CN115025038A - Method for preparing polylactic acid microneedle based on fused deposition and polylactic acid microneedle - Google Patents
Method for preparing polylactic acid microneedle based on fused deposition and polylactic acid microneedle Download PDFInfo
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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Abstract
The invention discloses a method for preparing a polylactic acid microneedle based on fused deposition and a polylactic acid microneedle, which are based on the technology of preparing a biocompatible polylactic acid microneedle structure by fused deposition and matched with hydrolytic etching, and the subsequent step of reducing a columnar structure by hydrolyzing polylactic acid to enable the columnar structure to reach the microneedle size, thereby having positive significance for simplifying microneedle processing difficulty and popularizing microneedle application. The prepared polylactic acid microneedle has enough mechanical strength to pierce animal skin tissues. The drug can be coated on the surface of the polylactic acid microneedle and enters the dermis layer along with the microneedle. Due to the top-down processing mode, the inclination of the polylactic acid column body prepared by fused deposition can be customized. The subsequent hydrolytic etching only reduces the size of the polylactic acid column and does not change the gradient of the initial design. The processing method is simple and reasonable in process, does not need a large amount of labor cost, and enables scientific researchers to produce the microneedles in a large scale for scientific research even under the background without the micro-processing professional knowledge.
Description
Technical Field
The invention belongs to the technical field of transdermal microneedle array processing, particularly relates to a method for preparing polylactic acid microneedles based on fused deposition and polylactic acid microneedles, and particularly relates to a technical means for preparing a self-defined microneedle structure based on a fused deposition method.
Background
Microneedles are a new generation of transdermal delivery devices that can penetrate the stratum corneum layer of the skin to perform medical applications in the dermis layer. The basic shape of the microneedles is a cone. With the deep research on the microneedles, researchers find that the attaching force of the microneedles on the skin can be improved by improving the inclination angle of the microneedles, so that the microneedles can be better kept in a state of being implanted into the skin. The traditional manufacturing process of the microneedle mainly comprises an inverted mold method and a stretching method. However, none of these conventional fabrication processes are suitable for fabricating angled microneedle structures.
The fused deposition process is one of the 3D printing techniques. Fused deposition 3D printers build up the plastic in the molten state into the target model layer by recognizing the digitized three-dimensional model. Due to the bottom-up deposition process of fused deposition, some microneedle structures that cannot be produced by conventional fabrication processes can be fabricated by fused deposition. The polylactic acid is an advantage of the fused deposition process.
Polylactic acid is a biocompatible thermoplastic and is widely applied to the medical fields of orthopedic implantation, human tissue suture lines, drug sustained-release media and the like. Polylactic acid can be enzymolyzed into lactic acid monomers harmless to the human body in the human body, and the safety of the polylactic acid makes the polylactic acid become one of the most suitable biological materials for manufacturing the micro-needle. At present, the mainstream fused deposition 3D printing technology is difficult to control the printing precision below 500 μm, and is mainly limited by the bottleneck of parameter balance between the printing nozzle and the feeding amount of the printer.
The polylactic acid can accelerate hydrolysis under the catalysis of alkaline conditions. The invention utilizes the characteristic of hydrolysis, and the polylactic acid columnar structure prepared by fused deposition can be etched into a micro-needle structure at the micron level. The prepared polylactic acid microneedle can be coated with a medicament in a dipping coating mode to prepare a coated microneedle. After the coated micro-needle penetrates the stratum corneum and enters the dermis, the medicine coated on the surface of the micro-needle can be put into the dermis, so that the medical purpose is achieved.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects in the prior art and overcome the limitation of low dimensional accuracy of polylactic acid products produced by the prior fused deposition technology, the invention provides a method for preparing polylactic acid micro-needles based on fused deposition and the polylactic acid micro-needles, which are a combined processing mode that firstly a polylactic acid columnar structure is produced based on fused deposition and then the columnar structure is reduced to the micro-needle structure by hydrolytic etching. By using the processing mode, the inclination design of the micro-needle can be flexibly realized.
The technical scheme is as follows: in order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a microneedle array for skin implantation, which comprises a substrate and a plurality of microneedles arranged on the substrate, wherein the microneedles and the substrate are made of polylactic acid materials, the microneedles are in a nanoscale conical structure, the base of the microneedles is connected with the substrate, and the surfaces of the microneedles can be coated with medicaments.
In one embodiment of the present invention, the molecular weight of the polylactic acid is 50k to 140 kDa.
In one embodiment of the invention, the height of the needle body of the microneedle is 500-2000 μm, the diameter of the needle tip is less than 100 μm, and the diameter of the needle bottom is less than 500 μm. This shape and size design can reduce the stinging sensation caused by the microneedles piercing the skin.
In one embodiment of the present invention, the inclination angle of the microneedles is 30 ° to 90 °, such as 30 °, 45 °, 60 °, 75 °, 90 °, and the like, and changing the inclination of the microneedles can adjust the attachment force of the microneedles to the skin, so that the microneedles can be more stably maintained in the state after being implanted into the skin.
In one embodiment of the present invention, the microneedle is inclined at an angle of 45 ° to 90 °.
In one embodiment of the invention, the substrate has a thickness of 1500 ± 150 μm.
In one embodiment of the present invention, the microneedle of the present invention has a conical shape in consideration of deformation and elastic resistance of the skin, a height of a needle body is 500 to 2000 μm, a diameter of a needle point is less than 100 μm, a diameter of a needle base is less than 500 μm, a thickness of the base is 1500 ± 150 μm, and an inclination angle of the microneedle is 30 to 90 °.
In one embodiment of the invention, the yield strength of the microneedles is higher than 1000 mN.
A second object of the present invention is to provide a method for preparing a polylactic acid microneedle array, comprising the steps of:
(1) preparing a substrate and a columnar structure from a polylactic acid raw material by a fused deposition manufacturing process;
(2) the columnar structure is catalyzed and hydrolyzed under alkaline conditions, and the polylactic acid columnar structure is etched into a microneedle structure through hydrolysis;
(3) coating the drug on the surface of the microneedle structure to prepare the coated microneedle array, wherein the drug comprises hyaluronic acid or carboxymethyl cellulose.
Fused deposition is a production technology for heating and melting filament-shaped thermoplastic plastics, accurately placing the melted filament-shaped thermoplastic plastics in a preset substrate area of a system through a heating nozzle, and stacking the melted filament-shaped thermoplastic plastics layer by layer into a pre-designed three-dimensional structure. The main parameters in the fused deposition process include the build-up layer thickness, the printing speed, the printing temperature, etc. The properties of surface roughness, layer-to-layer adhesion and the like of the final printed product can be changed by the parameters and different combinations. The minimum unit, i.e., accuracy, that fused deposition can print is limited by the size of the print nozzle. As the diameter of the print nozzle of commercial fused deposition printers is typically greater than 500 μm. This limitation makes current state-of-the-art fused deposition techniques incapable of producing microneedle structures with tip diameters less than 100 μm.
Polylactic acid is a thermoplastic aliphatic polyester, and is widely used in biomedical engineering at present due to its biocompatibility, and is used as orthopedic implants, tissue sutures, drug sustained release media, and the like. Polylactic acid is one of the most commonly used materials for fused deposition printing technology due to its good thermoplastic and mechanical properties. The polylactic acid can be slowly hydrolyzed into micromolecular polylactic acid under neutral condition. Under alkaline conditions, the extra hydroxide ions can stimulate carbonyl in the long chain of the polylactic acid, reduce the stability of the polylactic acid and catalyze and accelerate the hydrolysis process. By utilizing the principle, the polylactic acid columnar structure with larger size can be reduced to a micro-needle structure by hydrolytic etching under the catalytic action of hydroxide ions. As the hydrolysis of the polylactic acid surface satisfies isotropy, the diameter of the tip of the polylactic acid columnar structure becomes smaller and smaller during the hydrolysis process, but the inclination does not change.
The invention aims to provide a technology for preparing a polylactic acid micro-needle structure based on fused deposition and matched with hydrolytic etching, and has positive significance for simplifying the micro-needle processing difficulty and popularizing the micro-needle application. The invention provides a processing method for preparing a biocompatible polylactic acid columnar structure based on fused deposition and subsequently reducing the columnar structure by hydrolyzing polylactic acid to enable the columnar structure to reach the size of a microneedle. The polylactic acid micro-needle processed by the processing method has enough mechanical strength to pierce through animal skin tissues. The drug can be coated on the surface of the polylactic acid microneedle and enters the dermis layer along with the microneedle. Due to the top-down processing mode, the inclination of the polylactic acid column body prepared by fused deposition can be customized. The subsequent hydrolytic etching only reduces the size of the polylactic acid column and does not change the gradient of the initial design. The processing method is simple and reasonable in process, does not need a large amount of labor cost, and enables scientific researchers to produce the microneedles in a large scale for scientific research even under the background without the micro-processing professional knowledge.
In one embodiment of the present invention, in step (1), the ambient temperature during the fused deposition process is 150 ℃ and above. During the fused deposition printing process, the environmental temperature is controlled to be more than 150 ℃, such as 150 ℃, 160 ℃, 170 ℃ and the like, so as to promote the welding between the layers of the polylactic acid deposition unit. The effective welding force between layers is the key for ensuring that the polylactic acid cylinder is not disintegrated in the subsequent hydrolysis etching process.
In one embodiment of the present invention, the thickness of each layer of polylactic acid during the fused deposition process is 100 + -10 μm, and the diameter of the polylactic acid column is 500 + -50 μm.
In one embodiment of the present invention, in step (2), the polylactic acid column array is immersed in an alkaline solution having a pH of 14, the solution temperature is 55 ± 1 ℃, and the hydrolysis time is 30 h.
In one embodiment of the present invention, in step (3), the concentration of the drug solution is 15 ± 1% m/v.
In one embodiment of the invention, the drug solution is coated on the surface of the microneedle by means of dip coating, and the dipping time of the polylactic acid microneedle in the drug solution is 10 +/-2 s.
In one embodiment of the present invention, in the step (3), when the drug is hyaluronic acid, the concentration of the hyaluronic acid solution is 15 ± 1% m/v.
In one embodiment of the invention, the drug such as hyaluronic acid solution is coated on the surface of the microneedle by dip coating, and the dipping time of the polylactic acid microneedle in the drug such as hyaluronic acid solution is 10 +/-2 s.
In one embodiment of the invention, the prepared polylactic acid microneedle with the columnar structure is immersed in a hyaluronic acid solution pool with the concentration of 15 +/-1% m/v for 10 +/-2 seconds and then air-dried under the low-temperature condition to prepare the microneedle coated with the hyaluronic acid.
In one embodiment of the present invention, step (3) is further followed by: air drying at low temperature of not higher than 20 deg.C.
In one embodiment of the present invention, a plurality of microneedles are disposed on one of the polylactic acid microneedle arrays, and the number of microneedles is determined by the dosage of the coating drug and the area of the affected skin; the array distribution thereof can be freely realized by the fused deposition technique.
In one embodiment of the present invention, the morphological change process of the polylactic acid columnar structure after hydrolytic etching and change into the microneedle structure is demonstrated by MATLAB simulation. Simulating the morphological change of a straight cylinder with a polylactic acid columnar structure and a height of 500-2000 mu m in the hydrolytic etching process and the morphological change of a polylactic acid cylinder with a height of 1000 mu m and an inclination angle of 30-90 degrees in the hydrolytic etching process. The simulation result proves that the height and the inclination angle of the polylactic acid cylinder can not be changed in the hydrolytic etching process.
The third purpose of the invention is to provide a polylactic acid microneedle array or the application of the method in the field of transdermal microneedles.
Has the beneficial effects that: compared with the traditional microneedle production technology, the production method provided by the invention is based on the fused deposition production technology, and the polylactic acid microneedle array is prepared by matching hydrolytic etching as a post-processing means. The prepared micro-needle array is dipped in a hyaluronic acid solution pool to dip hyaluronic acid, and finally the polylactic acid micro-needle array wrapped with the hyaluronic acid coating is obtained by matching with low-temperature air drying. The manufacturing process provided by the invention is simple and reasonable, and extremely high-precision production equipment is not required, so that a manufacturer can produce the microneedle for medical research even under the background of no micro-processing.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
Fig. 1 is a schematic diagram of a coated microneedle prepared by producing a polylactic acid microneedle array based on a fused deposition and hydrolytic etching process and finally coating a drug on the surface of the microneedle.
Fig. 2 is a simulation diagram of the morphological change of the polylactic acid columnar structure in the isotropic hydrolytic etching process. [A] The change trend of a 90-degree straight polylactic acid columnar structure in hydrolytic etching is within the range of 500-2000 mu m in height. [B] The change trend of the polylactic acid columnar structure with the inclination angle of 30-75 degrees and the vertical height of 1000 mu m in the hydrolytic etching process.
FIG. 3 is a comparison of polylactic acid columnar structures before and after hydrolytic etching. [A] The figure is shown for the hydrolytic etching results of straight polylactic acid cylinders. [B] The figure is shown as the result of the hydrolytic etching of the polylactic acid column with a gradient of 45 degrees.
Fig. 4 is a graph comparing the force of adhesion to the skin after implantation of straight polylactic acid microneedles and inclined (45 ° inclination) microneedles. [A] Straight micro-needle extracts the skin tissue picture. [B] And (5) obliquely drawing out a skin tissue picture by the microneedle. [C] The micro-needles with different inclinations have higher attachment force to the skin than the straight micro-needles under the contrast of the attachment force to the skin in the process of pulling out the skin tissue.
Fig. 5 is a mechanical strength test chart of straight polylactic acid microneedles and inclined (45 ° inclination) microneedles. Because the inclined micro-needle is influenced by radial force when stressed, the mechanical strength of the inclined micro-needle is weaker than that of a straight micro-needle, but the mechanical strength of the micro-needle prepared by the invention is higher than 1000 mN.
Fig. 6 is a graph showing the effect of the straight polylactic acid microneedle and the inclined (45 ° inclination) microneedle coated with the drug. [A] Figure shows straight polylactic acid microneedles coated with encapsulated drug. [B] Oblique microneedle coating is shown encapsulating a drug.
Detailed Description
The invention will be further described with reference to the following figures and examples. The present invention will be better understood from the following examples. However, it is readily understood by those skilled in the art that the specific material proportions, process conditions and results thereof described in the examples are merely illustrative of the invention and should not, nor should they limit the invention as detailed in the claims.
Microneedles are short for micron-sized needle structures made of biocompatible materials. The surface of the micro-needle can be coated with a coating drug, and the drug carried by the micro-needle can be released by the dermis after the micro-needle passes through the stratum corneum and enters the dermis.
The invention discloses a technology for producing a polylactic acid microneedle array, and a prepared microneedle surface is coated with a coating drug for medical application, which has guiding significance for the industrialized development of a novel transdermal drug delivery technology.
The production method of the microneedle array is realized based on two processes of fused deposition and hydrolytic etching, and the whole process is shown in figure 1. Wherein the quantity and arrangement of the microneedles on the array can be designed through three-dimensional modeling and realized through a fused deposition technology; the hydrolytic etching is a processing mode after the fused deposition, so as to break through the limitation of low printing precision of the current fused deposition technology. The coating on the surface of the polylactic acid micro-needle is formed by hyaluronic acid dried at low temperature.
The surface of the polylactic acid micro-needle array prepared by the invention can be used for coating medicines, wherein the medicines mainly comprise hyaluronic acid and can also be applied to medicines such as carboxymethyl cellulose and the like. Specifically, the method for coating the drug (taking hyaluronic acid as an example) on the surface of the polylactic acid microneedle array comprises the following steps:
(1) preparing a polylactic acid columnar structure array from a polylactic acid raw material by a fused deposition technology;
(2) the polylactic acid columnar structure array is subjected to hydrolytic etching to prepare a polylactic acid micro-needle structure array;
(3) and coating the surface of the prepared microneedle with a hyaluronic acid solution to prepare the coated microneedle array.
The polylactic acid microneedle can be prepared by a fused deposition and hydrolytic etching process, and the coating medicament is coated on the surface of the polylactic acid microneedle by a dipping mode after the polylactic acid microneedle is prepared.
The experimental materials used in the embodiment of the invention are as follows:
polylactic acid (MP05780, MakerBot) has an average molecular mass of 100 kDa.
A fused deposition printer (Taz 6) was purchased from Lulzbot corporation, usa.
The main raw material of the hydrolytic etching solution is sodium hydroxide (S5881) purchased from Sigma-Aldrich.
Hyaluronic acid was purchased from Dorsush pharmaceutical Co., Ltd and had an average molecular weight of 1500 kDa.
Example 1
A method for coating a drug (taking hyaluronic acid as an example) on the surface of a polylactic acid microneedle array comprises the following steps:
(1) preparing a polylactic acid columnar structure array from a polylactic acid raw material by a fused deposition technology;
the polylactic acid raw material (MP05780, MakerBot) adopts a fused deposition manufacturing process, the ambient temperature in the fused deposition process is kept at 160 ℃, as shown in the left picture of figure 2A, the thickness of each layer of polylactic acid in the fused deposition process is 100 micrometers, the diameter of each polylactic acid column is 500 micrometers, the height of each polylactic acid column is 500 micrometers, 1000 micrometers, 1500 micrometers and 2000 micrometers, a substrate and a columnar structure made of the polylactic acid raw material are manufactured, and the thickness of the substrate is 2000 micrometers.
The height and inclination of the polylactic acid column printed by the fused deposition technique in the present invention can be changed according to the design requirements, and the inclination angle of the microneedle in this embodiment is set to be 90 °.
(2) The polylactic acid columnar structure array is subjected to hydrolytic etching to prepare a polylactic acid micro-needle structure array;
the columnar structure obtained in step (1) was immersed in an alkaline solution of sodium hydroxide at pH 14, at a temperature of 55 ℃, for a hydrolysis time of 30 h. The polylactic acid columnar structure array is catalyzed and hydrolyzed under alkaline conditions, the polylactic acid columnar structure is etched into a micro-needle structure through hydrolysis, the micro-needle is in a conical shape, the height of a needle body is unchanged, the diameter of a needle point is 80 mu m, the diameter of a needle bottom is 450 mu m, and the thickness of a substrate is 1500 mu m, as shown in figure 3A.
(3) And coating the surface of the prepared microneedle with a hyaluronic acid solution to prepare the coated microneedle array.
The coating medicine is coated on the surface of the microneedle by a dipping mode, and specifically comprises the following steps: after dipping the microneedles in 15% m/v hyaluronic acid solution for 10s, air-drying at a low temperature of not higher than 20 ℃ to prepare coated microneedles having a coating thickness of 20 μm, as shown in fig. 6A. The prepared microneedle array was stored in a sterile environment at 4 ℃.
Example 2
A method for coating a drug (taking hyaluronic acid as an example) on the surface of a polylactic acid micro-needle array comprises the following steps:
(1) preparing a polylactic acid columnar structure array from a polylactic acid raw material by a fused deposition technology;
the polylactic acid raw material (MP05780, MakerBot) adopts a fused deposition manufacturing process, the ambient temperature in the fused deposition process is kept at 160 ℃, as shown in the left picture of figure 2B, the thickness of each layer of polylactic acid in the fused deposition process is 100 mu m, the diameter of a polylactic acid cylinder is 500 mu m, the height of the polylactic acid cylinder is 1000 mu m, and a substrate and a columnar structure made of the polylactic acid raw material are manufactured, wherein the thickness of the substrate is 2000 mu m.
The height and inclination of the polylactic acid column printed by the fused deposition technique in the present invention can be changed according to the design requirements, and the inclination angles of the microneedles in this embodiment are set to be 75 °, 60 °, 45 °, and 30 °, respectively.
(2) The polylactic acid columnar structure array is subjected to hydrolytic etching to prepare a polylactic acid micro-needle structure array;
the columnar structure obtained in step (1) was immersed in an alkaline solution of sodium hydroxide at pH 14, at 55 ℃ for 30 h. The polylactic acid columnar structure array is catalyzed and hydrolyzed under alkaline conditions, the polylactic acid columnar structure is etched into a micro-needle structure through hydrolysis, the micro-needle is in a conical shape, the height of a needle body is unchanged, the diameter of a needle point is 80 mu m, the diameter of a needle bottom is 450 mu m, the thickness of a substrate is 1500 mu m, the hydrolysis etching result of the polylactic acid column with the inclination of 45 degrees is shown in figure 3B, and the inclination angles of 75 degrees, 60 degrees and 30 degrees are the same as the results.
(3) And coating the surface of the prepared microneedle with a hyaluronic acid solution to prepare the coated microneedle array.
The coating medicine is coated on the surface of the microneedle by a dipping mode, and specifically comprises the following steps: after being immersed in 15% m/v hyaluronic acid solution for 10s, the microneedle is air-dried at a low temperature of not higher than 20 ℃ to prepare a coated microneedle, wherein the thickness of the coating is 20 micrometers, the surface of the microneedle with the inclination of 45 degrees is coated with the coating agent, and the inclination angles of 75 degrees, 60 degrees and 30 degrees are the same as the results of the coating microneedle, as shown in fig. 6B. The prepared microneedle array was stored in a sterile environment at 4 ℃.
Example results comparison and analysis
The performance tests and comparisons of the microneedles obtained in examples 1 and 2 include the height and inclination angle of the microneedles, the force of the microneedles attached to the skin after being implanted into the skin, and the mechanical strength of the microneedles.
(1) Variation of height and inclination angle of microneedles
As shown in the dynamic size change simulation diagram of the polylactic acid columnar structure shown in fig. 2, in the isotropic hydrolytic etching process, the polylactic acid is hydrolytically etched layer by layer, and since the hydrolysis of the polylactic acid surface satisfies the isotropy, the diameter of the tip of the polylactic acid columnar structure becomes smaller and smaller in the hydrolysis process, so that a tapered structure with a narrow top and a narrow bottom is gradually formed, but the inclination does not change. Therefore, during the hydrolysis process, the height and inclination of the polylactic acid column are kept unchanged during the design, and the dimensional change during the etching process can be simulated by MATLAB software.
The hydrolytic etching result is shown in fig. 3, the thickness of the substrate prepared by the production method of the embodiment of the invention is 1500 +/-150 μm, the height of the needle body of the microneedle is 500-2000 μm, and the substrate is kept consistent before and after hydrolytic etching; the diameter of the needle tip is less than 100 mu m, and the diameter of the needle bottom is less than 500 mu m; the inclination angle of the micro-needle can be selected within the range of 30-90 degrees according to the design, and enough stability can be kept.
(2) The micro needle is attached to the skin after being implanted into the skin
The present invention compares the attachment force to the skin when straight microneedles (90 ° microneedle prepared in example 1, fig. 4A) and inclined microneedles (45 ° microneedle prepared in example 2, fig. 4B) of the same size are implanted into the skin and then pulled out, using a mechanical sensor. As shown in fig. 4A, 4B, the inclined microneedles are more difficult to extract the skin tissue than the straight microneedles; as shown in fig. 4C, in contrast to the skin adhesion force of the microneedles with different inclinations during the skin tissue extraction process, the skin adhesion force of the inclined microneedles is higher than that of the straight microneedles. This result demonstrates that the oblique microneedles produced according to the present invention can be more permanently maintained in an implanted state in tissue.
(3) Mechanical Strength of microneedle
According to past studies, the force required for a single microneedle structure to effectively penetrate human skin is at least 58 mN. As shown in fig. 5, the inflection point of the curve corresponds to the yield force of the microneedle, and it can be found that the yield force of a straight microneedle at 90 ° is close to 12000mN, the yield force of an inclined microneedle at 45 ° is close to 2500mN, and the mechanical strength of the inclined microneedle is weaker than that of the straight microneedle due to the influence of the radial force when the inclined microneedle is stressed, but the mechanical strength of the microneedles prepared by the present invention is higher than 1000mN, which fully indicates that the polylactic acid microneedles prepared by the present production technology have sufficient mechanical strength to pierce the skin.
In conclusion, the invention researches and simplifies the preparation process of the polylactic acid microneedle, can efficiently produce the microneedle structure with complex shape, and can ensure that producers can still conveniently produce microneedle products even without the background of micromachining knowledge. The technology has important significance for medical application of the microneedle array and improvement of production efficiency.
The above description is only of the preferred embodiments of the present invention, and it should be noted that: it will be apparent to those skilled in the art that various modifications and adaptations can be made without departing from the principles of the invention and these are intended to be within the scope of the invention.
Claims (10)
1. A microneedle array for implanting into skin comprises a substrate and a plurality of microneedles arranged on the substrate, and is characterized in that the microneedles and the substrate are made of polylactic acid materials, the microneedles are of nanoscale conical structures, the needle bottoms of the microneedles are connected with the substrate, and the surfaces of the microneedles can be coated with drugs.
2. The polylactic acid microneedle array according to claim 1, wherein the molecular weight of the polylactic acid is 50k to 140 kDa.
3. The polylactic acid microneedle array according to claim 1, wherein the height of the body of the microneedle is 500 to 2000 μm, the diameter of the tip is less than 100 μm, and the diameter of the base is less than 500 μm; the inclination angle of the microneedle is 30-90 degrees; the thickness of the substrate is 1500 +/-150 mu m.
4. A polylactic acid microneedle array according to claim 1, wherein said microneedles have a yield strength higher than 1000 mN.
5. The method for preparing a polylactic acid microneedle array according to any one of claims 1 to 4, comprising the steps of:
(1) preparing a substrate and a columnar structure from a polylactic acid raw material by a fused deposition manufacturing process;
(2) the columnar structure is catalyzed and hydrolyzed under alkaline conditions, and the polylactic acid columnar structure is etched into a microneedle structure through hydrolysis;
(3) and coating a drug solution on the surface of the microneedle structure to prepare a coated microneedle array, wherein the drug comprises hyaluronic acid or carboxymethyl cellulose.
6. The method according to claim 5, wherein in step (1), the ambient temperature during the fused deposition is 150 ℃ or more;
the thickness of each layer of polylactic acid in the melting deposition process is 100 +/-10 mu m, and the diameter of the polylactic acid cylinder is 500 +/-50 mu m.
7. The method according to claim 5, wherein in step (2), the polylactic acid column array is immersed in an alkaline solution having a pH of 14, wherein the alkaline solution comprises a sodium hydroxide or potassium hydroxide solution; the solution temperature is 55 +/-1 ℃, and the hydrolysis time is 30 h.
8. The method according to claim 5, wherein in step (3), when the drug is hyaluronic acid, the concentration of the hyaluronic acid solution is 15 ± 1% m/v;
the hyaluronic acid solution is wrapped on the surface of the micro needle in a dipping coating mode, and the dipping time of the polylactic acid micro needle in the hyaluronic acid solution is 10 +/-2 s.
9. The method of claim 5, wherein step (3) is further followed by: air drying at low temperature of not higher than 20 deg.C.
10. Use of a polylactic acid microneedle array according to any of claims 1 to 4, or a method according to any of claims 5 to 9, in the field of transdermal microneedles.
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| CN110448541A (en) * | 2019-08-02 | 2019-11-15 | 中山大学 | Difunctionalization nanoparticle, soluble micropin and the preparation method and application thereof |
| CN111375124A (en) * | 2020-03-19 | 2020-07-07 | 上海缓释新材料科技有限公司 | Anti-aging slow-release soluble microneedle based on polylactic acid compound and preparation method thereof |
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| CN110448541A (en) * | 2019-08-02 | 2019-11-15 | 中山大学 | Difunctionalization nanoparticle, soluble micropin and the preparation method and application thereof |
| CN111375124A (en) * | 2020-03-19 | 2020-07-07 | 上海缓释新材料科技有限公司 | Anti-aging slow-release soluble microneedle based on polylactic acid compound and preparation method thereof |
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