CN114225210A - Novel transdermal drug delivery micro-nano structure and preparation method thereof - Google Patents

Abstract

The invention relates to a novel transdermal drug delivery micro-nano structure which comprises a base, wherein main needle points are distributed and fixed on the outer wall of the bottom of the base in an array manner, and auxiliary needle points are distributed on the outer walls of two sides of the top end of the main needle points; the structure shape of the auxiliary needle point is one or a combination of a plurality of needle shapes, hemispheres, rectangles and trapezoids; the auxiliary needle points are in various combinations of different orientations, different sizes, different shapes and different effects; the transdermal drug delivery micro-nano structure can have irregular micro-structure arrangement, more and smaller micro-structures with drug guiding effect are added on a single micro-structure of a traditional transdermal drug delivery device, the density of the micro-needles is higher, and the product effect can be improved due to more micro-needle structures in unit area; the need for vertical insertion of conventional microneedles can be reduced or eliminated in use; the contact area is large, and the multi-directional absorption can be realized; through the optimization of the micro-needle arrangement in different directions, the transdermal depth can be controlled more accurately.

Description

Novel transdermal drug delivery micro-nano structure and preparation method thereof

Technical Field

The invention relates to the technical field of transdermal drug delivery, in particular to a novel transdermal drug delivery micro-nano structure and a preparation method thereof.

Background

The transdermal drug delivery technology has the advantages of convenience, rapidness, no pain, good use effect and the like, and has increasingly wide application in the aspects of wrinkle resistance, whitening, beauty treatment and blood sugar control; the common transdermal drug delivery is realized by a micro-needle structure, and the depth of the micro-nano structure is usually dozens to hundreds of micrometers, so that the micro-nano structure is used for penetrating the stratum corneum of the skin to facilitate the absorption of the drug components; the common micro-needle structure is periodically arranged, template processing is carried out in modes of precision machinery, laser engraving and the like, and the template usually takes an array structure as a main use mode;

the Chinese patent CN111467667B discloses a multilayer microneedle array and a preparation method thereof, and the multilayer microneedle array is prepared by a method of repeatedly utilizing a template for copying; the unique multilayer structure of the needle tip enables the microneedle array to realize mechanical interlocking with tissues, so that the tissue adhesion capability of the microneedle array is enhanced; but the transdermal drug delivery microstructure formed by the method has single design and large performance limitation; an implantable double-invar microneedle patch and a preparation method thereof are disclosed in Chinese patent CN110870943A, the microneedle is provided with an upper section of needle point made of biodegradable water-insoluble high polymer material, a lower section of integrated base made of water-soluble high polymer material is used for forming a two-section microneedle with the needle point insoluble in water and the base soluble in water, after the two-section microneedle acts on the skin, the lower section of integrated base absorbs the water in the skin to be quickly dissolved, the quick separation is realized, the upper section of needle point can be embedded into the skin, and a user can ensure the long-term release of the drug in the body without pasting the microneedle for a long time;

however, the traditional transdermal micro-needle delivery array structure has the defects of low micro-needle density, relatively limited drug effect, vertical attachment of the micro-needles when the micro-needles are used in a single direction, difficulty in further improvement of the effect and the like, and the existing transdermal micro-nano delivery structure has the difficulties of local optimization and the like less according to the detailed condition of the skin surface of a human body.

Disclosure of Invention

The invention aims to provide a novel transdermal drug delivery micro-nano structure and a preparation method thereof, and solves the problems in the background art.

In order to achieve the purpose, the invention provides the following technical scheme: the utility model provides a novel transdermal micro-nano structure that doses, includes the base, it is fixed with main needle point to distribute the array on the bottom outer wall of base, it is provided with the supplementary needle point to distribute on the outer wall of main needle point top both sides.

As a preferred embodiment of the invention, the structural shape of the auxiliary needle point is one or more of needle type, hemisphere type, rectangle and trapezoid.

As a preferred embodiment of the present invention, the auxiliary needle tip is a combination of different orientations, different sizes, different shapes, and different effects.

The invention also provides a preparation method of the novel transdermal drug delivery micro-nano structure, which comprises the following steps: s1, taking the substrate; s2, spreading photoresist; s3, exposure and development; s4, etching the main needle point hole; s5, etching the auxiliary needle point hole; s6, preparing a microneedle array;

in S1, polydimethylsiloxane and a curing agent are mixed, poured into a substrate template and cured, and the cured polydimethylsiloxane is stripped from the substrate template; obtaining a polydimethylsiloxane substrate;

in S2, taking a single layer of photoresist as an etching mask, and spreading the photoresist on the outer wall of the polydimethylsiloxane substrate in a spin coating mode, wherein the thickness of the photoresist layer is 60 microns;

in S3, a photosensitive film output by a high-resolution laser phototypesetter is used as an exposure mask, a polyfluorinated ethylene propylene transparent anti-sticking film is placed between a photoresist and the exposure mask, and then exposure is carried out by an exposure machine; after exposure, developing with absolute ethyl alcohol acting developing solution for 20 s;

in S4, the exposed and developed polydimethylsiloxane substrate is flatly placed in a plasma etcher, under vacuum low pressure, radio frequency generated by an ICP radio frequency power supply is output to a ring-shaped coupling coil, mixed etching gas in a certain proportion generates high-density plasma through coupled glow discharge, and the plasma bombards the surface of a substrate under the action of RF radio frequency of a lower electrode, chemical bonds in a substrate developing area are broken, volatile substances are generated with the etching gas, are separated from the substrate in a gas form, and are pumped out from a vacuum pipeline, so that the etching of a main needle point hole is completed;

in S5, the polydimethylsiloxane substrate which completes the etching of the main pinpoint hole is obliquely fixed in a plasma etching machine, and the auxiliary pinpoint holes with different shapes are obtained under the condition that the main pinpoint hole is at different positions and has the same opening size by adjusting the etching gas flow proportion, etching parameters, hardware structure and the like in a menu of the etching machine; obtaining a polydimethylsiloxane template with conical holes;

in S6, filling a raw material solution into a polydimethylsiloxane template with a conical main needle point hole and auxiliary needle point holes with different shapes, solidifying the raw material solution, and then stripping the solidified material from the template to obtain a microneedle array and a base to obtain the novel transdermal drug delivery micro-nano structure.

In a preferred embodiment of the present invention, in S2, the photoresist comprises the following raw materials by weight: 40-70% of epoxy acrylate, 8-15% of tripropylene glycol diacrylate, 20-50% of tricyclodecane methyl diacrylate, 2-4% of 1-hydroxy hexyl phenyl ketone, 0.2-2% of organic alkyl coupling agent KH-570, 0.2-1% of organic alcohol defoaming agent, 0.2-1% of organic alkyl leveling agent and the total amount of the raw materials is 100%.

In a preferred embodiment of the present invention, in S3, the polyperfluoroethylene propylene transparent release film has a thickness of 0.1 mm.

In a preferred embodiment of the present invention, in S3, after developing the photoresist, the photoresist is completely cured by irradiating the photoresist with an ultraviolet high-pressure mercury lamp with a power of 500W for 3 min.

In a preferred embodiment of the present invention, in S6, the raw material solution is mainly one or more selected from the group consisting of ethoxylated trimethylolpropane triacrylate, polyethylene glycol diacrylate, polyethylene glycol methyl methacrylate, methacrylate gelatin, and methylated hyaluronic acid.

In a preferred embodiment of the present invention, in S5, the obtained polydimethylsiloxane template is placed in an ultrasonic cleaning machine and heated to 100 ℃ to remove the surface photoresist.

Compared with the prior art, the invention has the following beneficial effects:

1. the transdermal drug delivery micro-nano structure can have irregular micro-structural arrangement, more and smaller micro-structures (auxiliary needle points) with drug guiding effect are added on a single micro-structure (main needle point) of a traditional transdermal drug delivery device, the micro-needle density is higher, and the product effect can be improved due to more micro-needle structures in unit area; the bottom/top size and the side size of each fine microneedle can be adjusted by design; the microneedles with multiple directions are oriented, so that the requirement of vertical insertion of the traditional microneedles can be reduced or eliminated in use; the contact area is large, multi-directional absorption can be realized, the dissolution time is shortened, and the use feeling is improved; through the optimization of the micro-needle arrangement in different directions, the transdermal depth can be controlled more accurately.

2. The preparation method of the transdermal drug delivery micro-nano structure solves the problems that the traditional precision machining process is difficult to realize and various micro-nano machining processes are usually required to be directly combined with each other, and is inconvenient, is realized by pertinently inclining the angle of the substrate in the etching process, and can realize that different micro-nano morphological structures are obtained under the condition of the same opening size at different positions by optimizing the etching gas flow proportion, power supply parameters and the like in the etching process; through adjusting or changing the size, position and shape of the microstructure, and material proportion, process parameters and process design in the template copying process, the related difficulty of the template volume production process can be further reduced, the original appearance of the microstructure is kept, and the efficiency and yield of the template copying process are improved.

Drawings

Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:

fig. 1 is a structural diagram of a novel transdermal drug delivery micro-nano structure provided by the invention;

FIG. 2 is a structural diagram of a template in the preparation method of the novel transdermal drug delivery micro-nano structure provided by the invention;

fig. 3 is a flow chart of steps in the preparation of the novel transdermal drug delivery micro-nano structure provided by the invention.

In the figure: 1. a base; 2. a main needle tip; 3. an auxiliary needle tip; 4. a substrate; 5. photoresist; 6. a primary needle tip aperture; 7. auxiliary needle point holes.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.

In the description of the present invention, it is to be understood that the terms "upper", "lower", "front", "rear", "left", "right", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, are merely for convenience in describing the present invention and simplifying the description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus, should not be construed as limiting the present invention.

Referring to fig. 1-3, the present invention provides a technical solution: the utility model provides a novel transdermal micro-nano structure that doses, includes base 1, distributes on the bottom outer wall of base 1 array and is fixed with main needle point 2, distributes on the 2 top both sides outer walls of main needle point and is provided with supplementary needle point 3.

In the invention, the structure shape of the auxiliary needle point 3 is one or a combination of a plurality of needle types, hemispheres, rectangles and trapezoids.

In the invention, the structure shape of the auxiliary needle point 3 is one or a combination of a plurality of needle types, hemispheres, rectangles and trapezoids.

It should be noted that the novel transdermal drug delivery micro-nano structure can have irregular micro-structure arrangement, and a plurality of smaller micro-structures (auxiliary needle points 3) with drug guiding function are added on a single micro-structure (main needle point 2) of the traditional transdermal drug delivery device, and the micro-structures generally comprise needle shapes, hemispheres, rectangles, trapezoids or combinations of the micro-structures; the newly added microstructure (the auxiliary needle tip 3) in the novel transdermal drug delivery micro-nano structure can be combined with various microstructures with different orientations, sizes, appearances and efficacies; the microneedle structure has higher density, and more microneedle structures are arranged in a unit area, so that the product effect can be improved; the bottom/top size and the side size of each fine microneedle can be freely adjusted; the microneedles with multiple directions are oriented, so that the requirement of vertical insertion of the traditional microneedles can be reduced or eliminated in use; the contact area is large, multi-directional absorption can be realized, the dissolution time is shortened, and the use feeling is improved; through the optimization of the micro-needle arrangement in different directions, the transdermal depth can be controlled more accurately.

The invention also provides a preparation method of any one of the novel transdermal drug delivery micro-nano structures, which comprises the following steps: s1, taking the substrate 4; s2, spreading photoresist 5; s3, exposure and development; s4, etching the main needle point hole 6; s5, etching the auxiliary needle point hole 7; s6, preparing a microneedle array;

in S1, polydimethylsiloxane and a curing agent are mixed, poured into a substrate template and cured, and the cured polydimethylsiloxane is stripped from the substrate template; obtaining a polydimethylsiloxane substrate;

in S2, taking a single layer of photoresist as an etching mask, and spreading the photoresist on the outer wall of the polydimethylsiloxane substrate in a spin coating mode, wherein the thickness of the photoresist layer is 60 microns; after the thickness of the glue layer is increased, the etching mask is difficult to damage by the tiny bubbles distributed randomly, so that the etching defect caused by the bubbles is eliminated;

in S3, a photosensitive film output by a high-resolution laser phototypesetter is used as an exposure mask, a polyfluorinated ethylene propylene transparent anti-sticking film is placed between a photoresist and the exposure mask, and then exposure is carried out by an exposure machine; after exposure, developing with absolute ethyl alcohol acting developing solution for 20 s;

in S4, the exposed and developed polydimethylsiloxane substrate is flatly placed in a plasma etcher, under vacuum low pressure, radio frequency generated by an ICP radio frequency power supply is output to a ring-shaped coupling coil, mixed etching gas in a certain proportion generates high-density plasma through coupled glow discharge, and the plasma bombards the surface of a substrate under the action of RF radio frequency of a lower electrode, chemical bonds in a substrate developing area are broken, volatile substances are generated with the etching gas, are separated from the substrate in a gas form, and are pumped out from a vacuum pipeline, so that the etching of a main needle point hole is completed;

in S5, the polydimethylsiloxane substrate which completes the etching of the main pinpoint hole is obliquely fixed in a plasma etching machine, and the auxiliary pinpoint holes with different shapes are obtained under the condition that the main pinpoint hole is at different positions and has the same opening size by adjusting the etching gas flow proportion, etching parameters, hardware structure and the like in a menu of the etching machine; obtaining a polydimethylsiloxane template with conical holes;

in S6, filling a raw material solution into a polydimethylsiloxane template with a conical main needle point hole and auxiliary needle point holes with different shapes, solidifying the raw material solution, and then stripping the solidified material from the template to obtain a microneedle array and a base 1, thereby obtaining the novel transdermal drug delivery micro-nano structure.

In an alternative embodiment, in S2, the photoresist contains the following raw materials by weight: 40-70% of epoxy acrylate, 8-15% of tripropylene glycol diacrylate, 20-50% of tricyclodecane methyl diacrylate, 2-4% of 1-hydroxy hexyl phenyl ketone, 0.2-2% of organic alkyl coupling agent KH-570, 0.2-1% of organic alcohol defoaming agent, 0.2-1% of organic alkyl leveling agent and the total amount of the raw materials is 100%.

In an alternative embodiment, in S3, the polyperfluorinated ethylene propylene transparent release film has a thickness of 0.1 mm.

In an alternative embodiment, in S3, after developing the photoresist, the photoresist is completely cured by irradiating with an ultraviolet high-pressure mercury lamp with a power of 500W for 3 min.

In an alternative embodiment, in S6, the raw material solution is mainly one or more selected from the group consisting of ethoxylated trimethylolpropane triacrylate, polyethylene glycol diacrylate, polyethylene glycol methyl methacrylate, methacrylate gelatin, and methylated hyaluronic acid.

In an alternative embodiment, the resulting polydimethylsiloxane template is placed in an ultrasonic cleaner and heated to 100 ℃ to perform the removal of the surface photoresist in S5.

It should be noted that, the transdermal drug delivery device is usually copied in batch by the processes or combination of processes of biodegradation, hot stamping, ultraviolet stamping, injection molding, etc. of the forming template having the above characteristic structure, so as to reduce the production cost; the transdermal drug delivery micro-nano structure is formed by optimizing a template processing micro-nano process, and the common micro-nano processing processes comprise various methods and combinations of photoetching, isotropic dry etching, anisotropic dry etching, wet etching, film deposition, laser direct writing, 3D printing, precision machining and the like; the transdermal drug delivery micro-nano structure template optimization processing technology can be realized by pertinently inclining the angle of the substrate in the etching process, and further optimization is carried out through the etching gas flow proportion, power supply parameters, hardware structures and the like in the etching process menu, so that different micro-nano morphology structures can be obtained under the condition of the same opening size at different positions; by adjusting or changing the size, position and shape of the microstructure, the material proportion, process parameters and process design in the template copying process, the related difficulty of the mass production process of the template can be further reduced, the original appearance of the microstructure is maintained, and the efficiency and yield of the template copying process are improved; can be directly combined with each other through a plurality of micro-nano processing technologies; performance optimization can be performed through 3D printing and laser direct writing gray level exposure; the angle and the number of each direction are freely defined by using an inclined etching process; the further effect enhancement or performance optimization of the micro-needle structure can be achieved through the selection and the proportioning of subsequent biological materials.

While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims (9)

1. The novel transdermal drug delivery micro-nano structure is characterized by comprising a base (1), wherein a main needle point (2) is fixed on the outer wall of the bottom of the base (1) in an array mode, and auxiliary needle points (3) are distributed on the outer walls of the two sides of the top end of the main needle point (2).

2. The novel transdermal drug delivery micro-nano structure according to claim 1, is characterized in that: the auxiliary needle point (3) is in one or more of needle shape, hemisphere shape, rectangle shape and trapezoid shape.

3. The novel transdermal drug delivery micro-nano structure according to claim 1, is characterized in that: the auxiliary needle points (3) are in various combinations of different orientations, different sizes, different appearances and different efficacies.

4. A preparation method of a novel transdermal drug delivery micro-nano structure according to any one of claims 1 to 3, which is characterized by comprising the following steps: the method comprises the following steps: s1, taking the substrate (4); s2, spreading photoresist (5); s3, exposure and development; s4, etching the main needle point hole (6); s5, etching the auxiliary needle point hole (7); s6, preparing a microneedle array;

in S1, polydimethylsiloxane and a curing agent are mixed, poured into a substrate template and cured, and the cured polydimethylsiloxane is stripped from the substrate template; obtaining a polydimethylsiloxane substrate;

in S2, taking a single layer of photoresist as an etching mask, and spreading the photoresist on the outer wall of the polydimethylsiloxane substrate in a spin coating mode, wherein the thickness of the photoresist layer is 60 microns;

in S3, a photosensitive film output by a high-resolution laser phototypesetter is used as an exposure mask, a polyfluorinated ethylene propylene transparent anti-sticking film is placed between a photoresist and the exposure mask, and then exposure is carried out by an exposure machine; after exposure, developing with absolute ethyl alcohol acting developing solution for 20 s;

in S4, the exposed and developed polydimethylsiloxane substrate is flatly placed in a plasma etcher, under vacuum low pressure, radio frequency generated by an ICP radio frequency power supply is output to a ring-shaped coupling coil, mixed etching gas in a certain proportion generates high-density plasma through coupled glow discharge, and the plasma bombards the surface of a substrate under the action of RF radio frequency of a lower electrode, chemical bonds in a substrate developing area are broken, volatile substances are generated with the etching gas, are separated from the substrate in a gas form, and are pumped out from a vacuum pipeline, so that the etching of a main needle point hole is completed;

in S5, the polydimethylsiloxane substrate which completes the etching of the main pinpoint hole is obliquely fixed in a plasma etching machine, and the auxiliary pinpoint holes with different shapes are obtained under the condition that the main pinpoint hole is at different positions and has the same opening size by adjusting the etching gas flow proportion, etching parameters, hardware structure and the like in a menu of the etching machine; obtaining a polydimethylsiloxane template with conical holes;

in S6, filling a raw material solution into a polydimethylsiloxane template with a conical main needle point hole and auxiliary needle point holes with different shapes, solidifying the raw material solution, and then stripping the solidified material from the template to obtain a microneedle array and a base to obtain the novel transdermal drug delivery micro-nano structure.

5. The preparation method of the novel transdermal drug delivery micro-nano structure according to claim 4, characterized in that: in the step S2, the photoresist comprises the following raw materials in percentage by weight: 40-70% of epoxy acrylate, 8-15% of tripropylene glycol diacrylate, 20-50% of tricyclodecane methyl diacrylate, 2-4% of 1-hydroxy hexyl phenyl ketone, 0.2-2% of organic alkyl coupling agent KH-570, 0.2-1% of organic alcohol defoaming agent, 0.2-1% of organic alkyl leveling agent and the total amount of the raw materials is 100%.

6. The preparation method of the novel transdermal drug delivery micro-nano structure according to claim 4, characterized in that: in the S3, the polyperfluoroethylene propylene transparent release film has a thickness of 0.1 mm.

7. The preparation method of the novel transdermal drug delivery micro-nano structure according to claim 4, characterized in that: in S3, after the photoresist was developed, the photoresist was completely cured by irradiating it with an ultraviolet high-pressure mercury lamp with a power of 500W for 3 min.

8. The preparation method of the novel transdermal drug delivery micro-nano structure according to claim 4, characterized in that: in S6, the raw material solution is mainly one or more selected from the group consisting of ethoxylated trimethylolpropane triacrylate, polyethylene glycol diacrylate, polyethylene glycol methyl methacrylate, methacrylate gelatin, and methylated hyaluronic acid.

9. The preparation method of the novel transdermal drug delivery micro-nano structure according to claim 4, characterized in that: and in the step S5, the obtained polydimethylsiloxane template is placed into an ultrasonic cleaning machine, and is heated to 100 ℃ to remove the surface photoresist.

Images