CN116212216A

CN116212216A - Soluble microneedle and preparation method thereof

Info

Publication number: CN116212216A
Application number: CN202310035608.7A
Authority: CN
Inventors: 苏洁; 邹帅; 程微; 倪孟飞; 代龙飞; 刘亮
Original assignee: Xiangbang Suzhou Biomaterial Technology Co ltd; Suzhou University
Current assignee: Xiangbang Suzhou Biomaterial Technology Co ltd; Suzhou University
Priority date: 2023-01-10
Filing date: 2023-01-10
Publication date: 2023-06-06

Abstract

The invention discloses a preparation method of a soluble microneedle, which comprises the following steps: s1, preparing a silicon microneedle array on the surface of a silicon wafer; s2, spreading the soluble microneedle material solution on the surfaces of the silicon microneedle array and the silicon wafer, and curing to obtain a soluble microneedle membrane; s3, stripping the soluble microneedle membrane from the silicon microneedle array and the surface of the silicon wafer through acid washing, wherein the back of the soluble microneedle membrane is provided with a micro-groove array; s4, pouring a soluble microneedle material solution and/or a supporting material solution into the micro-groove array of the soluble microneedle membrane, and curing to obtain the soluble microneedle. The preparation method of the soluble microneedle is simple, the service life of the silicon wafer template is long, the process cost is low, the large-area preparation can be realized, the preparation method is suitable for mass industrialized production, and the prepared microneedle has high mechanical strength.

Description

Soluble microneedle and preparation method thereof

Technical Field

The invention belongs to the technical field of microneedles, and particularly relates to a soluble microneedle and a preparation method thereof.

Background

Microneedle transdermal delivery is a novel technology for delivering drugs on the skin in a minimally invasive manner, and has been a research hotspot in biotechnology and medical fields. The technology loads the medicine or the active ingredient into the micro-needle array with the micron size, forms a micro-size channel on the surface of the skin, and leads the medicine or the active ingredient to be directly guided into the epidermis or the upper dermis through the stratum corneum barrier, so that the medicine or the active ingredient can directly participate in microcirculation through capillary vessels, and local accurate treatment is realized. In addition, since the microneedle does not touch the pain nerve in the dermis, the administration of the microneedle does not cause pain to the human body and skin injury.

The preparation of the microneedle array is the core of the transdermal drug delivery technology of the microneedles, and is a novel physical permeation promotion technology, which is formed by arranging miniature needlepoints with the length of tens of micrometers to several millimeters and the tip diameter of less than tens of micrometers on a base in an array mode. Microneedles can be classified into solid microneedles and soluble microneedles according to the kind of manufacturing materials. Solid microneedles are generally administered in two types: firstly, the solid micro-needle array is used for penetrating the skin, so that micron-sized channels are generated on the surface of the skin, and medicines penetrate into the skin layer through the channels, so that the aim of transdermal administration is fulfilled; secondly, by coating the drug on the surface of the microneedle (i.e., coated microneedle) or placing the drug in the hole of the microneedle with a hole (i.e., hollow microneedle), the drug is delivered into the epidermis of the skin while penetrating the skin. Soluble microneedles are typically formed from biodegradable polymers into arrays of soluble microneedles and encapsulate the drug or active ingredient, which are dissolved and released after penetration into the skin. Compared with the solid micro-needle, the whole soluble micro-needle is a medicine carrying area, and has obvious advantages in medicine carrying amount. In addition, the soluble microneedle also has no risk of breaking needle residues of the solid microneedle, has relatively low cost and has better commercialized prospect.

In the prior art, the soluble microneedle is generally prepared by adding a soluble microneedle raw material solution into a PDMS microneedle female mold, and stripping the soluble microneedle raw material solution from the mold after the soluble microneedle raw material solution is sufficiently solidified. Such as: in chinese patent CN111603435a, firstly, a microneedle male mold is prepared by using a laser direct writing technique, then a PDMS microneedle female mold is obtained by reverse molding of the male mold, and finally, a prepared mixture of soluble microneedle raw materials is added into the PDMS female mold, and a soluble microneedle is obtained by demolding; in Chinese patent CN111544758A, a PDMS mould plate is prepared by utilizing PDMS and a curing agent, then a microneedle female mould is prepared by utilizing an integrated optical fiber carbon dioxide laser marking machine to etch the PDMS mould plate, and finally the prepared soluble microneedle raw material mixed solution is added into the PDMS female mould prepared by the method, and a soluble microneedle is obtained by demoulding; in China CN113069683A, a PDMS microneedle female die is prepared by utilizing an ETPTA microneedle template through reverse molding, then a microneedle female film is filled with a soluble microneedle raw material solution in a high-speed centrifugal mode, ultraviolet light is used for curing, and finally the soluble microneedle is prepared by demolding after full curing; in patent CN114681604a, it is mentioned that a mixed solution of PDMS and a curing agent is poured into a cuboid container in which a single crystal silicon male mold microneedle is placed, a female mold of the PDMS microneedle is prepared by curing, and then a soluble microneedle of a hand-foot-and-mouth vaccine is prepared by a vacuum mold-in method. In addition, other patent CN115363992A, CN110897996A, CN111558128A et al mentions the use of microneedle negative mold plates to prepare soluble microneedle arrays.

In the prior art, a microneedle array female die made of materials such as PDMS which is easy to solidify is firstly prepared, then a soluble microneedle raw material solution is injected into the female die for solidification, and the soluble microneedle is prepared through demolding. The preparation method is complex; the PDMS female mold has the problem of unclean demolding, special treatment (such as plasma treatment) is usually needed before use, even if the treatment is carried out, the problems of incomplete demolding of the microneedle and low yield of the microneedle still exist, and the service life is lower; in addition, since the prepared soluble microneedles need to have both functionalities, the mechanical strength is relatively poor.

Accordingly, in view of the above-mentioned technical problems, there is a need to provide a soluble microneedle and a method for preparing the same.

Disclosure of Invention

In view of the above, the present invention is directed to a soluble microneedle and a method for preparing the same.

In order to achieve the above object, an embodiment of the present invention provides the following technical solution:

a method of preparing a soluble microneedle, the method comprising the steps of:

s1, preparing a silicon microneedle array on the surface of a silicon wafer;

s2, spreading the soluble microneedle material solution on the surfaces of the silicon microneedle array and the silicon wafer, and curing to obtain a soluble microneedle membrane;

s3, stripping the soluble microneedle membrane from the silicon microneedle array and the surface of the silicon wafer through acid washing, wherein the back of the soluble microneedle membrane is provided with a micro-groove array;

s4, pouring a soluble microneedle material solution and/or a supporting material solution into the micro-groove array of the soluble microneedle membrane, and curing to obtain the soluble microneedle.

In one embodiment, the step S1 includes:

preparing a patterning mask on the surface of a silicon wafer;

etching the surface of the silicon wafer by a wet chemical etching process;

and removing the mask to form a silicon microneedle array on the surface of the silicon wafer.

In one embodiment, the preparation of the patterned mask on the surface of the silicon wafer is specifically:

preparing a silicon oxide layer with the thickness of 0.5-2 mu m on a silicon wafer;

coating a photoresist layer with the thickness of 5-10 mu m on the surface of the silicon oxide layer, and baking and curing;

and (3) photoetching, exposing and developing, and transferring a mask pattern on the mask plate onto the photoresist layer, wherein the diameter of a circular spot in the mask pattern is 200-600 mu m, and the center distance between adjacent circular spots is 500-2000 mu m.

In one embodiment, in the silicon microneedle array, the height of the silicon microneedles is 0.1 mm-1 mm, the bottom dimension of the silicon microneedles is 0.1 mm-1 mm, and the distance between adjacent silicon microneedles is 0.3 mm-2 mm.

In one embodiment, the step S1 further includes:

and preparing a silicon oxide layer and/or a silicon nitride layer on the surface of the silicon microneedle array and the silicon wafer.

In one embodiment, the preparation of the silicon oxide layer on the surface of the silicon microneedle array and the silicon wafer is specifically as follows:

oxidizing the surface of the silicon wafer at 600-1200 ℃ by introducing oxidizing gas for 0.5-24 h, and preparing the silicon oxide layer with the thickness of 0.02-2 mu m, wherein the oxidizing gas is oxygen or water vapor or mixed gas of the oxygen and the water vapor.

In one embodiment, the preparation of the silicon nitride layer on the surface of the silicon microneedle array and the silicon wafer is specifically as follows:

introducing ammonia gas and silane gas into a tubular vacuum furnace tube according to the proportion of 2:1-10:1, adopting a PECVD process to deposit a silicon nitride film, wherein the discharge pressure is 150 Pa-300 Pa, the discharge power is 1000W-3000W, the substrate temperature is 300-500 ℃, the deposition time is 0.5-12 h, and the silicon nitride layer with the thickness of 0.05-1 mu m is prepared.

In one embodiment, the step S3 specifically includes:

the silicon wafer with the prepared soluble microneedle membrane is placed into an acid solution containing fluorine to react, the reaction temperature is 0-50 ℃, and the reaction time is 5-5000 s.

In one embodiment, the acidic solution containing fluorine is an aqueous solution containing hydrofluoric acid, ammonium fluoride or ammonium bifluoride, and the mass concentration of the hydrofluoric acid, the ammonium fluoride or the ammonium bifluoride is 0.1% -20%.

In one embodiment, the soluble microneedle material comprises at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen tripeptide, polylactic acid, polyethylene, polypropylene, polymethyl acrylate, polyvinyl alcohol, or polymethyl methacrylate.

In one embodiment, the supporting material comprises at least one of gelatin, silicone rubber, polyacrylamide polymer, polymethyl methacrylate, polydioxanone, and polydimethylsiloxane.

The technical scheme provided by the other embodiment of the invention is as follows:

a soluble microneedle prepared by the above-described preparation method.

The invention has the following beneficial effects:

the preparation method of the soluble microneedle is simple, the service life of the silicon wafer template is long, the process cost is low, the large-area preparation can be realized, the preparation method is suitable for mass industrialized production, and the prepared microneedle has high mechanical strength.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments described in the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 is a schematic flow chart of a method for preparing soluble microneedles according to the present invention;

FIGS. 2a to 2f are process flow diagrams of the method for preparing soluble microneedles according to the present invention;

fig. 3a and 3b are scanning electron microscope images of soluble microneedles at different magnifications in an embodiment of the present invention.

Detailed Description

In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.

Referring to fig. 1, the preparation method of the soluble microneedle of the present invention comprises the following steps:

s1, referring to FIG. 2a, a silicon microneedle array 20 is prepared on the surface of a silicon wafer 10.

The silicon microneedle array can be prepared by adopting a photoetching preparation mask and a wet chemical etching process, and can also be prepared by adopting a laser or water jet mask scribing and a wet chemical etching process.

Illustratively, preparing a silicon microneedle array using a photolithographic preparation mask and a wet chemical etching process comprises:

preparing a patterning mask on the surface of a silicon wafer;

etching the surface of the silicon wafer by a wet chemical etching process;

Preferably, the preparation process of the patterned mask specifically comprises the following steps:

coating a photoresist layer with the thickness of 5-10 mu m on the surface of the silicon oxide layer, and baking and curing, wherein the photoresist layer is preferably negative photoresist;

Preferably, in the silicon microneedle array of the present invention, the height of the silicon microneedles is 0.1mm to 1mm, the size of the bottom of the silicon microneedles is 0.1mm to 1mm, and the distance between adjacent silicon microneedles is 0.3mm to 2mm.

Further, step S1 further includes:

referring to fig. 2b, a silicon oxide layer 30 and/or a silicon nitride layer (not shown) is prepared on the surface of the silicon microneedle array 20 and the silicon wafer 10.

The silicon oxide layer 30 is prepared by adopting a thermal oxidation process, and specifically comprises the following steps:

The silicon nitride layer is prepared by adopting a PECVD process, and specifically comprises the following steps:

The advantage of preparing a silicon oxide layer or a silicon nitride layer is that:

on one hand, the silicon oxide layer or the silicon nitride layer is prepared as a stripping material, so that the stripping of the soluble micro needle is facilitated;

alternatively, the porous silicon oxide or silicon nitride layer may allow for the conformal of the soluble microneedle material on the surface of the silicon microneedles.

S2, referring to FIG. 2c, the soluble microneedle material solution is spread on the surfaces of the silicon microneedle array 20 and the silicon wafer 10, and the soluble microneedle membrane 40 is obtained after solidification.

The soluble microneedle material comprises at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen tripeptide, polylactic acid, polyethylene, polypropylene, polymethyl acrylate, polyvinyl alcohol or polymethyl methacrylate, etc.

Further, other drugs or active ingredients may be added during this step depending on the function of the microneedles.

S3, referring to FIG. 2d, the soluble microneedle membrane 40 is peeled off from the silicon microneedle array 20 and the surface of the silicon wafer 10 by acid washing, and the back surface of the soluble microneedle membrane 40 is provided with a micro groove array 41.

The process of peeling the soluble microneedle patch 40 is specifically:

Wherein the fluorine-containing acidic solution is an aqueous solution containing hydrofluoric acid, ammonium fluoride, ammonium bifluoride or the like, and the mass concentration of the hydrofluoric acid, the ammonium fluoride, the ammonium bifluoride or the like is 0.1-20%.

S4, referring to FIG. 2e, a soluble microneedle material solution and/or a support material solution is poured into the micro-groove array 41 of the soluble microneedle membrane 40, and the soluble microneedle shown in FIG. 2f is obtained after curing.

Wherein the soluble microneedle material comprises at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen tripeptide, polylactic acid, polyethylene, polypropylene, polymethyl acrylate, polyvinyl alcohol or polymethyl methacrylate, etc.;

the supporting material comprises at least one of gelatin, silicone rubber, polyacrylamide polymer, polymethyl methacrylate, polydioxanone, polydimethylsiloxane and the like.

In one embodiment of the present invention, the method for preparing the soluble microneedle comprises the steps of:

1. and preparing a silicon microneedle array distributed on the monocrystalline silicon wafer by adopting a photoetching preparation mask and wet chemical etching process, wherein the height dimension of the silicon microneedles is about 200 mu m, the bottom dimension of the silicon microneedles is about 150 mu m, and the distance between adjacent silicon microneedles is about 450 mu m.

2. Placing monocrystalline silicon wafer with silicon microneedle array in oxidation furnace, passing through 2500sccm flow of O ₂ The water vapor is carried into the furnace and used as oxidation source gas for oxidation, the oxidation temperature is 1000 ℃, the oxidation time is 1h, and the thickness of the prepared silicon oxide layer is about 250nm.

3. Preparing a soluble microneedle material solution, which comprises the following components in parts by mass: 30 parts of hyaluronic acid, 20 parts of collagen tripeptide, 10 parts of hyaluronic acid, 10 parts of glutathione, 5 parts of ascorbic acid, 5 parts of nicotinamide, 3 parts of salicylic acid, 2 parts of other active substances and 15 parts of deionized water.

Then placing the monocrystalline silicon wafer with the prepared silicon microneedle array into a sterile cuboid groove container, adding the prepared soluble microneedle material solution into the container to uniformly spread the solution on the surface of the silicon microneedle array, and then placing the container into a vacuum sterile reaction cavity for curing at the temperature of 200 ℃ under the pressure of 50-100Pa for 10min to obtain the soluble microneedle membrane.

4. And (3) placing the monocrystalline silicon wafer with the prepared soluble microneedle membranes in a hydrofluoric acid solution with the mass concentration of 2%, and reacting for 10min to enable the soluble microneedle membranes to be peeled off from the surfaces of the silicon microneedle arrays and the silicon wafer.

5. The stripped soluble microneedle membrane is turned over and spread on a fixing device, the prepared soluble microneedle material solution is injected into a micro-groove array on the back, and the solution is placed in a vacuum sterile reaction cavity again for curing, wherein the curing temperature is 200 ℃, the pressure is 50-100Pa, and the curing time is 10min, so that the soluble microneedle for removing the spots is prepared, and the scanning electron microscope images of the soluble microneedle are shown in figures 3a and 3b (the magnification is 60 times and 300 times respectively).

The outer layer of the soluble microneedle has higher compressive yield strength, namely higher mechanical strength, compared with the conventional soluble microneedle after being subjected to twice curing treatment; in addition, the soluble micro-needle can avoid the problem of sacrificing mechanical strength due to the function of the absorption layer, and ensures the function of the micro-needle and simultaneously gives consideration to the mechanical property of the micro-needle through the inner and outer layer staged curing control in the invention.

It should be understood that the above embodiments are exemplary illustrations of methods of preparing soluble microneedles, and that other types of soluble microneedles may be prepared from other soluble microneedle material solutions or support material solutions in other embodiments, and are not illustrated herein.

As can be seen from the technical scheme, the invention has the following advantages:

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in 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 disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims

1. A method of preparing a soluble microneedle, comprising the steps of:

s1, preparing a silicon microneedle array on the surface of a silicon wafer;

2. The method according to claim 1, wherein the step S1 comprises:

preparing a patterning mask on the surface of a silicon wafer;

etching the surface of the silicon wafer by a wet chemical etching process;

3. The method according to claim 2, wherein the preparation of the patterned mask on the surface of the silicon wafer is specifically:

4. The method according to claim 1, wherein in the silicon microneedle array, the height of the silicon microneedles is 0.1 mm-1 mm, the size of the bottoms of the silicon microneedles is 0.1 mm-1 mm, and the distance between adjacent silicon microneedles is 0.3 mm-2 mm.

5. The method according to claim 1, wherein the step S1 further comprises:

6. The method of claim 5, wherein the silicon oxide layer is prepared on the surface of the silicon microneedle array and the silicon wafer specifically comprises:

oxidizing the surface of the silicon wafer at 600-1200 ℃ by introducing oxidizing gas for 0.5-24 h to prepare a silicon oxide layer with the thickness of 0.02-2 mu m, wherein the oxidizing gas is oxygen or water vapor or mixed gas of the oxygen and the water vapor;

and/or the number of the groups of groups,

the preparation of the silicon nitride layer on the surface of the silicon microneedle array and the silicon wafer comprises the following steps:

7. The preparation method according to claim 1, wherein the step S3 specifically comprises:

8. The method according to claim 7, wherein the acidic solution containing fluorine is an aqueous solution containing hydrofluoric acid, ammonium fluoride, or ammonium bifluoride, and the mass concentration of hydrofluoric acid, ammonium fluoride, or ammonium bifluoride is 0.1% to 20%.

9. The method of claim 1, wherein the soluble microneedle material comprises at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen tripeptide, polylactic acid, polyethylene, polypropylene, polymethyl acrylate, polyvinyl alcohol, or polymethyl methacrylate; and/or the number of the groups of groups,

the supporting material comprises at least one of gelatin, silicone rubber, polyacrylamide polymer, polymethyl methacrylate, polydioxanone and polydimethylsiloxane.

10. A soluble microneedle, characterized in that it is produced by the production method according to any one of claims 1 to 9.