CN113082500A

CN113082500A - Transdermal delivery device and method of manufacture

Info

Publication number: CN113082500A
Application number: CN202110220321.2A
Authority: CN
Inventors: 李志宏; 任英杰; 李君实
Original assignee: Peking University
Current assignee: Peking University
Priority date: 2021-02-26
Filing date: 2021-02-26
Publication date: 2021-07-09

Abstract

The invention provides a percutaneous delivery device and a preparation method, the percutaneous delivery device comprises: a substrate having a working side for conforming to a target object; at least two micropins, at least two micropins with substrate integrated into one piece, the micropin has working section and link, the working section is followed the working side outwards stretches out, link and working section pass through hollow transfer passage intercommunication, transfer passage runs through the substrate, the link deviates from the working side. According to the percutaneous delivery device and the preparation method, the plurality of hollow micro-needles are arranged on the substrate, and the drug can be injected or the tissue fluid can be extracted through the connecting ends, so that the precise and rapid active drug delivery or tissue fluid extraction can be realized, and the drug delivery efficiency and the tissue fluid extraction efficiency can be improved.

Description

Transdermal delivery device and method of manufacture

Technical Field

The invention relates to the technical field of wearable equipment, in particular to a percutaneous conveying device and a preparation method thereof.

Background

The drug plays a very important role in the treatment of diseases, and the administration of a proper dose of the drug to an organism in an appropriate manner can help the health of the organism, and the main modes of administration for the organism at present are divided into three types: injection, oral administration and external application.

Among them, injection administration can meet the dosage requirements of most drugs, but there are risks of injection site infection and needle infection, and pain and bleeding at the injection site can also be caused. The oral administration can reduce the risk brought by injection while ensuring the dosage, but the applicable types of the medicines are limited, for example, certain hormones and enzyme-containing medicines can be decomposed in the digestive tract and are influenced by the metabolic function of the liver and the first pass effect of the intestinal tract, and the absorbed dosage is obviously lower than the oral dosage, so that the drug effect can be reduced. The external application drug delivery is limited by the limitation of skin structure, the drug delivery efficiency is lower, and certain macromolecular drugs cannot be effectively absorbed by human bodies through the skin, so the current drug delivery mode easily causes infection risks and the efficiency is lower.

Meanwhile, it plays an important role in the treatment of diseases in living bodies and the monitoring of physical conditions in order to diagnose in time. The extraction of a body fluid sample is the primary and critical step in a timely diagnosis. Blood is often used for timely diagnosis because it is rich in metabolites. However, the blood sampling needs to pierce the skin and penetrate the dermal layer rich in nerve cells, which causes problems such as pain and skin irritation.

The skin tissue fluid has similar components to blood, and the composition of the skin tissue fluid changes with the change of the plasma composition, so the skin tissue fluid can be used for sample extraction instead of blood. Generally, skin tissue fluid can be extracted by a pipette technique and a microtubule insertion technique, but these procedures are complicated and easily cause discomfort to the living body.

Disclosure of Invention

The invention provides a percutaneous conveying device and a preparation method thereof, which are used for solving the defects that the administration mode in the prior art is easy to cause infection risk and the efficiency is low, and the existing tissue fluid extraction method has complex procedures and is easy to cause discomfort of organisms, and realizing the improvement of the administration efficiency and the tissue fluid extraction efficiency.

The present invention provides a percutaneous delivery device comprising: a substrate having a working side for conforming to a target object; at least two micropins, at least two micropins with substrate integrated into one piece, the micropin has working section and link, the working section is followed the working side outwards stretches out, link and working section pass through hollow transfer passage intercommunication, transfer passage runs through the substrate, the link deviates from the working side.

According to the present invention there is provided a percutaneous delivery device, the working section comprising: the first section is connected with the working side face, the cross sectional area of the first section is gradually reduced along the direction far away from the working side face, and the outer surface of the first section is a curved surface; a second segment connected to the first segment, the second segment having a needle tip for penetrating a target object.

According to the percutaneous delivery device provided by the invention, the second section is provided with a first chamfer, and the first chamfer and the outer peripheral surface of the second section form the needle tip.

According to the percutaneous delivery device provided by the invention, the second section is provided with a second oblique plane and a third oblique plane, the second oblique plane and the third oblique plane are intersected with the first oblique plane, the second oblique plane is intersected with the third oblique plane, and the first oblique plane, the second oblique plane and the third oblique plane form the needle point.

According to the percutaneous delivery device provided by the invention, the second oblique plane and the third oblique plane are both concave arc-shaped.

According to the invention there is provided a percutaneous delivery device, the second section having a cross-sectional area which is smaller than the cross-sectional area of the first section, the cross-sectional area of the second section decreasing in a direction away from the working side.

According to the percutaneous delivery device provided by the invention, the outer peripheral surface of the second section is provided with a convex section, the cross-sectional area of the second section is gradually increased from the joint of the second section and the first section to the convex section, and is gradually reduced from the convex section along the direction away from the working side surface.

According to the percutaneous delivery device provided by the invention, the substrate is a flexible substrate.

According to the percutaneous delivery device provided by the invention, the length of the microneedle is 500-1000 μm; alternatively, the diameter of the base circle of the microneedle is 200 μm to 300 μm. Alternatively, the central distance between adjacent microneedles is 500 μm to 1000 μm.

The present invention also provides a method of making a transdermal delivery device as described in any of the above, comprising: making a male mold of the percutaneous delivery device; placing the male die in a pouring container, pouring a liquid elastic material into the pouring container, and curing the liquid elastic material after the pouring is finished to obtain a female die; and placing the female die on a horizontal table, dropwise adding a liquid polymer material to the female die, scraping the liquid polymer material after the dropwise adding is finished, and curing the liquid polymer to obtain the percutaneous conveying device.

According to the percutaneous delivery device and the preparation method, the plurality of hollow micro-needles are arranged on the substrate, and the drug can be injected or the tissue fluid can be extracted through the connecting ends, so that the precise and rapid active drug delivery or tissue fluid extraction can be realized, and the drug delivery efficiency and the tissue fluid extraction efficiency can be improved.

Drawings

In order to more clearly illustrate the technical solutions of the present invention or the prior art, the drawings needed for the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and those skilled in the art can also obtain other drawings according to the drawings without creative efforts.

FIG. 1 is one of the schematic structural views of a percutaneous delivery device provided in the present invention;

FIG. 2 is a second schematic structural view of a percutaneous delivery device provided in the present invention;

FIG. 3 is a third schematic structural view of a percutaneous delivery device provided in the invention;

FIG. 4 is a fourth schematic view of the percutaneous delivery device provided in the invention;

FIG. 5 is a fifth schematic view of a percutaneous delivery device provided in the present invention;

FIG. 6 is a sixth schematic view of a percutaneous delivery device provided in the present invention;

FIG. 7 is a schematic structural view of a male mold of a method of making a transdermal delivery device provided by the present invention;

FIG. 8 is a schematic illustration of a process for making a negative mold of a method of making a transdermal delivery device provided in the present invention;

FIG. 9 is a schematic illustration of the female and male mold separation process of the method of making a transdermal delivery device provided by the present invention;

FIG. 10 is a schematic illustration of the process of casting into a female mold of the method of making a transdermal delivery device provided by the present invention;

FIG. 11 is a schematic process diagram of curing a transdermal delivery device according to a method of making a transdermal delivery device provided by the present invention;

FIG. 12 is a schematic illustration of a process for separating a transdermal delivery device according to a method of making a transdermal delivery device provided by the present invention;

FIG. 13 is a schematic structural view of a preliminary sample obtained by the method of preparing a transdermal delivery device provided by the present invention;

fig. 14 is a schematic structural view of a final sample obtained by the method for preparing a transdermal delivery device provided by the present invention.

Reference numerals:

10: a substrate; 11: a working side surface; 20: microneedles;

21: a working section; 22: a first stage; 23: a second stage;

24: a protruding section; 25: a connecting end; 26: a first chamfer;

27: a second chamfer; 28: a third bevel face; 29: a delivery channel;

30: a male mold; 31: a microneedle mould part; 32: a substrate mold portion;

40: a female die; 41: a female mold body; 42: a micro-annular hole array;

43: a micro-pillar array; 50: pouring a container; 60: a circular ring-shaped protrusion.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The transdermal delivery device and method of making of the present invention are described below in conjunction with fig. 1-14.

As shown in FIG. 1, the present invention provides a percutaneous delivery device comprising: a substrate 10 and at least two microneedles 20.

Wherein the substrate 10 has a working side 11 for attaching to a target object, the substrate 10 may be a sheet-like structure, and the thickness of the substrate 10 may be 10 μm to 100 μm, for example, may be 50 μm. The working side 11 is used for contacting with a target object, which may be various organisms, such as a human body, or other animal bodies, such as certain domestic animals or pets.

Here, the substrate 10 may be rigid or flexible, and the present embodiment does not limit this.

The number of the microneedles 20 may be two or more, and a plurality of the microneedles 20 may be arranged in an array on the substrate 10.

The microneedle 20 has a hollow needle-like structure.

The plurality of microneedles 20 are integrally formed with the substrate 10, and the microneedles 20 and the substrate 10 may be made of the same material, and may be a biocompatible polymer, such as polyimide or SU-8.

The microneedle 20 has a working section 21 and a connecting end 25, the working section 21 projects outwardly from the working side 11, the connecting end 25 and the working section 21 communicate via a hollow transfer channel 29, the transfer channel 29 extends through the substrate 10, and the connecting end 25 faces away from the working side 11.

It can be understood that, the working segment 21 of the microneedle 20 is located on the working side surface 11 side of the substrate 10, the connecting end 25 of the microneedle 20 is located on the side of the substrate 10 away from the working side surface 11, the connecting end 25 and the working segment 21 are connected with each other, the microneedle 20 has a hollow conveying channel 29, the conveying channel 29 penetrates through the substrate 10 along the thickness direction of the substrate 10, the conveying channel 29 can communicate the connecting end 25 with the working segment 21, that is, when the substrate 10 is attached to the skin of a target object, the part of the working segment 21 can pierce the skin of the target object, at this time, the side of the substrate 10 away from the working side surface 11 can be located, the connecting end 25 injects a drug into the working segment 21, the connecting end 25 can be a notch structure, and can also be a joint structure, an injector can be detachably connected with the connecting end 25, and.

An array of the plurality of microneedles 20 may be used as a syringe needle, and the syringe may be connected to the connection end 25 to supply the liquid medicine to the plurality of microneedles 20, and the plurality of microneedles 20 may deliver the liquid medicine to a living body.

Certainly, the connecting end 25 can also be connected with an extraction device, the extraction device can provide negative pressure for the transmission channel 29, so that the working section 21 can extract the tissue fluid from the skin, the extracted tissue fluid can be transmitted to the extraction device through the working section 21, the transmission channel 29 and the connecting end 25, the tissue fluid in the skin can be extracted, certain ions or proteins in the extracted tissue fluid can be detected, and certain physiological indexes can be evaluated.

In the aspect of treating diseases, drugs play an important role in treating diseases, and currently, the main modes of administration to human bodies are divided into three types: injection, oral administration and external application. It is well known that the amount of a drug dose plays an important role in the efficacy of the drug after the correct drug is selected. Among them, injection administration can meet the dosage requirements of most drugs, but has risks of injection site infection and needle infection. The injection administration can also cause pain and bleeding of the injection part, and is not easy to accept by audiences with needle phobia and blood sickness; oral administration can reduce the risk of injection while ensuring the dosage, but the types of drugs that are suitable for oral administration are limited, for example, some hormones and enzyme-containing drugs are decomposed in the digestive tract. Meanwhile, the oral drug is influenced by the metabolic function of the liver and the first pass effect of the intestinal tract, and the absorbed dose is obviously lower than the oral dose. Thus, oral administration is relatively inefficient, has a slow onset of action, and is not effective in controlling certain diseases in a timely manner. Topical administration is limited by the structural limitations of the skin, such as the stratum corneum, and is less effective, and certain macromolecular drugs cannot be effectively absorbed by the body through the skin.

In order to overcome the defects of the three administration modes, in recent years, emerging devices with microneedle arrays on the surfaces can penetrate through the stratum corneum of the outermost layer of the skin and directly penetrate into the epidermis layer or the dermis layer for administration, so that the medicine can quickly and effectively reach the skin to directly enter the microcirculation in vivo for absorption. Meanwhile, although the microneedle array belongs to a minimally invasive instrument, the diameter and the length of the microneedles are small, so that the microneedles cannot touch nerve endings and capillaries after penetrating into the skin, so that remarkable pain and bleeding cannot be caused, and micropores left on the surface of the skin after administration can be quickly recovered after the microneedles are removed.

Currently, various microneedle arrays are mainly classified into four major categories: solid microneedles, coated microneedles, degradable microneedles and hollow microneedles. The solid microneedles are administered by removing the microneedle array after piercing the skin, leaving small holes in the skin surface, and then placing the topical drug over the resulting holes, which then diffuses into the skin. Due to the self-repairing function of human skin, the small hole generated after the micro-needle is penetrated can be automatically repaired within a certain time, and further the continuous diffusion of the medicine is prevented, so that the administration dosage and the administration efficiency of the solid micro-needle are extremely low. The coating of the microneedle is that a layer of medicine is coated on the surface of the solid microneedle, then the medicine is directly sent into the skin while the microneedle penetrates the skin, and the microneedle is removed after the medicine is diffused. Compared with solid microneedles, the drug delivery efficiency of the coated microneedles is slightly improved, but the drug dosage is still very low. The degradable micro-needle is prepared by mixing a drug with a certain polymer which can be degraded in biological tissues, so that the degradable micro-needle has certain mechanical properties, and the micro-needle is degraded in tissue fluid to release the drug after penetrating into skin. Although the dosage and the efficiency of the degradable microneedles are improved slightly, the dosage of the degradable microneedles still cannot meet the requirements of most drugs due to the small size of the microneedles. Therefore, the solid microneedle, the coated microneedle and the degradable microneedle have the defects of small dosage, low efficiency, incapability of continuously administering drugs and the like, and are difficult to meet the requirements and applications of medical grade.

Hollow microneedles are understood to be the miniaturization and arraying of conventional syringes to allow for timed and quantitative effective delivery of drugs through an external interface after penetration into the skin. However, the main reasons for limiting the wide application of hollow microneedles at present are the complex manufacturing process, the high cost, and the poor adhesion of the rigid substrate to the skin surface.

The inventor finds that the microneedle 20 can be supplied through the groove on the substrate 10 without providing the through-going delivery channel 29, but this solution allows the drug in the groove to slowly permeate into the living body through the microneedle 20, so that the administration efficiency is low, the administration dose and the administration speed cannot be controlled, and the accuracy is not sufficient.

In the treatment of diseases and monitoring of physical conditions in living organisms, the timely diagnosis plays an important role. The extraction of a body fluid sample is the primary and critical step in a timely diagnosis. Blood is often used for timely diagnosis because it is rich in metabolites. However, the blood sampling needs to pierce the skin and penetrate the dermal layer rich in nerve cells, which causes problems such as pain and skin irritation.

According to the invention, the plurality of microneedles are arranged on the substrate, the connecting ends of the microneedles are connected with the extraction device, and negative pressure is provided for the microneedles through the extraction device, so that the microneedles can extract interstitial fluid from the skin, no obvious pain or bleeding is generated, the trauma to an organism can be reduced, and the interstitial fluid can be extracted through the microneedles, so that the interstitial fluid extraction efficiency can be improved.

According to the percutaneous delivery device provided by the invention, the substrate 10 is provided with the hollow micro-needles 20, and the connecting ends 25 can be used for injecting medicines or extracting interstitial fluid, so that the precise and quick active administration or tissue fluid extraction can be realized, and the administration efficiency and the interstitial fluid extraction efficiency can be improved.

As shown in fig. 2, in some embodiments, the microneedle 20 may have a circular ring shape in cross-section, and the working section 21 includes: a first section 22 and a second section 23.

Wherein the first section 22 is connected to the working side 11, and the first section 22 may be disposed to protrude from the working side 11.

The diameter of the first section 22 is gradually reduced along the direction away from the working side surface 11, the first section 22 is the root of the working section 21, the buffering effect can be achieved, the pressure of the micro-needle 20 on the substrate 10 can be reduced, and the reliability of the substrate 10 can be improved.

The outer surface of the first section 22 is curved and may be smoothly curved, which further enhances the cushioning effect.

The second section 23 is connected to the first section 22, the second section 23 having a needle tip for penetrating the target subject, the second section 23 being capable of penetrating the skin of the target subject.

It should be noted that the sectional shape of the microneedle is not limited to the shape shown in the drawings, and those skilled in the art can select the sectional shape of the microneedle according to actual needs, and suitable sectional shapes of the microneedle are within the scope of the present invention.

In some embodiments, as shown in FIG. 2, the second section 23 has a first chamfered surface 26, and the first chamfered surface 26 forms a needle tip with the outer peripheral surface of the second section 23.

As shown in fig. 3, in some embodiments, the second section 23 has a second chamfer 27 and a third chamfer 28, the second chamfer 27 and the third chamfer 28 both intersect the first chamfer 26, the second chamfer 27 intersects the third chamfer 28, the first chamfer 26 can be perpendicular to the second chamfer 27, the first chamfer 26 can be perpendicular to the third chamfer 28, and the second chamfer 27 can be perpendicular to the third chamfer 28.

The first chamfer 26, the second chamfer 27 and the third chamfer 28 form a needle tip, and the needle tip structure is sharper by the arrangement of the first chamfer 26, the second chamfer 27 and the third chamfer 28 which are intersected, so that the needle tip can pierce the skin of a target object more easily.

As shown in fig. 4, in some embodiments, the second chamfer 27 and the third chamfer 28 are both concave arcs, and the penetration force when penetrating the skin can be further reduced by setting the second chamfer 27 and the third chamfer 28 to be concave arcs, so that the needle tip can more easily penetrate the skin of the target object.

In some embodiments, the diameter of the second segment 23 is smaller than the diameter of the first segment 22, and the diameter of the microneedle 20 can be made to change abruptly at the intersection of the second segment 23 and the first segment 22, the first segment 22 acts as a root of the working segment 21, and acts as a primary buffer, and therefore has a larger diameter, while the second segment 23 can penetrate the skin directly, and therefore has a smaller diameter.

The diameter of the second section 23 decreases in a direction away from the working side 11, which facilitates the piercing of the skin of the target object by the second section 23 and reduces drag.

As shown in fig. 5, in some embodiments, the outer peripheral surface of the second section 23 has a protruding section 24, and the diameter of the second section 23 gradually increases from the junction of the second section 23 and the first section 22 to the protruding section 24, and gradually decreases from the protruding section 24 in a direction away from the working side 11.

It can be understood that the diameter of the second segment 23 increases along the direction away from the working side surface 11, and then decreases, that is, the middle position of the second segment 23 is thickened properly to form a convex structure, that is, a pointed structure is formed at the needle point of the microneedle 20, so that the second segment 23 can be better clamped in the skin after penetrating the skin, and is not easy to fall off.

In some embodiments, the substrate 10 is a flexible substrate 10, and the substrate 10, which is a flexible material, can conform to the shape of the skin surface of the subject, can adhere well to virtually any skin surface, and reduces discomfort to the subject.

In some embodiments, the microneedles 20 are 500 μm to 1000 μm in length, such as may be 800 μm.

Alternatively, the diameter of the base circle of the microneedle 20 is 200 μm to 300 μm, and may be 250 μm, for example.

Alternatively, the center distance between the neighboring microneedles 20 is 500 μm to 1000 μm, that is, the distance between the centers of the neighboring microneedles 20, for example, may be 800 μm.

As shown in fig. 6, the cross section of the microneedle 20 may also be triangular, that is, the cross section of the microneedle of the transdermal delivery device provided by the present invention is not limited to the shape shown in the drawings, and those skilled in the art can select the cross section of the microneedle according to actual needs, and suitable cross section of the microneedle is within the scope of the present invention.

The present invention also provides a method of manufacturing a transdermal delivery device according to any of the embodiments described above, as shown in fig. 7-14, the method comprising:

step 110, fabricating a male mold 30 for the percutaneous delivery device.

As shown in fig. 7, the male mold 30 of the percutaneous delivery device can be implemented by assembly, machining, 3D printing, stereolithography, or micro-nano machining. Male mold 30 and female mold 40 are corresponding, male mold 30 may have microneedle mold section 31 and substrate mold section 32 corresponding to the transdermal delivery device; the female mold 40 may be made on the basis of the male mold 30. The structural parameters of the male die 30 can be flexibly adjusted according to requirements, and the male die 30 can be rigid or flexible. The array parameters of the male mold 30, such as microneedle 20 topography, pitch, and array size, determine the array parameters of the microneedles 20 of the transdermal delivery device.

The manufactured male mold 30 can be cleaned and then thoroughly dried by blow-drying to be dried. If the male mold 30 is manufactured by 3D printing or stereolithography, the male mold 30 usually belongs to a photosensitive resin material, and the female mold 40 and the male mold 30 are easily adhered and the female mold 40 is incompletely cured in subsequent operations, so that the male mold 30 can be subjected to ultraviolet irradiation and/or heating in advance to enhance molecular crosslinking inside the photosensitive resin, or a layer of metal or polymer film can be directly deposited on the surface of the male mold 30 to completely coat the photosensitive resin material, so as to effectively reduce the adhesion between the male mold 30 and the female mold 40 and avoid the problem of incomplete curing of the female mold 40, and prevent the female mold 40 from being difficult to demold and incomplete curing and the like as much as possible.

Step 120, the male die 30 is placed in the pouring container 50, a liquid elastic material is poured into the pouring container 50, and the liquid elastic material is cured after the pouring is finished, so that the female die 40 is obtained.

As shown in fig. 8, the microneedle mould part 31 of the processed male mould 30 is placed into a casting container 50, the casting container 50 can be a container without a cover, and then a prepared liquid elastic material, such as a liquid silicone elastomer material, for example, platinum-catalyzed silicone rubber Ecoflex, is cast, so that the liquid level completely submerges the male mould 30, and the liquid level minus the thickness of the substrate mould part 32 of the male mould 30 is the thickness of the female mould 40. The uncovered container is kept horizontal in the subsequent operation, and the condition that the surface of the female die 40 is uneven in height is prevented. And then vacuumizing and heating are carried out to completely solidify the micro-needle mold, wherein the vacuumizing has the function of completely pumping out the gas in the needle hole of the micro-needle mold part 31 of the male mold 30 so as to completely infiltrate the liquid silicone elastomer material.

As shown in fig. 9, the fully cured silicone elastomer is removed from the lidless container along with the encased male mold 30 and then cut along the edges of the male mold 30 so that the female mold 40 is slightly larger than or equal to the size of the substrate mold portion 32 of the male mold 30. And then slowly lifted along the four sides of the female mold 40 to the edges of the microneedle mold section 31. Considering the problem of the separation of the micropillar array 43 of the female mold 40 and the male mold 30 formed inside the pinholes of the microneedle mold part 31 of the male mold 30 from each other, the male mold 30 and the female mold 40 are placed in an aqueous solution of deionized water or a surfactant (such as sodium dodecyl sulfate or sodium dodecyl benzene sulfonate) for ultrasonic treatment and soaking, so that the adhesion of the micropillar array 43 of the female mold 40 and the inner wall of the male mold 30 is significantly reduced. After removal, the female mold 40 is slowly removed from the male mold 30. Different from the conventional micro-rollover process, the micro-pillar array 43 of the female mold 40 has a high aspect ratio and is positioned in the pinholes of the micro-needle mold part 31 of the male mold 30, and the micro-pillar array 43 of the female mold 40 is easy to break during demolding, so that the integrity problem of the micro-pillar array 43 of the female mold 40 is caused, and the uncovering direction needs to be changed at any time to relieve the stress condition of the micro-needle mold part 31, so that the micro-pillar array 43 of the female mold 40 can be completely separated from the male mold 30. If the female die 40 and the male die 30 are completely separated, the operation is repeated by changing to another side and re-tearing after tearing off several times from one side. The male mold 30 is cleaned and replaced for the next use.

Step 130, placing the female die 40 on a horizontal table, dripping the liquid polymer material on the female die 40, scraping the liquid polymer material after finishing dripping, and curing the liquid polymer to obtain the transdermal delivery device.

The prepared female die 40 comprises a female die body 41, a micro annular hole array 42 and a micro column array 43, wherein the micro column array 43 is vertically formed in the middle of the micro annular hole array 42, the height of the micro column array 43 in the female die 40 is determined by the specific depth of the pinhole cavity of the microneedle die part 31 in the male die 30, and the height can be adjusted according to the use condition, but is not suitable to be too long. The parameters of the micro annular hole array 42 are completely determined by the parameters of the inner and outer walls of the pinhole cavity of the microneedle mould part 31 of the male mould 30, and the thickness of the inner and outer walls of the pinhole cavity of the microneedle mould part 31 of the male mould 30 is not too thick to realize painless and bloodless minimally invasive puncture. The thickness of the female mold 40 is determined by the specific thickness of the silicone elastomer that was previously cast on the male mold 30. The array topography of the final female mold 40 is completely complementary to the microneedle array topography on the male mold 30.

The female mold 40 may be heated for a period of time and/or soaked in a surfactant for a period of time to reduce its surface tackiness to aid in subsequent demolding before it is used for further processing.

As shown in fig. 10, the cleaned female mold 40 is placed on a horizontal table with the micropillar array 43 facing upward, and each micropillar of the micropillar array 43 of the female mold 40 is observed and secured vertically in the middle of the micro-annular well array 42 before the liquid polymer material is added. Then a liquid biocompatible polymer, such as polyimide or SU-8, is added dropwise. So that the droplets completely cover the micropillar array 43 of the female mold 40.

A vacuum is applied to fill the micro-annular array of holes 42 in the female mold 40 with liquid polymer. The liquid polymer is then scraped to a thin thickness using an auxiliary tool such as a doctor blade, while ensuring that the micropillar array 43 of the female mold 40 penetrates the surface of the liquid polymer completely and vertically. This step strictly controls the thickness and surface size of the liquid polymer after the strike-off, considering the effects of surface tension of the liquid at the micro-scale, etc., which causes the micro-pillar array 43 to bend or pour directly on the surface of the liquid.

As shown in fig. 11, unlike the conventional micro-rollover process, this design uses a method of scraping off the liquid polymer and solidifying separately twice, the first time is to completely remove the liquid polymer far from the array, and only leave the micropillar array 43 of the female mold 40 and the liquid polymer near the micropillar array, and at this time, the thickness of the liquid polymer is strictly controlled, and the influence of the surface tension on the micropillar array 43 of the female mold 40 is minimized, and the thickness of the liquid polymer depends on the height of the micropillar array 43 of the female mold 40, and generally the thickness of the liquid polymer is relatively good when reaching 1/3-1/2 of the height of the micropillar array 43 of the female mold 40.

Heating to initially cure the liquid polymer. After curing, it is confirmed whether the micropillar array 43 of the female mold 40 vertically penetrates completely through the cured polymer. The thickness of the solidified polymer is reduced by evaporation of some of the liquid polymer solvent as a result of the solidification, and the reduced thickness polymer may affect the micropillar array 43 of the female mold 40, and if it causes a large deformation of the micropillar array 43 of the female mold 40, such as bending or falling on the surface of the polymer, it is necessary to slowly remove the polymer and begin to pour the female mold 40 again. After a satisfactory effect is achieved, liquid polymer is dripped into a blank area outside the micro-column array 43 of the female die 40, and the blank area is scraped and heated to be primarily solidified.

To observe whether the thickness of the surface of the substrate 10 is consistent throughout the transdermal delivery device, the thickness of the substrate 10 should be as consistent as possible to ensure flexibility and reduce stress. Then, the next operation is carried out according to the specific preparation conditions of the used polymer, such as the requirement of high temperature for imidization of non-photosensitive polyimide, the requirement of ultraviolet exposure crosslinking and high temperature imidization of photosensitive polyimide, and the requirement of ultraviolet exposure crosslinking and post-baking curing of SU-8.

As shown in fig. 12, the microneedles 20 and the female mold 40 of the transdermal delivery device are slowly uncovered along the edges of the substrate 10 of both to the outermost side of the microneedle array, and because there is some adhesion between the two, the use of brute force to separate the two can result in damage to the microneedles 20 of the transdermal delivery device or irreversible damage to the micropillar array 43 of the female mold 40. Considering the yield of demold and the reusability of the female mold 40, the two are not directly separated for a while. The female die 40 and the microneedles 20 of the transdermal delivery device are placed in an aqueous solution of deionized water or a surfactant (such as sodium dodecyl sulfate or sodium dodecyl benzene sulfonate) for ultrasonic treatment and soaking, so that the adhesion between the micro-column array 43 of the female die 40 and the inner walls of the microneedles 20 of the transdermal delivery device is remarkably reduced. After removal, the microneedles 20 of the transdermal delivery device are slowly removed from the female mold 40. Different from the conventional micro-rollover process, the structure of the micro-pillar array 43 of the female die 40 has a higher depth-to-width ratio, and the micro-pillar array 43 of the female die 40 is easy to break during demolding, so that the integrity problem of the micro-pillar array 43 of the female die 40 is caused, and the direction of the micro-pillar array 43 of the female die 40 needs to be changed at any time during uncovering, so that the stress condition of the micro-pillar array 43 of the female die 40 is relieved, and the micro-pillar array 43 of the female die 40 can be completely separated from the. After several peels from one side, the other side is replaced and the device is peeled again, and the process is repeated to finally separate the female mold 40 and the microneedles 20 of the transdermal delivery device completely. This allows to avoid to the maximum extent the structure of the micropillar array 43 of the female mold 40 from being damaged. The removed female mold 40 is cleaned and returned for the next use.

As shown in fig. 13 and 14, the isolated preliminary sample of the transdermal delivery device includes the substrate 10, the microneedles 20, and the backside micro-annular protrusions 60. Due to the surface tension, the back surface of the substrate 10 of the transdermal delivery device has minute annular protrusions 60, which are generated due to the adhesion of the liquid polymer on the micropillar array 43 of the female mold 40 due to the surface tension, and can be slowly sanded with sand paper or the like to obtain the final sample. Because the height of the protruding structure is very low, no inconvenience is caused to subsequent application after polishing. And cleaning the polished percutaneous conveying device. The topographical parameters of the percutaneous delivery device completely correspond to those of the micropillar array 43 and the micro-annular aperture array 42 of the female mold 40, i.e., are completely replicated from those of the male mold 30.

According to different final use scenes, the substrate 10 of the percutaneous delivery device is cut to be a proper size for timed, quantitative, accurate and effective drug delivery.

The above-described embodiments of the apparatus are merely illustrative, and the units described as separate parts may or may not be physically separate, and parts displayed as units may or may not be physical units, may be located in one place, or may be distributed on a plurality of network units. Some or all of the modules may be selected according to actual needs to achieve the purpose of the solution of the present embodiment. One of ordinary skill in the art can understand and implement it without inventive effort.

Through the above description of the embodiments, those skilled in the art will clearly understand that each embodiment can be implemented by software plus a necessary general hardware platform, and certainly can also be implemented by hardware. With this understanding in mind, the above-described technical solutions may be embodied in the form of a software product, which can be stored in a computer-readable storage medium such as ROM/RAM, magnetic disk, optical disk, etc., and includes instructions for causing a computer device (which may be a personal computer, a server, or a network device, etc.) to execute the methods described in the embodiments or some parts of the embodiments.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. A percutaneous delivery device, comprising:

a substrate having a working side for conforming to a target object;

at least two micropins, at least two micropins with substrate integrated into one piece, the micropin has working section and link, the working section is followed the working side outwards stretches out, link and working section pass through hollow transfer passage intercommunication, transfer passage runs through the substrate, the link deviates from the working side.

2. The percutaneous delivery device according to claim 1, wherein the working segment comprises:

the first section is connected with the working side face, the cross sectional area of the first section is gradually reduced along the direction far away from the working side face, and the outer surface of the first section is a curved surface;

a second segment connected to the first segment, the second segment having a needle tip for penetrating a target object.

3. The percutaneous delivery device according to claim 2, wherein the second segment has a first chamfered surface that forms the needle tip with an outer peripheral surface of the second segment.

4. The percutaneous delivery device according to claim 3, wherein the second segment has a second chamfer and a third chamfer, the second chamfer and the third chamfer both intersecting the first chamfer, the second chamfer intersecting the third chamfer, the first chamfer, the second chamfer and the third chamfer forming the needle tip.

5. The percutaneous delivery device according to claim 4, wherein the second and third beveled surfaces are each concavely curved.

6. A percutaneous delivery device according to any of claims 2 to 5, wherein the cross-sectional area of the second section is smaller than the cross-sectional area of the first section, the cross-sectional area of the second section decreasing in a direction away from the working side.

7. The percutaneous delivery device according to any one of claims 2 to 5, wherein the outer peripheral surface of the second section has a convex section, and the cross-sectional area of the second section gradually increases from the junction of the second section and the first section to the convex section and gradually decreases from the convex section in a direction away from the working side.

8. A transdermal delivery device according to any of claims 2 to 5, wherein the substrate is a flexible substrate.

9. The transdermal delivery device according to any of claims 2-5, wherein the microneedles are 500-1000 μ ι η in length;

or the diameter of the bottom circle of the microneedle is 200-300 μm;

alternatively, the central distance between adjacent microneedles is 500 μm to 1000 μm.

10. A method of making a transdermal delivery device according to any of claims 1 to 9 comprising:

making a male mold of the percutaneous delivery device;

placing the male die in a pouring container, pouring a liquid elastic material into the pouring container, and curing the liquid elastic material after the pouring is finished to obtain a female die;

and placing the female die on a horizontal table, dropwise adding a liquid polymer material to the female die, scraping the liquid polymer material after the dropwise adding is finished, and curing the liquid polymer to obtain the percutaneous conveying device.