CN115737531A - Method for preparing microneedle array by double-permeation micro-perfusion method, microneedle array and application - Google Patents
Method for preparing microneedle array by double-permeation micro-perfusion method, microneedle array and application Download PDFInfo
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Abstract
The invention discloses a method for preparing a microneedle array by a double-permeation micro-perfusion method, the microneedle array and application. The method comprises the following steps: mixing at least 3 polymers with different molecular weights with water to obtain a mixed solution, filling the mixed solution into a double-transmission microneedle array mold under the action of external force, and demolding after the mixed solution is dried and cured to obtain a microneedle array; wherein the tapered array tip of the double-transmission microneedle array mold has an opening; the polymer includes a first polymer having a molecular weight of 1800 to 2200 kDa. According to the invention, the microneedle with high mechanical strength, water supplementing, moisture preserving and wrinkle removing functions can be prepared by improving the whole preparation process flow and the components of the microneedle. The invention is especially suitable for high-concentration polymer solution, can simplify the preparation process and shorten the forming time.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a method for preparing a microneedle array by a double-permeation micro-perfusion method, the microneedle array and application.
Background
The skin is composed of epidermis, dermis and hypodermis, wherein the dermis is important in the aging process and contains collagen and elastic fibers forming an integral three-dimensional fiber network, the former maintaining the toughness of the skin and the latter ensuring the softness of the skin. The two important components continuously produced by fibroblasts in the dermis act together to make the young skin full of elasticity and free of wrinkles. However, with age, the rate of collagen and elastic fibers in the dermis increases at a rate less than the rate of degradation, and collagen and elastic fibers decrease and subcutaneous fat also gradually decreases, so that the skin elasticity decreases and wrinkles begin to appear.
The currently selectable anti-aging wrinkle-removing beauty treatment methods mainly comprise injection filling type professional medical beauty treatment and external application and pasting type self-use skin care products. Although the effect of professional medical cosmetology is obvious, the defects of large wound and more adverse reactions exist; self-use skin care products are generally mild in nature, but due to the barrier effect of the stratum corneum of the skin, the active ingredients of the skin care products often cannot enter the dermis easily, thereby achieving good effects. The skin can be smooth and tender only in a short time after the skin care product is used, the bad skin states of dry skin, lack of water, wrinkle accumulation and the like cannot be really improved, and the current requirements of consumers cannot be completely met.
The micro-needle serving as a novel transdermal drug delivery technology can directly deliver active ingredients such as drugs and the like into the skin, and has great potential in the field of medical cosmetology. However, the existing cosmetic microneedles are generally prepared by a droplet forming air drying method (Jung Dong Kim, et al. Journal of Controlled release.2013,170, 430-436), and the microneedles prepared by the method have a relatively large long diameter and are easily broken during transdermal penetration. Although people adopt a silicon mold and prepare the conical microneedle array by utilizing a micro-template method, the conical microneedle array is influenced by the viscosity of a high molecular solution and the hydrophobicity of the silicon mold, and the existing microneedle preparation method generally needs additional negative pressure (vacuumizing and centrifuging) or O 2 Plasma treatment promotes solution entryPutting into a mould; on the other hand, concentrated solutions of low molecular weight polymers are generally used to reduce the effect of solution viscosity on injection molding, but this approach reduces the mechanical strength of the microneedles. Hyaluronic acid with a molecular weight of 40 million or more, as preferred in patent CN101687090B, was used to prepare soluble microneedles. Although the microneedles formed from high molecular weight hyaluronic acid (molecular weight. Gtoreq.1000 kDa) have good mechanical strength, the larger the molecular weight, the more viscous the aqueous solution formed. On the one hand, can produce the bubble in the micropin course of working and cause the micropin defect, reduce micropin mechanical strength, on the other hand is unfavorable for pouring into in the micropore of micropin mould. Patent CN201410150501.8 blends degradable hyperbranched polymer into hyaluronic acid to reduce the viscosity of the solution, but the long-term biocompatibility of these polyester/polysulfone amines is yet to be further studied.
Disclosure of Invention
Aiming at the defects or improvement requirements of the prior art, the invention provides a method for preparing a microneedle array by a double-permeation micro-perfusion method, the microneedle array and application, and aims to prepare the microneedle with high mechanical strength, water supplementing, moisture preserving and wrinkle removing functions by improving the whole preparation process flow and the components of the microneedle. Is suitable for high-concentration polymer solution, and can simplify the preparation process and shorten the molding time.
To achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing a microneedle array by a double-permeation micro-infusion method, comprising the steps of: mixing at least 3 polymers with different molecular weights with water to obtain a mixed solution, filling the mixed solution into a double-penetrating microneedle array mold under the action of external force, and demolding after the mixed solution is dried and solidified to obtain a microneedle array; wherein the tapered array tip of the double-transmission microneedle array mold has an opening; the polymer includes a first polymer having a molecular weight of 1800 to 2200 kDa.
Preferably, the mass fraction of the first polymer in the polymers is 1% to 10%.
Preferably, the polymer further includes a second polymer having a molecular weight of 1 to 10kDa, a third polymer having a molecular weight of 10 to 1000kDa and a fourth polymer having a molecular weight of 1000 to 1800 kDa. Wherein, the molecular weight of the ultra-low molecular weight sodium hyaluronate of the second polymer is 1-10 kDa, and the ultra-low molecular weight sodium hyaluronate has the effects of promoting the supply of skin nutrients and the excretion of wastes, and quickly achieving the effects of moisturizing, removing wrinkles and resisting aging. The molecular weight of the low molecular weight sodium hyaluronate of the third polymer is 10-1000 kDa, and the low molecular weight sodium hyaluronate has the effect of lasting moisture preservation, and in addition, the low molecular weight sodium hyaluronate has good solubility, so that the microneedle can be quickly dissolved after being permeated through skin, and the mechanical strength of the microneedle array can be improved. The molecular weight of the sodium hyaluronate with the medium molecular weight of the fourth polymer is 1000-1800 kDa, the molecular weight of the sodium hyaluronate with the high molecular weight of the first polymer is 1800-2200 kDa, and the two kinds of hyaluronic acid have the effects of promoting the proliferation and differentiation of epidermal cells, eliminating free radicals, reducing the friction force between skin tissues and prolonging the moisturizing effect.
Preferably, the mass fraction of the second polymer in the polymer is 1% to 20%, the mass fraction of the third polymer in the polymer is 60% to 97%, and the mass fraction of the fourth polymer in the polymer is 1% to 10%.
Preferably, the mixed solution further comprises a plasticizer, and the mass fraction of the polymer in the mixed solution is 10-40%, the mass fraction of the plasticizer is 0.1-5%, and the mass fraction of water is 55-89.9%. The plasticizer is used for adjusting the flexibility of the microneedle array and improving the moisturizing effect of the microneedle array.
Preferably, the first, second, third and fourth polymers are all sodium hyaluronate.
Preferably, the plasticizer is at least one of glycerin, amino acid, propylene glycol, gelatin, sorbitol, ceramide, polyethylene glycol, and polyvinyl alcohol.
Preferably, the diameter of the opening of the conical array tip on the double-transmission microneedle array mould is 10-50 μm. The bottom edge opening of the double-transmission microneedle array mold is 200-600 mu m, and the height of the double-transmission microneedle array mold is 300-1000 mu m.
Preferably, the external force applied in step (2) can improve the tightness of the arrangement of hyaluronic acid molecules in the microneedles, and improve the mechanical strength of the microneedle array after curing.
According to another aspect of the present invention, there is provided a microneedle array.
Preferably, the degradation time of the microneedle array in the skin is 7 to 30 days.
According to still another aspect of the present invention, there is provided a use of the microneedle array for preparing a transdermal drug delivery formulation for a spot-removing, beauty medicine, acne-removing or wrinkle-removing medicine.
In general, at least the following advantages can be obtained by the above technical solution contemplated by the present invention compared to the prior art.
(1) The invention adopts the double-penetration mold to replace the traditional microneedle mold, reduces the resistance when the formula solution enters the mold pore canal, and leads the microneedle to rapidly enter the mold pore canal. The double-permeation micro-irrigation method is suitable for high-concentration polymer solution, can simplify the preparation process and shorten the forming time. On the other hand, the invention optimizes and adjusts each component in the solution of the formula to obtain the microneedle which has high mechanical strength, effective transdermal penetration and good flexibility; the mixed solution obtained by mixing at least 3 polymers with different molecular weights and water is used as the microneedle forming solution, so that the degradation time of the microneedle in the skin can be adjusted, the microneedle is endowed with good moisturizing and wrinkle removing functions, and the effective time of the microneedle is prolonged.
(2) The microneedle patch disclosed by the invention can effectively pierce the skin to form a pore channel on the surface of the skin, and along with the fact that the degradable material of the main body supporting component is quickly dissolved in the skin, the functional component can be quickly absorbed by the dermis layer to supplement moisture and nutrient substances, so that the skin water-deficient state is fundamentally improved, the effects of supplementing water and preserving moisture are lasting, the skin is obviously younger, and the safety is high. The preparation method of the microneedle patch is simple and is easy for batch production.
Drawings
Fig. 1 is a schematic structural view of a mold for a double-transmission microneedle array according to the present invention;
fig. 2 is a photomicrograph of a subject before and after using the cosmetic microneedle patch prepared according to the present invention in application example 1;
fig. 3 (a) and (b) are graphs showing the number of wrinkles and skin hydration amount, respectively, before and after the subject uses the present invention in application example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
The embodiment provides a method for preparing a microneedle array by a double-permeation micro-perfusion method, which comprises the following steps:
1. etching a 6cm × 6cm Polydimethylsiloxane (PDMS) mold with the diameter of the bottom edge of 200 microns, the diameter of the opening of the tip of 10 microns, the height of 300 microns and the center distance between adjacent microneedles of 1000 microns by using a laser engraving machine, and cleaning for later use; the microneedle mould used in this example is shown in fig. 1.
2. Hyaluronic acid (10% of ultra-low molecular weight sodium hyaluronate, 88% of low molecular weight sodium hyaluronate, 1% of medium molecular weight sodium hyaluronate and 1% of high molecular weight sodium hyaluronate) and glycerol are prepared into a mixed aqueous solution (10% of hyaluronic acid and 0.1% of glycerol) which is laid on the surface of a mould.
3. Pressing the solution into the pore canal of the mold by a polytetrafluoroethylene pressure plate, drying at room temperature, and demolding to obtain the microneedle array, wherein the metabolism time of the obtained microneedle array in vivo is 15 days.
Examples 2 to 6
Examples 2-6 were prepared according to the same procedure as in example 1, except for the mold size and hyaluronic acid molecular weight and concentration, as shown in table 1 below:
TABLE 1 microneedle array different preparation parameter table
Application example 1
The cosmetic microneedles obtained in example 1 were cut into an eye patch shape and used for eye care of 63 asian male/female aged 35 to 60 years 2 times a week for 9 consecutive weeks (double blind test). Photographs of the eyes of the subjects were taken during the care period (fig. 2), and the wrinkles of the eyes of the subjects were analyzed using Visia software (fig. 3).
Referring to fig. 2 and (a) and (b) of fig. 3, it can be seen that the number of eye wrinkles of a subject is significantly reduced without affecting the moisture content of the skin after using the microneedle of the present invention.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A method for preparing a microneedle array by a double-permeation micro-perfusion method is characterized by comprising the following steps:
mixing at least 3 polymers with different molecular weights with water to obtain a mixed solution, filling the mixed solution into a double-transmission microneedle array mold under the action of external force, and demolding after the mixed solution is dried and cured to obtain a microneedle array; wherein the tapered array tip of the double-transmission microneedle array mold has an opening; the polymer includes a first polymer having a molecular weight of 1800 to 2200 kDa.
2. The method of claim 1, wherein the mass fraction of the first polymer in the polymer is between 1% and 10%.
3. The method of claim 1 or 2, wherein the polymers further comprise a second polymer having a molecular weight of 1-10 kDa, a third polymer having a molecular weight of 10-1000 kDa, and a fourth polymer having a molecular weight of 1000-1800 kDa.
4. The method of claim 3, wherein the mass fraction of the second polymer in the polymers is from 1% to 20%, the mass fraction of the third polymer in the polymers is from 60% to 97%, and the mass fraction of the fourth polymer in the polymers is from 1% to 10%.
5. The method according to claim 1, wherein the mixed solution further comprises a plasticizer, and the mass fraction of the polymer in the mixed solution is 10% to 40%, the mass fraction of the plasticizer is 0.1% to 5%, and the mass fraction of water is 55% to 89.9%.
6. The method of claim 4, wherein the first, second, third, and fourth polymers are each sodium hyaluronate.
7. The method of claim 5, wherein the plasticizer is at least one of glycerol, amino acids, propylene glycol, gelatin, sorbitol, ceramide, polyethylene glycol, and polyvinyl alcohol.
8. The method of claim 1, wherein the tapered array tip on the mold for the bi-transparent microneedle array has an opening diameter of 10 to 50 μm.
9. A microneedle array prepared by the method of any one of claims 1-8.
10. Use of a microneedle array according to claim 9 for the preparation of a transdermal drug delivery formulation for the removal of freckles, cosmetic drugs, acne or wrinkles.
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