prolamin interfacial porous active controlled release membrane preparation.
Example 1 zein interfacial self-assembly one-step method for preparing active controlled release film
(1) Weighing 2.0g of zein, adding the zein into 8.0mL of 80% ethanol aqueous solution with volume fraction, stirring, performing ultrasonic treatment until the zein is completely dissolved, and then adding 10mg of curcumin to prepare a zein active film stock solution with mass fraction of 20%;
(2) taking 50mL of deionized water as an anti-solvent, controlling the pH value to be 5.2 and the temperature to be 25 ℃;
(3) and (3) dropping the prolamin film stock solution obtained in the step (1) into the anti-solvent obtained in the step (2) at a ratio of 50 mu L/drop to form a porous film through self-assembly.
Fig. 2 shows that the prolamin interfacial porous active controlled-release film prepared in this example has a film-forming time of 2.8 seconds, an average pore diameter of the interfacial film of 2.16 μm, and a microscopic porosity of the film of 42.15%. The loading rate of curcumin can reach 80.15%, the burst release is 50.16% in the first 5min, and the complete release is close to 100% after 7 h.
Example 2 zein interfacial self-assembly one-step method for preparing active controlled release film
The difference from example 1 is that in step (1), a 15% zein film stock solution is prepared from an 80% ethanol aqueous solution by volume fraction.
Fig. 3 shows that the prolamin interfacial porous active controlled release film prepared in this example has a film forming time of 2.5 seconds, an average pore diameter of the interfacial film of 2.63 μm, and a microscopic porosity of 60.11%. The loading rate of curcumin can reach 68.90%, the curcumin is suddenly released in the first 5min to reach 55.62%, and the curcumin is completely released after 5h to reach 100%.
Example 3 zein interfacial self-assembly one-step method for preparing active controlled release film
The difference from example 1 is that in step (1), a 10% zein film stock solution is prepared from an 80% ethanol aqueous solution by volume fraction.
Fig. 4 shows that the prolamin interfacial porous active controlled release film prepared in this example has a film forming time of 3.0 seconds, an interfacial film pore size of 3.12 μm, and a film micro-porosity of 63.16%. The loading rate of curcumin can reach 71.98%, the burst release is 58.13% in the first 5min, and the complete release is close to 100% after 7 h.
Example 4 zein interfacial self-assembly one-step method for preparing active controlled release film
The method is the same as the example 1 except that the step (1) is to adopt 80 percent ethanol water solution by volume fraction to prepare 30 percent zein film stock solution, and the added active substance is allicin; in the step (2), the temperature of the deionized water is controlled to be 40 ℃.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 2.5 seconds, the pore diameter of the interfacial film is 0.58 mu m, and the micro-porosity of the film is 22.67%. The allicin loading rate can reach 86.11%, the burst release rate is 53.54% in the first 5min, and the complete release rate is close to 100% after 7 h.
Example 5 zein interfacial self-assembly one-step method for preparing active controlled release film
The influence of the anti-solvent at different temperatures on the active controlled release membrane was verified:
the same as example 1 except that the temperature of the deionized water anti-solvent in step (2) was controlled to 25 deg.C, 30 deg.C, and 40 deg.C, respectively. The film forming time of the obtained prolamin interface porous active controlled release film is respectively 2.8 seconds, 2.7 seconds and 1.8 seconds, the pore diameter of the interface film is respectively 2.16 micrometers, 1.52 micrometers and 0.74 micrometers, and the micro porosity of the film is 42.15%, 35.37% and 28.37%. The load rates of curcumin respectively reach 80.15%, 83.27% and 88.11% to the maximum, the active controlled release membrane prepared at the temperature of 25 ℃ releases 50.16% in a burst at the first 5mn, and the active controlled release membrane completely releases nearly 100% after 7 h; the active controlled release membrane prepared at the temperature of 30 ℃ releases 46.09% suddenly in the first 5min and completely releases nearly 100% after 8 h; the active controlled release membrane prepared at the temperature of 40 ℃ releases 40.15 percent suddenly in the first 5min and completely releases nearly 100 percent after 8 h.
Fig. 5 is an SEM picture of a prolamin interfacial porous active controlled release film obtained under an anti-solvent at 25 ℃, 30 ℃, 40 ℃, and it can be seen from fig. 5 that the diffusion property of zein can be changed by adjusting the temperature of the anti-solvent, thereby affecting the microstructure of the interfacial film and entering the controlled release of the active substance.
Example 6 zein interfacial self-assembly one-step method for preparing active controlled release film
The influence of ethanol water solutions with different concentrations as a good solvent of zein on the active controlled-release membrane is verified:
the difference from example 1 is that 70% (v/v), 80% (v/v), 90% (v/v), and methanol aqueous solutions were used to dissolve zein in step (1).
The film forming time of the obtained prolamin interface porous active controlled release film is respectively 3.0 seconds, 2.8 seconds and 2.5 seconds, the pore diameter of the interface film is respectively 2.56 micrometers, 2.16 micrometers and 1.56 micrometers, and the micro porosity of the film is respectively 48.45%, 42.15% and 30.53%.
The load rates of curcumin are 76.11%, 80.15% and 73.54%, respectively, the good solvent is 70% methanol, and the active controlled release membrane prepared by the method can release 52.14% suddenly in the first 5min and completely release nearly 100% after 6 h; the active controlled-release membrane prepared by using 80% methanol as a good solvent is released suddenly for 50.16% in the first 5min and is completely released to be close to 100% after 7 h; the active controlled release membrane prepared by good solvent of 90 percent methanol has 47.96 percent of burst release in the first 5min and the complete release after 6h is close to 100 percent.
Fig. 6 is a photograph of a prolamin interface porous active controlled-release film prepared by using methanol aqueous solutions with different concentrations as a good solvent for zein, and it can be seen from fig. 6 that the diffusion performance of zein at the interface can be changed by adjusting the concentration of the good solvent, because zein contains more than 50% of hydrophobic amino acid, and along with the increase of the methanol concentration of the good solvent, the solubility of zein is increased, and the diffusion of zein at the interface is influenced, so that the microstructure of the interface film is influenced, and the controlled release of active substances is further adjusted.
Example 7 zein interfacial self-assembly one-step method for preparing active controlled release film
The effect of anti-solvents of different pH on the active controlled release membrane was verified:
the difference from example 1 is that the anti-solvent deionized water is adjusted to pH 3.0, 5.2 (pure water), 6.2 (isoelectric point), 7.0, 9.0 with sodium hydroxide and/or hydrogen chloride, respectively, and the loaded active substance is capsaicin.
The film forming time of the obtained prolamin interface porous active controlled release film is respectively 3.2 seconds, 2.8 seconds, 3.0 seconds, 3.2 seconds and 3.3 seconds, the pore diameter of the interface film is respectively 2.18 micrometers, 2.16 micrometers, 1.65 micrometers, 1.08 micrometers and 2.03 micrometers, and the micro-porosity of the film is 47.32%, 42.15%, 30.56%, 25.67% and 13.23%.
The loading rates of capsaicin are 72.22%, 80.15%, 66.45%, 65.87% and 77.09% respectively; when the pH value of the anti-solvent is 3.0, the prepared active controlled release membrane suddenly releases 52.34% in the first 5min and completely releases nearly 100% after 7 h; when the pH value of the anti-solvent is 5.2, the prepared active controlled-release membrane can release 50.16% suddenly in the first 5min, and can completely release nearly 100% after 7 h; the active controlled release membrane prepared when the pH value of the anti-solvent is 6.2 suddenly releases 49.26% in the first 5min and completely releases nearly 100% after 7 h; the active controlled release membrane prepared when the pH value of the anti-solvent is 7.0 suddenly releases 55.43% in the first 5min and completely releases nearly 100% after 7 h; the active controlled release membrane prepared when the pH value of the anti-solvent is 9.0 has a burst release rate of 50.56% in the first 5min and is completely released to be close to 100% after 7 h.
Fig. 7 is a graph showing the loading and controlled release of capsaicin by a prolamin interfacial porous active controlled release membrane prepared by anti-solvents with different pH, and it can be seen from fig. 7 (left graph) that the loading rate of capsaicin can be regulated by different pH of anti-solvents, the loading rate in pure water is the highest and is as high as 80.15%, and the loading rate in pure water is 76.31% when the pH is 9 times; as can be seen from FIG. 7 (right panel), the active membrane formed by different anti-solvent pH release 50-56% in the first 5min and close to 100% after 7 h.
The appearance result of the zein active interface film can be changed by regulating the pH of the anti-solvent, and different pH can influence the solubility of the zein, so that the self-aggregation speed of the zein in the anti-solvent is influenced, the zein has low solubility under an acidic condition, and is fast in self-aggregation and slow in diffusion; the isoelectric point pH6.2 has no charge influence, and has fast self-aggregation and slow diffusion; under alkaline conditions, the solubility of zein is increased, the self-aggregation acidity is slowed down, and the diffusion performance is enhanced; the microstructure of the interfacial film is different, so that the loading and controlled release effects of the interfacial active film on active matters are influenced.
Example 8 zein interfacial self-assembly one-step method for preparing active controlled release film
The influence of the anti-solvents with different ionic strengths on the active controlled-release membrane is verified:
the difference from example 1 is that the anti-solvent deionized water is adjusted to 50mM, 100mM, 200mM, 500mM of ionic strength with sodium chloride.
The film forming time of the obtained prolamin interfacial porous active controlled release film is respectively 2.5 seconds, 2.9 seconds, 3.0 seconds and 3.5 seconds, the pore diameter of the interfacial film is respectively 2.13 μm, 1.31 μm, 1.14 μm and 1.28 μm, and the micro-porosity of the film is respectively 35.36%, 42.31%, 27.26% and 17.39%.
The load rates of curcumin are 75.43%, 78.32%, 85.67% and 88.93% respectively, the active controlled release membrane prepared when the ionic strength is 50mM releases 35.54% suddenly in the first 5min, and the complete release is close to 100% after 6 h; the active controlled release membrane prepared when the ionic strength is 100mM releases 43.32% suddenly in the first 5min, and completely releases nearly 100% after 6 h; the active controlled release membrane prepared when the ionic strength is 200mM releases 20.18 percent suddenly in the first 5min, and completely releases nearly 100 percent after 7 h; the active controlled release membrane prepared at the ionic strength of 500mM releases 18.64% in a burst mode within the first 5min, and completely releases nearly 100% after 8 h.
Ionic strength indirectly affects the formation of protein aggregates as one of the factors affecting protein solubility. The anions and cations in the solution can be associated with protein molecules through electrostatic interaction, so that the surface charge of the protein molecules is changed, the surface charge of the protein can be shielded through electrostatic interaction at certain ionic strength, the stability of a protein solution system is damaged, and the aggregation reaction of the protein is aggravated by exposing more hydrophobic groups. The gradual increase of the ionic strength leads the surface charge of the protein to tend to be saturated, and the excessive ions lead the interaction between the protein molecules and the solvent to be enhanced, thereby inhibiting the aggregation of the protein; fig. 8 is a photograph of a prolamin interfacial porous active controlled release membrane prepared from anti-solvents with different ionic strengths, and it can be seen that the macro size of the anti-solvent 50-500mM is increased and then decreased, the macro size is an important factor for the self-aggregation and diffusion of the reactive protein at the interface, and the macro size can reflect the self-aggregation and diffusion degree of the ionic strength to the zein at the interface, so as to regulate and control the loading and controlled release of the membrane to the active substance.
Example 9 zein interfacial self-assembly one-step method for preparing active controlled release film
The effect of anti-solvents of different gel strengths on the active controlled release membrane was verified:
the difference is that the anti-solvent deionized water is adjusted to have the gel strength of 0, 5Pa, 10Pa, 15Pa, 20Pa and 25Pa by adopting gelatin.
The film forming time of the obtained prolamin interfacial porous active controlled-release film is respectively 2.8 seconds, 2.9 seconds, 3.2 seconds, 3.5 seconds, 4.3 seconds and 5 seconds, the pore diameter of the interfacial film is respectively 2.16 μm, 2.05 μm, 1.87 μm, 1.56 μm, 1.36 μm and 0.23 μm, and the micro-porosity of the film is respectively 42.15%, 40.13%, 32.75%, 23.11%, 12.23% and 5.43%.
The load rates of curcumin are respectively 80.15%, 81.23%, 85.16%, 88.16%, 88.67% and 89.38%; when the gel strength is 0, the prepared active controlled release membrane can release 50.16% suddenly in the first 5min, and can completely release nearly 100% after 7 h; when the gel strength is 5pa, the prepared active controlled release membrane can burst at 32.11% in the first 5min, and can completely release nearly 100% after 7 h; the prepared active controlled-release membrane with the gel strength of 10pa can release 25.87% suddenly in the first 5min, and completely release nearly 100% after 7 h; when the gel strength is 15pa, the prepared active controlled release membrane can release 20.13% suddenly in the first 5min, and the complete release is close to 100% after 8 h. When the gel strength is 20pa, the prepared active controlled release membrane can release 11.13% suddenly in the first 5min, and the complete release is close to 100% after 9 h. When the gel strength is 25pa, the prepared active controlled release membrane can release 6.13% in a burst mode within the first 5min, and the complete release is close to 100% after 24 h.
The result of the diffusion performance picture of the active controlled release membrane prepared by the anti-solvent with different gel strengths is shown in fig. 9, and it can be seen from the picture that along with the increase of the gel strength, the diffusion performance of the protein membrane stock solution at the interface is reduced, and the network structure of the gel has a barrier effect on the diffusion effect of zein molecules at the interface, so that the larger the gel strength is, the smaller the macroscopic size of the interface membrane is, when the membrane stock solution cannot diffuse at the interface, a more compact thin film is formed at the interface in a collapse situation, and thus the microscopic pore size of the membrane is reduced; as the gel strength increases, the dispersion and solubility of the active in the anti-solvent (gel) decreases, thus increasing the loading of the active.
Example 10 zein interfacial self-assembly one-step method for preparing active controlled release film
The same as example 1, except that the active substance added in step (1) is allicin; in the step (2), the anti-solvent is deionized water, the ionic strength I is 200mM, and the pH is 7.
FIG. 10 is a graph showing the loading rate of allicin, and it can be seen from the graph that the parameter for regulating the anti-solvent can regulate the loading rate of allicin.
Example 11 preparation of active controlled release Membrane by one step method of wheat gliadin interfacial self-Assembly
The difference from example 1 is that zein was replaced with wheat zein.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 4.6 seconds, the pore diameter of the interfacial film is 1.78 μm, and the micro-porosity of the film is 22.36%. The loading rate of curcumin is 86.22%, and the release result shows that the active controlled release membrane prepared by the embodiment can release 32.56% in a burst mode within the first 5min, and the complete release is close to 100% after 7 h.
Example 12 preparation of active controlled-release Membrane by one-step method of hordein interfacial self-Assembly
The difference from example 1 is that zein was replaced with hordein.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 4.1 seconds, the pore diameter of the interfacial film is 1.98 mu m, and the micro-porosity of the film is 34.76%. The loading rate of curcumin is 78.32%, and the release result shows that the active controlled release membrane prepared by the embodiment can release 45.13% suddenly in the first 5min, and the complete release is close to 100% after 7 h.
Example 13 zein interfacial self-assembly one-step preparation of active controlled-release films
The same as example 1, except that 80% (v/v) methanol aqueous solution was used to dissolve zein in step (1).
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 3.6 seconds, the pore diameter of the interfacial film is 2.11 microns, and the microscopic porosity of the film is 31.26%. The loading rate of curcumin is 83.61%, and the release result shows that the active controlled release membrane prepared by the embodiment can release 37.68% suddenly in the first 5min, and the complete release is close to 100% after 7 h.
Example 14 zein interfacial self-assembly one-step preparation of active controlled-release films
The same as example 1, except that 80% (v/v) acetic acid aqueous solution was used to dissolve zein in step (1).
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 3.2 seconds, the pore diameter of the interfacial film is 2.67 mu m, and the microscopic porosity of the film is 46.91%. The loading rate of curcumin is 65.23%, and the release result shows that the active controlled release membrane prepared by the embodiment can release 47.16% suddenly in the first 5min and completely release nearly 100% after 7 h.
Example 15 zein interfacial self-assembly one-step preparation of active controlled-release film
The same as example 1, except that 80% (v/v) acetone aqueous solution was used to dissolve zein in step (1).
The film forming time of the prolamin interfacial porous active controlled release film prepared in the embodiment is 2.3 seconds, the pore diameter of the interfacial film is 2.65 mu m, and the micro porosity of the film is 32.07%. The loading rate of curcumin is 79.09%, and the release result shows that the active controlled release membrane prepared by the embodiment has 46.33% of burst release in the first 5min and nearly 100% of complete release after 7 h.
Example 16 zein interfacial self-assembly one-step preparation of active controlled-release films
The same as example 13, except that 20% (v/v) methanol aqueous solution was used as an antisolvent in the step (2), and pH 5.2 was adjusted with sodium hydroxide and/or hydrogen chloride while controlling the temperature at 25 ℃.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 2.5 seconds, the pore diameter of the interfacial film is 1.71 mu m, and the microscopic porosity of the film is 33.21%. The loading rate of curcumin is 75.65%, and the release result shows that the active controlled release membrane prepared by the embodiment can release 43.22% suddenly in the first 5min, and the complete release is close to 100% after 7 h.
Example 17 zein interfacial self-assembly one-step preparation of active controlled-release films
The same as example 14, except that 20% (v/v) acetic acid aqueous solution was used as an antisolvent in step (2), and pH 5.2 was adjusted with sodium hydroxide and/or hydrogen chloride, and the temperature was controlled to 25 ℃.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 2.2 seconds, the pore diameter of the interfacial film is 1.76 mu m, and the micro-porosity of the film is 36.08%. The loading rate of curcumin is 70.07%, and the release result shows that the active controlled release membrane prepared by the embodiment has 40.18% of burst release in the first 5min and nearly 100% of complete release after 7 h.
Example 18 zein interfacial self-assembly one-step preparation of active controlled-release films
The same as example 15, except that 20% (v/v) acetone aqueous solution was used as an antisolvent in step (2), and pH was adjusted to 5.2 using sodium hydroxide and/or hydrogen chloride, and the temperature was controlled to 25 ℃.
The film forming time of the prolamin interfacial porous active controlled-release film prepared in the embodiment is 4.2 seconds, the pore diameter of the interfacial film is 2.32 mu m, and the microscopic porosity of the film is 43.11%. The loading rate of curcumin is 80.56%, and the release result shows that the active controlled release membrane prepared by the embodiment has 42.12% of burst release in the first 5min and nearly 100% of complete release after 7 h.
The results of the above embodiments show that by regulating the concentration of the cereal prolamin, the type of the good solvent in the antisolvent, the pH, the ionic strength and the like, the morphological structure, the hydrophilicity and hydrophobicity and the like of the upper and lower surfaces of the prolamin interface porous membrane can be changed, so that the load and the controlled release of the interface membrane on the active substance can be regulated and controlled, and the application of the cereal prolamin in the field of transdermal drug delivery is expanded.
Comparative example 1
The difference from example 1 is that step (1) is to prepare a 5% zein active film stock solution with a volume fraction of 80% ethanol aqueous solution.
The comparative example employed 5% zein, which formed a white flocculent form and was not cross-linked to form a continuous film, at which point the loading of curcumin was low, only 13.22%.
Comparative example 2
The difference from example 1 is that in step (1), a 50% mass zein film stock solution is prepared from 80% ethanol aqueous solution by volume fraction.
The membrane stock solution zein prepared by the comparative example has low solubility and high viscosity, and through anti-solvent titration, the solution has poor film forming and diffusing performance on an interface, and the interface membrane can not form a micro-pore structure, so that the controlled release effect on an active substance can not be achieved.
Comparative example 3
The difference from example 1 is that the temperature of the antisolvent in step (2) was controlled to 10 ℃. At the temperature, the zein molecule migration speed is low, the zein molecule is difficult to diffuse at an interface, and an interface film cannot form a micro-pore structure, so that the controlled release effect on an active substance cannot be achieved.
Comparative example 4
The difference from example 1 is that the temperature of the antisolvent in step (2) was controlled at 20 ℃. At the temperature, the diameter of a film formed by the zein on the interface is increased compared with 10 ℃, the thickness of the formed film is thicker, but the diffusion of the whole film solution on the interface is poorer, the microscopic aperture formed by the interface film is very small and is 0.12 mu m, and the controlled release effect on the active substances cannot be achieved.
Comparative example 5
The difference from example 1 is that the temperature of the antisolvent in step (2) is controlled at 50 ℃.
The film formed by the film prepared by the method of the comparative example has a large diameter, but the film can not be uncovered, because the temperature is too high, zein molecules diffuse too fast on the interface, the microscopic pore size of the formed film is large and is 6.23 mu m, and the loading rate of curcumin is low and is 40.22%.
Comparative example 6 preparation of zein film by tape casting
The other conditions were the same as in example 1 except that: the zein film is self-assembled into a film by pouring a zein film stock solution into a flat plate instead of anti-solvent titration through solvent evaporation, the film forming time of the method is 4 hours, the film prepared by the method cannot form a micro-pore structure, the programmed controlled release effect on an active substance cannot be achieved, the ethanol consumption is high and is 1L ethanol/m2A film.
Comparative example 7 preparation of zein film by tabletting method
The other conditions were the same as in example 1 except that: the extrudate was cut into pellets not by anti-solvent titration but by a pelletizer, the pellets were dried by hot air, then the extruded pellets were sheeted by secondary extrusion, and finally the mixed film-forming material was blown into a film by a blown film extruder. The method has more operation steps, and the prepared membrane has single controllability of the controlled release of the active substances.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. A prolamin interface porous active controlled release membrane is characterized in that prolamin and an active substance are dissolved in a good solvent to prepare a membrane stock solution with the prolamin concentration of 10-30 wt%, and then the membrane stock solution is dripped into an anti-solvent with the temperature of 25-40 ℃ to prepare the prolamin interface porous active controlled release membrane through a one-step method.
2. The active controlled-release membrane according to claim 1, wherein the prolamin protein comprises any one of zein, kafirin, Setarin, Rice gliadin, Triticum, hordein, and Avena.
3. The active controlled release membrane of claim 1, wherein the active is a lipid soluble active.
4. The active controlled-release membrane according to claim 1, wherein the good solvent comprises any one of an aqueous ethanol solution, an aqueous methanol solution, an aqueous acetic acid solution, and an aqueous acetone solution.
5. The active controlled-release membrane according to claim 4, wherein the good solvent comprises any one of 60% to 95% (v/v) ethanol aqueous solution, 60% to 90% (v/v) methanol aqueous solution, 80% to 100% (v/v) acetic acid aqueous solution, and 70% to 80% (v/v) acetone aqueous solution.
6. The active controlled-release film according to claim 1, wherein the anti-solvent comprises any one of water, an aqueous ethanol solution, an aqueous methanol solution, an aqueous acetic acid solution, and an aqueous acetone solution.
7. The active controlled-release membrane according to claim 6, wherein the anti-solvent comprises any one of water, 0.1-50% (v/v) ethanol aqueous solution, 0.1-60% (v/v) methanol aqueous solution, 0.1-60% (v/v) acetic acid aqueous solution, and 0.1-70% (v/v) acetone aqueous solution.
8. The active controlled-release membrane according to claim 1, wherein the anti-solvent has a pH of 3.0 to 10.0, an ionic strength of 0 to 700mM, and a gel strength of 0 to 100 Pa.
9. The active controlled-release membrane according to claim 1, wherein the dropping of the membrane stock solution into the anti-solvent at a temperature of 25-40 ℃ is a single titration, and the volume ratio of the membrane stock solution to the anti-solvent at the time of dropping is 1: 500 to 10000.
10. Use of a prolamin interfacial porous active controlled release film according to any of claims 1 to 9 for the preparation of a controlled release product of an active.
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