TECHNICAL FIELD

The present disclosure relates to the technical field of transdermal administrating formulation, particularly to a microneedle chip and a manufacturing method thereof.

BACKGROUND

The microneedle transdermal administrating technology is a novel method for transdermal administration. The silicon and silicon oxide microneedles were initially used. Such microneedles have a mature manufacturing process, but disadvantages of poor biocompatibility, brittle quality, low productive rate, and the like, limiting its industrialization. Another type is metal microneedles. Such microneedles have a good mechanical strength, but disadvantages of small drug loading capacity, complicated process, high processing cost, also limiting the industrial production and clinical application of such microneedles.

A soluble microneedle refers to those having a needle body formed of dissolvable or degradable excipients, with which drug components is mixed, directly stored in the needle body, and release after the needle body penetrates into the skin. Currently, it is still difficult to achieve mass production in the manufacture of such microneedle due to its small size (with an operable space within 1 mm3).

At this stage, the methods for manufacturing a soluble microneedle reported in the literatures, which are still in the laboratory stage, can be divided into two types: one method is to manufacture the soluble microneedle by dissolving a polymer material into water or ethanol, and by utilizing the viscosity of this solution, sandwiching and wire-drawing a small droplet of this solution between two plates (for example, WO 2008/010681A1). This method has the disadvantages of long time for production, precise control of the wire-drawing process, irregularly shaped needle bodies, formation of a needle body with a large base portion and a fine needle tip, easy breakage, slow industrial production rate, and poor controllability of production, and the like. Therefore, the soluble microneedle is still hard to realize in the pharmaceutical industry that must precisely control the dosage of drugs, but can be only used in the cosmetics industry.

The other method is to adopt a female mold microinjection to manufacture a soluble microneedle, the key step of which is to rapidly inject a flowing needle body material into a micropore; however, how to achieve an effective and rapid microinjection has become a crucial issue during the industrialization of the soluble microneedle. US patent No. US2009/0182306A1 and international patent publication No. WO2012/023044A1 propose to achieve a microinjection by the centrifugation or vacuum processes. However, it is difficult to achieve industrial production by the centrifugation process. Meanwhile, the process of vacuum depressurization or pressurization of 2 to 5 atmospheric pressures in a sealed container (as disclosed by Chinese patent No. CN104027324A) has a high requirement for the viscosity of solution used in the microinjection, and the viscosity should be controlled within 100 centipoise (cP); if the viscosity is higher, the solution will easily form an air embolism during the microinjection, leaving an incomplete injection. However, it is not true that the lower the viscosity is, the better the microinjection will be. For example, the drug such as vaccine, which requires only a dosage at nanogram level, must use other matrix as a filling material to achieve a physical strength and appearance required by transdermal administration. The solid content of the needle body solution has a certain correlation with the viscosity. In general, the higher the solid content is, the higher the viscosity will be; after drying, the needle body has small volume shrinkage. Therefore, a high-viscosity needle body solution is essential for the micro-injection. In the literatures, Rebecca E. M. Lutton and Sixing Yang et al. propose to use an extrusion or suction filtration process, wherein a mold used in the extrusion process must have the characteristics of good toughness, and whether the mold can fully recover after the needle hole is deformed under external force remains to be investigated. The key lies in that it is still hard to ensure that the liquid with high viscosity can be completely squeezed into each needle hole. Meanwhile, regarding the manufacture of soluble microneedles by suction filtration of the purple sand mold, whether the gas permeability of the mold is good or bad is a key issue in the production. Moreover, the mold of purple sand materials has a complicated manufacturing process, a calcination temperature as high as 1000° C., a tedious calcination process for over 15 hours, and also large energy consumption. Therefore, the industrialization is costly.

Thus, there is an urgent need to develop a method for manufacturing soluble microneedles that not only can be achieved in the laboratory, but also can be used in large-scale production.

SUMMARY

Based on this, in view of the above problems, it is necessary to provide a method for manufacturing a microneedle chip; the manufacturing method can be adapted to industrial production, and a microneedle chip obtained by the manufacturing method has a good quality.

A method for manufacturing a microneedle chip comprises the following steps:

Injecting a fluidized needle body liquid into a female mold, the fluidized needle body liquid containing a bioactive component, wherein the female mold is provided with a plurality of mold cavities matched with the shape of a needle body in the microneedle chip, each of the mold cavities is provided with an injecting inlet and an exhaust port, and the plurality of mold cavities are arranged in the same direction to form an array of mold cavities, and wherein the injecting inlet is open at one side surface of the female mold and located at a needle base end of the mold cavities, the exhaust port is open at the other side surface of the female mold and located at a needle tip end of the mold cavities, and a surface of the female mold having a plurality of the exhaust ports forms an exhaust surface;

passing gas through a gas-permeable membrane and retaining the liquid within the mold cavities when the exhaust surface of the female mold is covered with the gas-permeable membrane and the fluidized needle body liquid is injected;

demoulding after the fluidized needle body liquid is cured and the microneedle chip is formed.

The above method for manufacturing a microneedle chip is used for manufacturing a microneedle chip comprising a needle base layer and a needle body, a plurality of the needle bodies being arranged in a form of array on the needle base layer. When the microinjection is performed with the fluidized needle body liquid, the gas in the mold cavities of the female mold is expelled through the exhaust port, so that the fluidized needle body liquid can be rapidly injected into a tiny micropore of the mold cavities; then, by combining with the gas-permeable membrane having a waterproof and breathable function, the fluidized needle body liquid can be retained so as to keep in the micropore of the mold cavities matched with the shape of the needle body of the microneedle chip while expelling gas smoothly through the gas-permeable, and after the fluidized needle body liquid is cured and demoulded, the microneedle chip therefore can be obtained.

In addition, since the exhaust port is combined with the gas-permeable membrane, gas can be expelled while retaining liquid. Therefore, even if the fluidized needle body liquid has a high viscosity, no air embolism is formed during the microinjection, resulting in a good microinjection process.

In one embodiment, when the fluidized needle body liquid is injected into the female mold, a positive pressure is applied at a injecting side of the female mold to promote the injection of the fluidized needle body liquid into the mold cavities; and/or a negative pressure is formed by vacuumizing at an exhaust port side of the female mold to promote the injection of the fluidized needle body liquid into the mold cavities. By applying a positive pressure and/or a negative pressure, the microinjection effect of the fluidized needle body liquid can be improved.

In one embodiment, the positive pressure applied at the injecting side of the female mold has an intensity of pressure in the range of 0.001 Mpa to 0.9 Mpa, and the negative pressure formed by vacuumizing at the exhaust port side of the female mold has an intensity of pressure in the range of −0.9 Mpa to −0.001 Mpa. A better microinjection effect can be achieved with only a low pressure within the above range, which has the advantage of strong operability in the industrial production.

In one embodiment, the fluidized needle body liquid has a viscosity in the range of 100 cps to 60,000 cps. The manufacturing method is suitable for a fluidized needle body liquid having a wide range of viscosity and has a good applicability.

In one embodiment, the fluidized needle body liquid has a viscosity in the range of 2,000 cps to 40,000 cps. The fluidized needle body liquid within the above range has the advantages of good microinjection effect and a small amount of shrinkage after the needle body of the microneedle chip is cured.

In one embodiment, the female mold includes a main body portion and a base portion; the main body portion is provided with the plurality of the mold cavities, the injecting inlet at one side surface and the exhaust port at the other side surface, and the exhaust surface is formed by a surface provided with the exhaust port; the base portion has an inner surface covering over the exhaust surface and is internally provided with an exhaust hole, the exhaust hole being in communication with the exhaust port at an end and open at an outer surface of the base portion at the other end, and having the same maximum radial size as that of the exhaust port and a length greater than 0 μm but less than or equal to 500 μm; and the gas-permeable membrane covers over the outer surface of the base portion. The above main body portion and the base portion are integrally molded to form a one-piece female mold. The demoulding will be easier and the content of the bioactive component of the needle body can be more easily controlled as the exhaust hole makes a shorter hole channel. Meanwhile, the longer the hole channel of the exhaust hole is, the greater the resistance will be, which is detrimental to micro-injection.

In one embodiment, the female mold has a thickness from an injecting inlet side to an outer surface side of the base portion in the range of 50 μm to 3,000 μm. The female mold having an overall thickness within the above range not only can satisfy the requirement for the manufacture of the microneedle, but also can be distinguished from the conventional needles for injection, and the effect of being painless or slightly painful from microneedle can be achieved.

In one embodiment, the exhaust port has a pore size in the range of 0.1 μm to 100 μm, preferably, in the range of 15 μm to 50 μm. It can be understood that if the exhaust port is round in shape, the diameter is the maximum radial size; if the exhaust port is square in shape, the diagonal line length is the maximum radial size. If the exhaust port has a small pore size, the gas will not be expelled smoothly during microinjection, while if the exhaust port has a large pore size, the injection will be adversely affected, and the needle tip of the microneedle chip manufactured will be too thick and affects its performance for inserting into the skin. By limiting the pore size of the exhaust port within the above range, it not only allows to ensure the smoothness of gas exhaust, but also to guarantee the smooth progress of the injection; when the microneedle chip is demoulded, it allows to guarantee the smooth demoulding of the microneedle, so as to obtain a microneedle chip with a shape that satisfying the requirement.

In one embodiment, the gas-permeable membrane is waterproof and has a gas permeability in the range of 120 to 1,500 cm3/(cm2/h)@0.1 bar under a positive pressure in the range of 0.001 Mpa to 0.5 MPa, or under a negative pressure in the range of −0.5Mpa to −0.001 Mpa. The gas permeability indicates that the gas-permeable membrane has a gas permeability of 120 to 1,500 cm3at per 1 cm2area for 1 hour under a pressure of 0.1 bar. The gas-permeable membrane needs to satisfy the above requirement in order to have a good waterproof and breathable function when a pressure is applied during micro-injection.

In one embodiment, the gas-permeable membrane is made of a polytetrafluoroethylene film or an adhesive fiber membrane of polytetrafluoroethylene and polyester fiber, wherein the polytetrafluoroethylene film further includes an expanded polytetrafluoroethylene film. The gas-permeable membrane is preferably an adhesive film of expanded polytetrafluoroethylene and expanded polyester fiber. By using the above material, the gas-permeable membrane has a good waterproof and breathable function.

In one embodiment, the female mold is made of polydimethylsiloxane. The female mold is preferably made of Sylgard 184 silicone elastomer or SILASTIC MDX4-4210 silicone elastomer. The female mold made of the above material will not cause the breakage of the needle body during demoulding due to a poor quality of the female mold, and can be well demoulded to give a complete microneedle chip.

Among them, Sylgard 184 silicone elastomer is dimethylvinylsiloxane-terminated dimethylsiloxane, dimethylvinylated silica, and trimethylsilylated silica, comprises a curing agent containing dimethylvinylsiloxane-terminated dimethylsiloxane, trimethylsiloxane-terminated dimethylmethylhydridosiloxane, dimethylvinylated silica, and trimethylsilylated silica.

SILASTIC MD X4-4210 silicone elastomer is a biopharmaceutical-grade silicone elastomer containing dimethylvinylsiloxane-terminated dimethylsiloxane and silica silylate, and comprises a curing agent containing dimethylvinylsiloxy-terminated dimethylsiloxane, and trimethylsiloxane-terminated dimethylmethylhydridosiloxane.

In one embodiment, after the fluidized needle body liquid is injected into the mold cavities of the female mold, a needle base material is coated on a needle base portion of the microneedle chip by means of coating, and the fluidized needle body liquid and the needle base material, after being cured, are demoulded to give a microneedle chip. Preferably, a membrane coated has a thickness in the range of 25 μm to 4,000 μm. In addition, preferably, excess fluidized needle body liquid outside the mold cavities is firstly scraped away after the fluidized needle body liquid is injected into the mold cavities of the female mold, and then the needle base material is coated on the needle body base of the microneedle chip by means of coating.

In one embodiment, the needle base material is at least one of polyvinylpyrrolidone, copolymer Gantrez AN-139, copolymer Gantrez S97 BF, and hyaluronic acid.

The present disclosure further discloses a microneedle chip manufactured according to the above method for manufacturing a microneedle chip.

The microneedle chip obtained by using the above manufacturing method has the advantages of a good uniformity and quality due to a good micro-injection effect and no air embolism formation during the microinjection, i.e., less prone to phenomenon of needle breakage or deficiency.

The above female mold can be made by the following method:

Firstly, manufacturing a male mold with a microneedle chip needle body model; injecting a female mold liquid solution into the above resulted male mold; curing; and demoulding, so as to give a female mold provided with an exhaust port in mold cavities.

By combining the female mold liquid solution with a male mold, a female mold provided with a tiny vent hole can be made. In the above male mold, the microneedle chip needle body model has a height in the range of 150 μm to 2,000 μm, a bottom diameter in the range of 100 μm to 500 μm, and a tip diameter of less than or equal to 50 μm.

In one embodiment, the female mold is obtained by the following steps: placing the male mold provided with an array of microneedle chip with the needle tip facing upward after the male mold with the microneedle chip needle body model is made; then injecting the female mold liquid solution into the male mold resulted from the above step; piercing a liquid surface of the female mold liquid solution with the needle tip of the microneedle chip in the male mold; contacting the needle tip with air to form an exhaust port; curing; and demoulding.

Alternatively, the female mold is obtained by the following steps: placing the male mold with the needle tip facing upward after the male mold with a microneedle chip needle body model is made; then injecting the female mold liquid solution into the male mold resulted from the above step so that the needle tip of the microneedle chip in the male mold is immersed into the female mold liquid solution; curing; demoulding so as to give a female mold provided with a needle hole at one side; and then perforating at a position corresponding to the needle hole at the other side of the female mold to form an exhaust port.

Alternatively, the female mold is obtained by the following steps: injecting a liquid solidifying solution into a container after the male mold with a microneedle chip needle body model is made; then placing the male mold on the container with the needle tip facing downwards so that the needle tip is inserted under a liquid surface of the solidifying solution; injecting the female mold liquid solution into the container after the solidifying solution is cured, so that a hollow chamber between the solidifying solution and the male mold is filled up with the female mold liquid solution; and demoulding after the female mold liquid solution is cured.

In one embodiment, the male mold comprises a substrate, an array of microneedle chip needle body model and a side plate. The array of microneedle chip needle body model is provided on the substrate, the substrate being provided with a pore for injecting a liquid; the side plate is cooperated with a side wall of the container, so that an opening of the container is closed with the male mold; and a fine adjusting knob for adjusting the height for placing the male mold is provided at a juncture between the side plate and the side wall of the container.

The above female mold can also be made by the following method:

placing the female mold liquid solution into the container; curing; demoulding so as to give a female mold without mold cavities; and then perforating the female mold to make mold cavities and an exhaust port so as to give the female mold.

Compared with the existing technology, the present disclosure has the following beneficial effects:

according to the method for manufacturing a microneedle chip of the present disclosure, when the fluidized needle body liquid is injected, the gas in the mold cavities of the female mold is expelled through the exhaust port, so that the fluidized needle body liquid can be rapidly injected into a tiny micropore of the mold cavities; then, by combining with the gas-permeable membrane having a waterproof and breathable function, the fluidized needle body liquid can be retained so as to keep in the micropore of the mold cavities matched with the shape of the needle body of the microneedle chip while passing gas smoothly through the gas-permeable; and after the fluidized needle body liquid is cured and demoulded, the microneedle chip therefore can be obtained.

In addition, since the exhaust port is combined with the gas-permeable membrane, gas can be expelled while retaining liquid. Therefore, even if the fluidized needle body liquid has a high viscosity, no air embolism is formed during the microinjection, resulting in a good microinjection effect.

In a process flow of the manufacturing method, it is not necessary to perform processes that are difficult to realize in industrial production, such as centrifugation, and the like, or to use technical means with high industrialization cost, such as applying a high pressure, applying a high temperature, and the like. The manufacturing method has the advantages of simplicity, feasibility, and low cost, and is suitable for promotional use in industrialization.

In addition, the manufacturing method, in which the exhaust port and exhaust hole is screened and optimized for shape and size and the best setting modes for the exhaust port and the exhaust hole are found, can guarantee not only a smooth gas exhaust but also no microneedle material of portions (exhaust port and exhaust hole) left at the needle tip of the microneedle chip.

In the manufacturing method, the gas-permeable membrane is further screened and optimized for material, and the material specification of the gas-permeable membrane that is optimally matched with the exhaust port are found, further enhancing the operability of manufacturing method.

The microneedle chip obtained by using the above manufacturing method, due to a good microinjection effect and no air embolism formation during the microinjection, i.e., less prone to phenomenon of needle breakage or deficiency, has a better uniformity and quality than those manufactured by conventional methods.

