CN112245792A

CN112245792A - Hollow metal microneedle array, preparation method thereof and transdermal drug delivery patch

Info

Publication number: CN112245792A
Application number: CN202011260037.XA
Authority: CN
Inventors: 岳瑞峰; 王燕
Original assignee: Tsinghua University
Current assignee: Tsinghua University
Priority date: 2020-11-12
Filing date: 2020-11-12
Publication date: 2021-01-22
Also published as: CN113952609A; CN113952609B

Abstract

The invention discloses a hollow metal microneedle array, a preparation method thereof and a transdermal drug delivery patch, wherein the array comprises a substrate, a plurality of metal capillaries and structural adhesive; the surface of the same side of the substrate is provided with a groove, two side walls of the groove are provided with a plurality of pairs of through positioning grooves, and the plurality of pairs of positioning grooves are arranged at a set interval along the length direction of the substrate and are mutually parallel; the metal capillaries are respectively arranged in the positioning grooves in a one-to-one correspondence manner, and one ends of the metal capillaries on the same side are needles and extend out of the substrate, so that a needle array is formed, and the needles in the same row in the needle array have main inclined planes in the same direction; and the structural adhesive is coated in the grooves and the pairs of positioning grooves and is solidified, and the plurality of metal capillary tubes are fixed on the substrate. The array is convenient for penetrating all the micro-needles into the skin without pain, and the single micro-needle has large drug-loading rate, firm and reliable structure, easy processing and low cost.

Description

Hollow metal microneedle array, preparation method thereof and transdermal drug delivery patch

Technical Field

The invention relates to the technical field of medical instruments and medicines, in particular to a hollow metal microneedle array, a preparation method thereof and a transdermal drug delivery patch.

Background

The microneedle array is a core component of a microneedle transdermal drug delivery patch, and is composed of a plurality of slender and short microneedles which are arranged at certain intervals and fixed on a substrate. Microneedle transdermal patches generally try to fix a tiny dose of drug on the needle tips of all microneedles in advance; in use, the drug is delivered directly into the skin or subcutaneously by pressing the substrate of the microneedle array against the surface of the patient's skin to ensure that all of the tips of the needles pierce the stratum corneum, which is the exterior of the skin, to a certain depth. During the period of temporarily fixing the microneedle array on the skin surface, the drug on the needle tip is absorbed into the systemic circulation through the capillary vessels through rapid diffusion to generate the drug effect. The drug delivery mode combining the medical instruments breaks through the barrier effect of the compact stratum corneum on the skin surface at one stroke, can realize quantitative targeting and sustained and controlled release transdermal drug delivery and achieve the purposes of quick acting and obvious effect, and has the characteristics of flexible and convenient use, no pain, high safety and good patient compliance, thereby becoming the key point of novel medicament research and development and being hopeful. Microneedle arrays for microneedle transdermal drug delivery patches are mainly of two types: the first type, the micro-needle and the substrate for fixing the micro-needle are solid micro-needle arrays which are integrally manufactured by adopting single materials such as monocrystalline silicon or plastics, metal and the like through the processes of photoetching, etching, injection molding or laser cutting and the like, but how to fix various medicaments on all needle points of the solid micro-needle arrays quantitatively, uniformly and repeatedly is very difficult, and when the micro-needle is applied, how to ensure that the micro-needle cannot be broken off in the process of piercing the stratum corneum and the medicaments on the needle points can be penetrated in a perfect and undamaged way without falling off in vitro faces a serious challenge; in the second category, the microneedles and the substrate are assembled from two different materials, such as patent documents CN101829396A and CN101912663A, but the manufacturing of such a combined structure requires that a large number of fine and short microneedles can be rapidly separated, clamped, transported, arranged, and precisely positioned, and the like, and on the other hand, sufficient fixing strength between the microneedles and the very thin substrate must be ensured, which is difficult to implement and costly, and thus, the automatic mass production has not been achieved. The existing microneedle array is generally composed of dozens to hundreds of microneedles and arranged in an array form of N × M, and compared with soft skin, a substrate for fixing the microneedles is generally much harder; since the height of the micro-needle protruding out of the substrate is generally only hundreds of micrometers, it is inevitable that only the micro-needle at the edge of the substrate can really penetrate into the stratum corneum, and therefore, the micro-needle in the middle of the substrate cannot transport the drug, and the dosage is uncertain. In addition, the patient cannot further divide the existing microneedle array structure according to the requirement of the actual administration dosage, which will undoubtedly limit the flexibility of the doctor to select the administration dosage (of the number of microneedles or the array area) according to the condition, age and administration position of the patient; meanwhile, because the medicines suitable for microneedle administration are various in types and have large differences between the characteristics and the administration amount, the problem that the microneedle array structure is difficult to self-divide inevitably greatly limits the application flexibility of the specification and variety of the existing microneedle array, so that the microneedle array structure is difficult to become a universal carrier suitable for various medicines, and great difficulty is brought to microneedle administration patch manufacturing, application and popularization of microneedle array manufacturers and various medicines.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. To this end, an object of the present invention is to provide a hollow metal microneedle array which facilitates ensuring that all microneedles are inserted into the skin without pain, a large drug loading of the individual microneedles and the drug is not dropped during the insertion period to avoid uncertainty of the dose, is structurally sound and reliable, is easy to process at low cost, and is suitable for automated mass production.

A hollow metallic microneedle array according to an embodiment of the first aspect of the present invention includes:

the substrate is in a straight strip shape, grooves extending along the length direction of the substrate are formed in the surface of the same side of the substrate, a plurality of pairs of through positioning grooves are formed in two opposite side walls of the substrate in the width direction, and the positioning grooves are arranged at set intervals along the length direction of the substrate and are parallel to each other;

the metal capillaries are respectively arranged in the positioning grooves in a one-to-one correspondence mode, one ends of the metal capillaries on the same side are needles and extend out of the substrate, so that a needle array is formed, and the needles in the same row in the needle array have main inclined planes in the same direction;

and the structural adhesive is coated in the grooves and the pairs of positioning grooves and is solidified, and the metal capillaries are fixed on the substrate.

According to some embodiments of the first aspect of the present invention, the groove penetrates the substrate in a length direction of the substrate, or both ends of the groove in the length direction of the substrate do not penetrate the substrate.

According to some embodiments of the first aspect of the present invention, a plurality of the grooves are provided on a surface of the substrate on the same side, and the plurality of the grooves are arranged at a set pitch along a length direction of the substrate, thereby forming a groove array.

According to some embodiments of the first aspect of the present invention, the substrate is provided with dimples that are easily recognizable and severable.

According to some embodiments of the first aspect of the present invention, the substrate further comprises a cover layer disposed on the substrate and located on the opening side of the groove, and the cover layer is fixed on the substrate by the structural adhesive.

According to some embodiments of the first aspect of the present invention, the width of the groove is 0.2 to 5 mm, and the depth of the groove is 0.2 to 3 mm; the width of the positioning groove is 0.16-0.45 mm, and the depth of the positioning groove is not more than that of the groove; the width of the substrate is 0.4-4 mm larger than that of the groove; the thickness of the groove bottom of the groove is 0.1-2 mm; the outer diameter of the metal capillary tube is 0.15-0.4 mm; the length of the needle protruding out of the side wall of the substrate is 0.2-1.8 mm.

According to some embodiments of the first aspect of the present invention, the recess and the pair of positioning grooves are provided on both the upper surface and the lower surface of the substrate; the primary bevel of the upper row of needles and the primary bevel of the lower row of needles in the needle array are mirror images of each other back to back.

According to some embodiments of the first aspect of the present invention, the outer diameter at the needle end of the metal capillary is smaller than the outer diameter of the middle section of the capillary, the inner diameter at the needle end of the metal capillary is larger than the inner diameter of the middle section of the capillary, and the wall of the middle section of the metal capillary is thinner than the wall of the middle section of the metal capillary.

The hollow metal microneedle array according to the first embodiment of the present invention has the following advantages: firstly, the metal capillary tube can be quickly and accurately positioned and can be firmly fixed on a substrate and is not easy to loosen and fall off; secondly, the needle head has good length controllability and strong consistency, sharp needle points and needle hole orientations can be formed to be consistent through the main inclined plane, all the micro-needles can be conveniently penetrated into the skin without pain, and the micro-needle array has a small and attractive structure; thirdly, the drug can be stored through the tube hole of the metal capillary, the drug-loading capacity of a single microneedle is large, and the drug in the tube hole cannot fall off when the single microneedle penetrates into the skin, so that accurate quantitative drug delivery can be realized; fourthly, the special dent structure which is easy to identify and break is convenient for a patient to break at the dent part according to medical advice, and the transdermal drug delivery patch obtained by loading the drug by the hollow metal microneedle array of the embodiment of the first aspect of the invention can realize flexible drug delivery according to requirements, and has better effect; fourthly, the method is easy to process, low in cost and suitable for automatic batch production.

The invention also provides a preparation method of the hollow metal microneedle array in the second aspect.

According to a second aspect of the present invention, there is provided a method for manufacturing a hollow metal microneedle array, the method comprising the steps of:

arranging N substrates in a row and N rows in order according to a set interval;

respectively placing a plurality of metal capillary tubes with the set length of several millimeters to several thousand millimeters in a plurality of pairs of positioning grooves of the N substrates in a one-to-one correspondence manner;

pouring or coating the structural adhesive in the grooves and the pairs of positioning grooves of the N substrates, and curing the structural adhesive;

cutting off the metal capillary connecting the N substrates;

and grinding one end of the metal capillary on each substrate, which protrudes out of the substrate and is on the same side, so as to form the main inclined plane with the same orientation.

The third aspect of the invention also provides a transdermal drug delivery patch.

A transdermal drug delivery patch according to an embodiment of the third aspect of the present invention includes: at least one array of hollow metallic microneedles according to any embodiment of the first aspect of the invention;

a drug having a therapeutic, health, or cosmetic composition, the drug being stored within the bore of the metal capillary and secured to the needle.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

fig. 1 is a top view of a substrate of a hollow metallic microneedle array according to a first embodiment of the first aspect of the present invention.

Fig. 2 is a side view of a substrate of a hollow metallic microneedle array according to a first embodiment of the first aspect of the present invention.

Fig. 3 is a top view of an array of hollow metallic microneedles according to a first embodiment of the first aspect of the present invention.

Fig. 4 is a top view of a substrate of a hollow metallic microneedle array according to a second embodiment of the first aspect of the present invention.

Fig. 5 is a top view of an array of hollow metallic microneedles according to a second embodiment of the first aspect of the present invention.

Fig. 6 is a perspective view of a hollow metal microneedle array according to a second embodiment of the first aspect of the present invention.

Fig. 7 is a perspective view of a hollow metal microneedle array according to a third embodiment of the first aspect of the present invention.

Fig. 8 is a top view of a substrate of a hollow metallic microneedle array according to a fourth embodiment of the first aspect of the present invention.

Fig. 9 is a top view of a substrate of a hollow metallic microneedle array according to a fifth embodiment of the first aspect of the present invention.

Fig. 10 is a top view of a substrate of a hollow metallic microneedle array according to a sixth embodiment of the first aspect of the present invention.

Fig. 11(a) is a partial sectional view of a hollow metallic microneedle array according to a seventh embodiment of the first aspect of the present invention.

Fig. 11(b) is a partial sectional view of a hollow metallic microneedle array according to an eighth embodiment of the first aspect of the present invention.

Fig. 12(a) to 12(e) are schematic views illustrating a method for manufacturing a hollow metal microneedle array according to an embodiment of the second aspect of the present invention.

Reference numerals:

hollow metal microneedle array 1000

Substrate 1 groove 101 notch 102 notch 103

Metal capillary 2 needle 201 primary bevel 2011 orifice 2012 secondary bevel 2013

Structural adhesive 3

Cover layer 4

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.

The following describes a hollow metal microneedle array, a method of manufacturing the same, and a transdermal drug delivery patch according to an embodiment of the present invention.

In a first aspect, the present invention provides a hollow metal microneedle array 1000.

As shown in fig. 1 to 10, a hollow metal microneedle array 1000 according to an embodiment of the first aspect of the present invention includes a substrate 1, a plurality of metal capillaries 2, and a structural adhesive 3. Wherein, the substrate 1 is in a shape of a straight lath, the surface of the same side of the substrate 1 is formed with a groove 101 extending along the length direction of the substrate 1, the grooves 101 are formed with a plurality of pairs of through positioning grooves 102 on two opposite side walls in the width direction of the substrate 1, the plurality of pairs of positioning grooves 102 are arranged at a set interval along the length direction of the substrate 1 and are parallel to each other; the metal capillaries 2 are respectively arranged in the positioning grooves 102 in a one-to-one correspondence manner, and one ends of the metal capillaries 2 on the same side are needles 201 and extend out of the substrate 1, so that a needle array is formed, and the needles 201 in the same row in the needle array have main inclined surfaces 2011 with the same orientation; the structural adhesive 3 is coated in the grooves 101 and the pairs of positioning grooves 102 to be cured and fix the plurality of metal capillaries 2 on the substrate 1.

Specifically, the substrate 1 is in a shape of a straight bar, a groove 101 extending in a length direction of the substrate 1 is formed on a surface on the same side of the substrate 1, a plurality of pairs of through positioning grooves 102 are formed on two side walls of the groove 101 opposite to each other in a width direction of the substrate 1 (i.e., a plurality of positioning grooves 102 are formed on one side wall of the groove 101, a plurality of positioning grooves 102 are also formed on the other side wall of the groove 101, the plurality of positioning grooves 102 on one side wall of the groove 101 and the plurality of positioning grooves 102 on the other side wall of the groove 101 are respectively aligned in the same line in a one-to-one correspondence manner in the width direction of the substrate 1), and the plurality of pairs of positioning grooves 102 are arranged at a set pitch in the length direction of the substrate 1 and are. In a normal case, the groove 101 is located at the center of the substrate 1, and the plurality of positioning grooves 102 are formed on the left and right side walls of the groove 101 in a one-to-one correspondence, and a plurality of pairs of positioning grooves 102 are formed to perpendicularly intersect the groove 101. It can be understood that, the substrate 1 adopts the structural form, on one hand, various plastics, metals, woods, ceramics, glass, paper or composite materials can be selected and manufactured by utilizing a mature batch processing method, and if the plastics such as PP, PVC, PE, PET, ABS, PC and the like are selected, the substrate 1 structure provided by the invention can be manufactured in a large batch at low cost by adopting a traditional injection molding method; on the other hand, a plurality of metal capillaries 2 can be accurately placed in the pairs of positioning grooves 102 parallel to each other on the substrate 1 in a one-to-one correspondence manner, because the metal capillaries 2 are very fine and the width of the substrate 1 is very narrow, while the adhesion of the existing medical structural adhesive 3 such as epoxy resin, PP and other plastics is poor, in order to reliably fix the metal capillaries 2 on the substrate 1, the grooves 101 are specially arranged on the surface of the substrate 1, and the grooves 101 are in cross communication with the pairs of positioning grooves 102, so that the structural adhesive 3 is coated and filled in the grooves 101 and the pairs of positioning grooves 102, thus the contact surface for bonding between the structural adhesive 3 and the substrate 1 can be greatly increased, the bonding strength and the structural strength of the hollow microneedle array can be obviously improved, the metal capillaries 2 can be firmly fixed on the substrate 1, the looseness and falling are not easy to occur, and the metal capillaries 2 can be effectively prevented from being cut and ground in the preparation process of the hollow metal microneedle array 1000 When the needle 201 is operated and the hollow metal microneedle array 1000 is actually used to pierce the skin, the metal capillary 2 is detached from the substrate or the metal capillary 2 and the structural adhesive 3 are detached from the substrate 1 together due to insufficient adhesive strength.

The metal capillaries 2 are respectively arranged in the pairs of positioning grooves 102 in a one-to-one correspondence manner, and one ends of the metal capillaries 2 on the same side are needles 201 and extend out of the substrate 1, so as to form a needle array, and it can be understood that the needles 201 in the same row in the needle array have main inclined surfaces 2011 with the same orientation, that is, the metal capillaries 2 are elongated hollow metal tubes, and the metal capillaries 2 have tube holes which can be used for storing medicines, compared with a mode that medicines are only fixed on needle points of solid microneedles in the prior art, the quantity of the medicines which can be stored by the metal capillaries 2 is undoubtedly much larger; in the prior art, the medicine is fixed on the needle point of the solid microneedle, when the solid microneedle penetrates into the skin, the medicine fixed on the needle point is very easy to fall off and stays on the surface of the skin, so that the treatment effect is difficult to achieve, but because the medicine is stored in the tube hole of the metal capillary tube 2, after the needle 201 penetrates through the horny layer of the skin, the medicine in the tube hole can quickly enter the body through the capillary tube to circulate to generate the medicine effect, the administration amount is accurate, the repeatability is good, not only the solid medicine can be transported, but also ointment or even liquid medicine can be transported, and the treatment effect is obvious. The metal capillary tube 2 may be a hollow circular tube, a conical tube, a polygonal tube, etc., i.e., the metal capillary tube 2 may have various shapes and sizes. If metal capillary 2 is a hollow round tube, orifice 2012 in the main bevel 2011 of the needle is generally oval in shape. The metal capillary 2 may be made of any one or more of titanium, copper, aluminum, iron, nickel, tungsten, stainless steel, titanium alloy, aluminum alloy, nickel alloy, and copper alloy, but is not limited thereto. A plurality of metal capillaries 2 are installed in the paired positioning grooves 102 with accurate positioning. The needles 201 of the metal capillaries 2 extend out of the substrate 1, so that the needles 201 can conveniently pierce the stratum corneum of the skin, the needles 201 in the same row in the needle array are provided with main inclined planes 2011, a sharp needle point can be formed, the skin stratum corneum piercing is more facilitated, the orifices 2012 at one ends of the tube holes of the metal capillaries 2 are located on the main inclined planes 2011, and after the needles 201 pierce the stratum corneum of the skin, the medicines in the tube holes can be rapidly diffused into the tissues in vivo to generate the medicine effect. In addition, other material thin films such as metal thin films of gold, platinum, titanium, etc., or polymer thin films may be deposited on the surface of the metal capillary 2.

The structural adhesive 3 is coated in the grooves 101 and the pairs of positioning grooves 102 to be cured and fix the plurality of metal capillaries 2 on the substrate 1. Because the liquid structure adhesive 3 has good fluidity and wettability in the groove 101 and the positioning groove 102, the metal capillaries 2 can be firmly fixed on the substrate 1 after the liquid structure adhesive is solidified by standing, heating or illumination, and the like, the appearance is smooth and attractive, the fixing operation mode is simple, and the cost is low.

The hollow metal microneedle array 1000 according to the first embodiment of the present invention has the following advantages: the first metal capillary tube 2 can be quickly and accurately positioned and can be firmly fixed on the substrate 1 and is not easy to loosen and fall off; secondly, the length of the needle 201 is controllable well and consistent, and sharp needle points and needle holes can be formed in consistent directions through the main inclined surface 2011, so that all microneedles can be conveniently punctured into the skin without pain; secondly, drugs are stored through the tube holes of the metal capillary tubes 2, so that the drug-loading capacity of a single microneedle is large, the drug cannot fall off when the microneedle penetrates into the skin, the accuracy, the repeatability and the consistency of the drug-delivery dosage can be ensured, and the curative effect is stable and reliable; thirdly, the processing is easy, the cost is low, and the method is suitable for automatic batch production; fourthly, the micro-needle array has small and exquisite structure and beautiful appearance.

According to some embodiments of the first aspect of the present invention, the groove 101 penetrates the substrate 1 in the length direction of the substrate 1 (as shown in fig. 1 to 3), so that the fluidity of the liquid structural adhesive can be fully utilized to simplify the glue filling process for mass production; alternatively, both ends of the groove 101 in the length direction of the substrate 1 do not penetrate through the substrate 1, that is, both ends of the groove 101 in the length direction of the substrate 1 have closed sidewalls (as shown in fig. 4 to 6), so that it is ensured that the structural adhesive 3 has a set thickness, uniform thickness and sufficient mechanical strength in the groove 101. Meanwhile, the embodiment of fig. 1-6 only has the groove 101 and the positioning groove 102 on the upper surface of the substrate 1, and only one row of microneedles is arranged on the groove and the thickness of the substrate can be reduced to the minimum, so that the size of the hollow microneedle array can be obviously reduced, and the hollow microneedle array is convenient to manufacture, carry and use in a large scale. In addition, to make the needle sharper to minimize pain during penetration, the needle 201 may also be provided with a second bevel 2013 or with more bevels, as shown in FIG. 5.

As shown in fig. 8 and 9, according to some embodiments of the first aspect of the present invention, a plurality of grooves 101 are provided on the surface of the same side of the substrate 1, and the plurality of grooves 101 are arranged at a set pitch along the length direction of the substrate 1, thereby forming an array of grooves 101. For example, as shown in fig. 8, three mutually independent grooves 101 are provided at a set pitch in the middle of the upper surface region of the substrate 1, and the three grooves 101 are arranged in line from one end of the substrate 1 to the other end to form an array of grooves 101. In addition, an indentation 103 which is easy to identify and break is further arranged between two adjacent grooves, so that a doctor can conveniently select the dosage according to the state of an illness, a patient can conveniently use the hollow microneedle array in a segmented mode, and the flexibility of dosage according to the requirement is obviously improved.

As shown in fig. 9, according to some embodiments of the first aspect of the present invention, although only one groove 101 is provided on the substrate 1, the groove width at the corresponding position is significantly narrowed due to the provision of the easily recognizable and segmented dimples 103 at the set pitch. In view of good fluidity, the adoption of the structure can also ensure that the liquid structural adhesive can smoothly fill the whole groove and greatly simplify the adhesive filling process, and the first aspect of the invention further obviously improves the production efficiency and the yield of the hollow microneedle array.

As shown in fig. 7, according to some embodiments of the first aspect of the present invention, the cover layer 4 is further included, the cover layer 4 is disposed on the substrate 1 and located on the opening side of the groove 101, and the cover layer 4 is fixed on the substrate 1 by the structural adhesive 3. By additionally arranging the covering layer 4 on the substrate 1, on one hand, the fixing effect on the plurality of metal capillaries 2 is further strengthened, the possibility that the metal capillaries 2 are separated from the adhesive and the substrate 1 from the weakest link on the substrate 1 can be thoroughly eliminated, and on the other hand, the appearance is beautified. The material used for the cover layer 4 may be the same as the material used for the substrate, but may be different from the material used for the substrate, and the thickness is usually 0.1 to 1 mm.

According to some embodiments of the first aspect of the present invention, the width of the groove 101 is 0.2 to 5 mm, and the depth of the groove 101 is 0.2 to 3 mm; the width of the positioning groove 102 is 0.16-0.45 mm, and the depth of the positioning groove 102 is not more than that of the groove 101; the width of the substrate 1 is 0.4-4 mm larger than that of the groove 101; the thickness of the bottom of the groove 101 is 0.1-2 mm; the outer diameter of the metal capillary 2 is 0.15-0.4 mm; the length of the needle 201 protruding from the sidewall of the substrate 1 is 0.2-1.8 mm. Therefore, the hollow metal microneedle array 1000 can be made smaller in size and have a certain mechanical strength.

Preferably, the width of the groove 101 is 0.2-3.0 mm, and the depth of the groove 101 is 0.2-2.0 mm; the width of the positioning groove 102 is 0.16-0.35 mm, and the depth of the positioning groove 102 is not more than that of the groove 101; the width of the substrate 1 is 0.4-2 mm larger than that of the groove 101; the thickness of the bottom of the groove 101 is 0.1-1 mm; the outer diameter of the metal capillary 2 is 0.15-0.3 mm; the length of the needle 201 protruding from the sidewall of the substrate 1 is 0.3-1.2 mm.

More preferably, the width of the groove 101 is 0.2-1.5 mm, and the depth of the groove 101 is 0.2-1.0 mm; the width of the positioning groove 102 is 0.16-0.3 mm, and the depth of the positioning groove 102 is not more than that of the groove 101; the width of the substrate 1 is 0.4-1 mm larger than that of the groove 101; the thickness of the bottom of the groove 101 is 0.1-0.5 mm; the outer diameter of the metal capillary 2 is 0.15-0.25 mm; the length of the needle 201 protruding from the sidewall of the substrate 1 is 0.3-0.8 mm.

According to some embodiments of the first aspect of the present invention, the substrate 1 is provided with a groove 101 and a pair of positioning grooves 102 on both the upper and lower surfaces thereof (as shown in fig. 10); the primary bevel 2011 of the upper row of needles 201 and the primary bevel 2011 of the lower row of needles 201 in the needle array are mirror images of each other back-to-back. Therefore, all needles 201 in the needle array can be ensured to smoothly penetrate into the skin and quickly diffuse the medicine in the needles, and the operation and observation of inputting the medicine into the capillary holes during the preparation of the transdermal drug delivery patch are facilitated.

According to some embodiments of the first aspect of the present invention, as shown in fig. 11(a), the conventional structure in which the metal capillary has the same outer diameter and inner diameter along the entire length of the metal capillary is easy and convenient to manufacture; as shown in fig. 11(b), the outer diameter at one end of the needle 201 of the metal capillary 2 is smaller than the outer diameter of the middle section of the capillary, the inner diameter at one end of the needle 201 of the metal capillary 2 is larger than the inner diameter of the middle section of the capillary, and the wall of the end of the needle 201 of the metal capillary 2 is thinner than that of the middle section of the metal capillary 2; here, the middle section of the metal capillary 2 means a portion where the metal capillary 2 is covered and fixed to the substrate 1 by the structural adhesive 3; because the outer diameter of one end of the needle 201 is small, the inner diameter is large and the tube wall is thin, the outer tube of the needle 201 is smaller, the drug loading capacity is larger, the drug can be more easily guided into the tube hole of the metal capillary 2, and the needle 201 can be more easily penetrated into the skin. The second aspect of the present invention also provides a method for preparing the hollow metal microneedle array 1000.

According to the method for manufacturing the hollow metal microneedle array 1000 according to the embodiment of the second aspect of the present invention, the hollow metal microneedle array 1000 is the hollow metal microneedle array 1000 according to the embodiment of the first aspect of the present invention, and the manufacturing method includes the following steps:

s1: n substrates 1 are arranged in a row and N rows at a predetermined pitch, that is, one substrate 1 is a row and N substrates 1 are a row, for example, as shown in fig. 12(a), a frame of PP plastic substrates 1 is a frame structure of PP plastic substrates in which four substrates 1 are arranged in a row and four rows at a predetermined pitch by injection molding.

S2: a plurality of metal capillaries 2 with the set length of several millimeters to several thousand millimeters are respectively arranged in a plurality of pairs of positioning grooves 102 of N substrates 1 in a one-to-one correspondence manner; that is, the plural pairs of positioning grooves 102 on the N substrates 1 are aligned in a straight line in the row direction, respectively, and the plural metal capillaries 2 are arranged in the plural pairs of positioning grooves 102 on the N substrates 1 in a one-to-one correspondence in plural rows, so that the processing efficiency can be improved. For example, as shown in fig. 12(b), a plurality of metal capillaries 2 cut in order and having a length of about 20 mm are respectively placed in pairs of positioning grooves 102 of four substrates 1 in a one-to-one correspondence.

S3: pouring or coating the structural adhesive 3 in the grooves 101 and the pairs of positioning grooves 102 of the N substrates 1, and curing the structural adhesive 3. For example, as shown in fig. 12(c), an epoxy resin glue solution is poured or coated into the grooves 101 and the pairs of positioning grooves 102 of the substrate 1, and then heated to 90 ℃ or higher for curing. It should be noted that after the pouring or coating of the structural adhesive 3 is completed and before the curing, the covering layer 4 may be placed on the structural adhesive 3 and then cured.

S4: one end of the metal capillary 2 on each substrate 1 protruding from the substrate 1 and on the same side is ground to form a main inclined surface 2011 having the same orientation, as shown in fig. 12 (d).

S5: the metal capillary 2 connecting the N substrates 1 is cut as shown in fig. 12 (e).

It should be noted that, in the actual operation process, the process sequence of steps S4 and S5 may be changed as needed.

In addition, the exposed needle tube portion may be further processed by chemical or electrochemical etching and polishing to form the needle 201 and needle tube structure shown in fig. 11 (b).

A transdermal drug delivery patch according to an embodiment of the third aspect of the present invention includes: at least one hollow metallic microneedle array 1000 according to any one embodiment of the first aspect of the present invention; the metal capillary 2 of the hollow metal microneedle array 1000 stores therein a drug, which contains components having therapeutic, health-care or cosmetic effects. The medicine can be in a solid state, an ointment state or even a liquid state, can be in a particle or powder state, and can be filled only in the hole at the main inclined plane of the needle tip or can fill the whole pipeline of the metal capillary 2 according to requirements. The transdermal patch usually further comprises an adhesive tape or other fixing structure, and when in use, the drug-carrying needle 201 of the hollow metal microneedle array 1000 is vertically or obliquely inserted into the stratum corneum, and then the hollow metal microneedle array 1000 is temporarily fixed on the skin surface by the adhesive tape or other fixing structure.

According to the transdermal drug delivery patch of the third aspect of the invention, all the needles 201 on the hollow metal microneedle array 1000 can be ensured to be penetrated into the skin for drug delivery, the drug loading capacity is large, the drug cannot fall off the skin, the use is flexible, convenient and safe, the pain sense is extremely low or completely painless, the input drug capacity is accurate, and the curative effect is obvious.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like are intended to mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

While embodiments of the invention have been shown and described, it will be understood by those of ordinary skill in the art that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A hollow metallic microneedle array comprising:

2. The hollow metal microneedle array according to claim 1, wherein the groove penetrates the substrate in a length direction of the substrate, or both ends of the groove in the length direction of the substrate do not penetrate the substrate.

3. The hollow metal microneedle array of claim 1, wherein a plurality of the grooves are formed on a surface of the same side of the substrate, and the plurality of the grooves are arranged at a predetermined pitch in a length direction of the substrate, thereby forming a groove array.

4. The hollow metal microneedle array of claim 1, wherein said substrate is provided with dimples for easy recognition and breaking.

5. The hollow metal microneedle array according to claim 1, further comprising a cover layer disposed on the substrate on the opening side of the groove, the cover layer being adhesively fixed on the substrate by the structural adhesive.

6. The hollow metal microneedle array according to claim 1, wherein the width of the groove is 0.2 to 5 mm, and the depth of the groove is 0.2 to 3 mm; the width of the positioning groove is 0.16-0.45 mm, and the depth of the positioning groove is not more than that of the groove; the width of the substrate is 0.4-4 mm larger than that of the groove; the thickness of the groove bottom of the groove is 0.1-2 mm; the outer diameter of the metal capillary tube is 0.15-0.4 mm; the length of the needle protruding out of the side wall of the substrate is 0.2-1.8 mm.

7. The hollow metallic microneedle array of any one of claims 1 to 6, wherein said grooves and said paired positioning grooves are provided on both of the upper and lower surfaces of said substrate; the primary bevel of the upper row of needles and the primary bevel of the lower row of needles in the needle array are mirror images of each other back to back.

8. The hollow metal microneedle array according to any one of claims 1 to 6, wherein an outer diameter at the needle-end of the metal capillary is smaller than an outer diameter of a middle section of the capillary, an inner diameter at the needle-end of the metal capillary is larger than an inner diameter of a middle section of the capillary, and a tube wall at the needle-end of the metal capillary is thinner than a tube wall of a middle section of the metal capillary.

9. A method for manufacturing a hollow metal microneedle array, wherein the hollow metal microneedle array is the hollow metal microneedle array according to any one of claims 1 to 8, the method comprising the steps of:

cutting off the metal capillary connecting the N substrates;

10. A transdermal patch, comprising: at least one array of hollow metallic microneedles according to any one of claims 1-8;