KR20200135266A - Apparatus and Process for Continuous Production of Microneedle - Google Patents

Abstract

The present invention relates to an apparatus and process capable of continuously producing micro-needles using a conveyor system and reduced pressure or vacuum. When using a method and apparatus for producing micro-needles according to the present invention, the continuous mass production of micro-needles is possible, thereby reducing the input of manpower and producing a large amount of products compared to the existing production methods.

Description

Apparatus and Process for Continuous Production of Microneedle}

The present invention relates to an apparatus and process for continuous microneedle manufacturing. More particularly, the present invention relates to an apparatus and a process capable of continuously manufacturing microneedles using a conveyor system and a vacuum.

Various methods have been studied for transdermal administration of a target substance with high efficiency. However, since the skin surface layer has a barrier function to prevent foreign substances from entering the body, it is very difficult to absorb the target substance in an amount sufficient to exert the desired effect. Definitely supplying is a very difficult task. Moreover, supplying target substances with very low bioavailability or pharmacological availability, such as lack of skin affinity (lipid affinity) or too large a molecular weight (500 Dalton or more) depending on the characteristics of the target substance, through the skin it's difficult.

Accordingly, in order to sufficiently supply the target material to a specific part of the skin surface layer irrespective of the type of the target material, a microneedle (micropile, micromissile capsule, etc.) technology has been recently proposed. In general, microneedles are used for delivery of active substances such as cosmetic active substances, drugs, and vaccines in vivo, detection of analytes in the body, and biopsy. Delivery of a pharmaceutical or cosmetically active ingredient using a microneedle is intended for delivery of an active substance through the skin, not through the circulatory system such as blood vessels or lymphatic vessels.

As the material of the microneedle, metal, silicon, etc. may be used, and may be made of a self-degradable material or a biodegradable material. A method of manufacturing a microneedle composed of a self-degradable material or a biodegradable material is mainly manufactured by making a mold and using casting or centrifugation. These methods are difficult to continuous process and have limitations in mass production.

Nevertheless, as the fields using microneedles increase, the need for process development for mass production continues to be raised.

Republic of Korea Patent Publication No. 10-2015-0005137

The problem to be solved by the present invention is to provide a method for manufacturing a microneedle and a microneedle patch through a continuous process, and an apparatus used therein.

One aspect of the present invention is a microneedle mold made of a porous material; A tray on which the mold is disposed; And a conveyor belt in which the tray moves, and an input unit along the movement of the conveyor belt; An application unit for supplying and applying the microneedle compounding solution to the mold; A filling part for filling the microcavity of the mold with the compounding solution; A drying unit for drying the moisture of the blended solution; And a separating unit for separating the microneedles manufactured in the drying unit from the mold, wherein the filling unit is provided with a device for forming a reduced pressure or vacuum under the mold. Is to do.

Conventionally, a method of manufacturing a microneedle is a method of manufacturing a mold, preparing a compounding solution, filling the mold with the compounding solution through casting or centrifugation, and drying the moisture contained in the compounding solution. Difficulty in mass production existed in the batch (batch) or cell (cell) method of producing by separating the process.

Accordingly, the inventors of the present invention used a conveyor belt-type continuous process, manufactured a microneedle mold of a porous material, and formed a physical force under pressure or vacuum under the mold, after a long study. By developing a method for allowing the polymer solution to penetrate, the above-described difficulties were solved, and a method and apparatus used for continuously manufacturing a microneedle and a microneedle patch were developed.

The suction pressure reducing device for forming a reduced pressure or a vacuum is separately installed in the filling part of the conveyor device, and refers to a device that creates a physical force only downward by forming a reduced pressure or vacuum, preferably a vacuum state, below the mold.

In addition, the inventors of the present invention are a tray in which a microneedle mold made of a porous material is disposed for use in a conveyor device for continuous microneedle production using a reduced pressure or vacuum, the porous material having nanopores, and the tray is drilled downward. In addition, a tray having a microneedle mold, characterized in that the reduced pressure or vacuum is formed under the tray, has been developed.

There may be several modes of forming a pressure reduction or vacuum only under the mold.According to one embodiment, the lower side of the tray in which the mold of the porous material is disposed, and the suction pressure reducing device is located under the tray. It is provided so that it is possible to form a physical force below the mold.

According to another embodiment, a tray in which a mold made of a porous material is disposed has a space in which air can stay, and a pathway or a hole through which air can pass between the inner space and the upper part of the tray ) Is formed, and the suction pressure reducing device may create a physical force below the mold by forming a reduced pressure or vacuum inside the tray.

Devices for forming a reduced pressure or vacuum under the mold include, for example, a suction device, a vacuum pump device, a decompressor, a pressure reducing orifice pressure reducer, an elevated water tank pressure reducing device, a pressure reducing valve, etc., but is not limited thereto.

In the conveyor apparatus of the present invention, one microneedle mold may be disposed on the tray, or a plurality of molds, for example, 1 to 20, 1 to 10, or 1 to 4 molds may be disposed.

The microneedle mold may have a plurality of fine intaglio patterns, and is a porous polymer selected from the group consisting of PDMS (Poly dimethyl siloxane), PMHS (Polymethyl hydrosiloxane), porous silicon, porous polyurethane, and porous PMMA (Polymethyl methacrylate). It may be manufactured.

In a preferred embodiment, the microneedle mold may be made of a porous silicon material including PDMS and PMHS.

Porous Silicon material is a material that introduces nanoporous pores in a silicon structure, and the essential requirements for the manufacture of porous silicon for use in different applications are to select appropriate manufacturing parameters to determine the shape and shape of the pores. You can decide. Due to the large surface area that increases interest in porous silicon in chemical and biological sensing applications, a large amount of bonds can be present on the silicon surface, which can be used in constant current, gas, pulsed iodine, chemical, orphotochemical etching procedures and/or It can be manufactured through strain etching.

The porous material may have nanopores having a pore width of a nanometer level, such as macro pores having a diameter of 50 nm or more, meso pores having a diameter of 2 to 50 nm, and/or a diameter of 2 nm or less. Micro pores may be formed, but are not limited thereto.

Another aspect of the present invention is a) disposing a microneedle mold of a porous material on a tray; b) putting the tray on a conveyor belt; c) supplying and applying a microneedle blending solution to the mold; d) filling the microcavities of the mold with a mixture solution by forming a reduced pressure or vacuum under the mold; e) drying the moisture of the blended solution to prepare a microneedle; And f) separating the manufactured microneedles from the mold. It is to provide a method of manufacturing the microneedles in a continuous process using a conveyor.

As a material constituting the microneedle blending solution according to the present invention, a general synthetic and natural polymer, preferably a water-soluble polymer may be used, or a self-dissolving or biodegradable material may be used.

In one embodiment, the microneedle blending solution is poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydride, polyorthoester, Biodegradable polymers including polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane or a copolymer thereof; And polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, It may include any one or more selected from the group consisting of non-biodegradable polymers including polyethylene oxide or a copolymer thereof.

Preferably, the microneedle blending solution is a substance that is dissolved when inserted into the skin and is absorbed into the body, for example, hyaluronic acid, sodium carboxymethyl cellulose, vinylpyrrolidone-vinyl acetate airborne Combined, polyvinyl alcohol, polyvinyl pyrrolidone, sugar, or a mixture thereof may be used, and as the sugar, xylose, sucrose, maltose (maltose), lactose (lactose), trehalose (trehalose) or mixtures thereof may be used.

More preferably, the microneedle blending solution may include hyaluronic acid, sodium carboxymethyl cellulose, and sugar, and most preferably 1 to 60% by weight of sodium carboxymethyl based on the total weight of the composition for preparing the microneedle. It may contain cellulose (sodium carboxymethyl cellulose), 1 to 60% by weight of hyaluronic acid and 3 to 60% by weight of sugar, and the sugar is even more preferably trehalose.

The microneedle blending solution according to the present invention may further contain a solubilizing agent, a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, etc. in addition to the above-described base. As such a plasticizer, for example, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin are used alone. Or it can be used in combination. In particular, as a result of various evaluations, glycerin was more preferable. As such a solubilizing agent, various components known in the art can be appropriately selected and used.

The microneedle blending solution according to the present invention may further include additional components for causing an additive or synergistic action depending on the target material.

The microneedle mixture solution according to the present invention may optionally contain various target substances, and the target substance may be, for example, a drug, a vaccine, a nutrient or a cosmetic ingredient depending on the use, but is not limited thereto, and , Nucleic acids, peptides, polysaccharides, lipids, etc. may be included. The target substance may exist between substances (base) that form the microneedle mixture liquid in a form impregnated with the microneedle mixture liquid, for example, or the substances (base) that form the microneedle mixture liquid are the target substance. It may exist in a form surrounding, but is not limited thereto.

On the other hand, the method of the present invention may further include a step of adhering a support including an adhesive to the prepared microneedle between the steps e) and f). In this case, the microneedle manufactured using a support including an adhesive The needle can be easily removed from the mold.

The support including the adhesive may have adhesiveness on a surface in contact with the skin. Here, "adhesiveness" refers to a property of sticky adhesion, and the degree of adhesion is not particularly limited, and the patch may touch a certain contact surface such as skin. It is understood that it is sticky if it does not fall off and sticks.

The adhesive support (patch) may be made of a flexible material in consideration of the curvature of the skin, for example, an acrylic type having adhesiveness to a sheet having a material such as polyurethane, polyethylene, polyester, polypropylene, polyvinyl chloride, etc. Or a rubber-based adhesive may be applied. The adhesive may be applied to a thickness of 1 to 100 μm, for example.

In one embodiment, a hydrocolloid adhesive may be used for the patch. The hydrocolloid adhesive may have a form in which hydrophilic hydrocolloid fine particles are dispersed in a hydrophobic polymer matrix by mixing a hydrophilic polymer and a hydrophobic polymer with a tackifier. The tackifier may include, for example, rosin ester, and the like, and all tackifiers generally used in the hydrocolloid adhesive in the industry may be included.

In another embodiment, the hydrocolloid adhesive may be attached to the microneedle in the form of lamination on a film made of polyurethane, polyethylene, polypropylene, polyvinyl chloride, or polyester.

The shape of the adhesive support is not particularly limited, and the shape may be manufactured in consideration of the possibility of contact with the skin and the shape of the microneedle array.

The adhesive support may include a plurality of fine-sized holes, and may have a structure in which moisture (or liquid) can be transferred to the microneedle along the holes. The number of holes is not limited, and may be appropriately selected in consideration of a difference in solubility according to the material of the microneedle.

In addition, the adhesive support may include a drug or a cosmetic ingredient-containing matrix or a reservoir. As such, when the skin adhesive support or patch contains a medical, pharmaceutical, or cosmetically active ingredient, there is an advantage that the active ingredient can quickly move into the skin from the patch.

The medical, pharmaceutical, or cosmetically active ingredient may be a small molecular weight compound, a protein, an effective substance such as an antibody, a vaccine, or a cosmetic substance such as botox, retinol, tocopherol, and vitamin C.

When the microneedle manufacturing method and apparatus according to the present invention is used, it is possible to continuously mass-produce the microneedles, thereby reducing the input of manpower and producing a large amount of products compared to the conventional production method.

1 is a schematic plan view of a tray on which a mold is placed.
2 is a diagram illustrating a schematic manufacturing sequence or process of a microneedle according to an embodiment of the present invention.
3 is an illustration of a continuous manufacturing process or apparatus of a microneedle according to an embodiment of the present invention.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention may be modified in various forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

In the present invention, the expression in the singular includes a plurality of expressions unless the context clearly indicates otherwise. In the present invention, terms such as "comprise" or "have" are intended to designate the presence of features, steps, actions, components, parts, or a combination thereof described in the specification, but one or more other features or steps. It is to be understood that the possibility of addition or presence of, action, component, part, or combination thereof, is not precluded.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms as defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and should not be interpreted as an ideal or excessively formal meaning unless explicitly defined in this application. Does not.

In this embodiment, four porous microneedle molds made of PDMS (PolyDiMethylSiloxane) material are fixed on a tray with a passage through which air can pass as shown in FIG. 1, and the tray with the mold is fixed on a conveyor belt. Was put in.

The microneedle blending solution is after dissolving 40 parts by weight of sodium carboxymethyl cellulose, 40 parts by weight of hyaluronic acid and 20 parts by weight of trehalose in purified water, and then Glycerin, HCO-40 and Peptide solution (Peptide 10%, DPG 90%) ) Was added, and a resin fluid dissolved therein was supplied to a hopper of a conveyor apparatus.

When the tray on which the porous mold was fixed reached the application portion according to the movement of the conveyor belt, the microneedle compounding solution was supplied and applied to the inside of the mold using the hopper.

에서 3시간 동안 건조시킨 후, 접착 필름을 이용하여 microneedle을 다공성 silicone mold로부터 분리해 내었다. Then, when the tray reached the filling portion according to the movement of the conveyor belt, the lower portion of the mold was vacuum-sucked by a suction machine installed and operating in the lower portion, and thus the compounding solution was deeply filled into the needle-forming portion of the mold. Then it's 70

After drying for 3 hours at, the microneedle was separated from the porous silicone mold using an adhesive film.

The microneedle patch prepared in this way can be packaged, stored, and transported.

Meanwhile, FIG. 3 illustrates a continuous manufacturing process or apparatus of a microneedle. In FIG. 3, 1, 2, 3, 4, and 5 denote a tray in which a mold is disposed, and moves according to the movement of a conveyor belt. Each process proceeds in the order listed and consists of an input unit, an application unit, a filling unit, a drying unit, and a separation unit. The filling part forms a vacuum inside the tray, and through this, the blending solution is filled into the microcavities of the porous mold.

Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art will be able to variously modify and change the present invention without departing from the spirit and scope of the present invention described in the following claims. You will understand that you can.

Claims (10)

A microneedle mold made of a porous material; A tray on which the mold is disposed; And a conveyor belt on which the tray moves,
An input unit along the movement of the conveyor belt; An application unit for supplying and applying the microneedle compounding solution to the mold; A filling part for filling the microcavity of the mold with the compounding solution; A drying unit for drying the moisture of the blended solution; And a separation unit for separating the microneedle manufactured in the drying unit from the mold,
Conveyor device for continuous microneedle manufacturing, characterized in that the filling unit is provided with a device for forming a reduced pressure or vacuum under the mold. The method of claim 1, wherein a lower side of the tray has a pathway or hole through which air can pass, and a device for forming the depressurization or vacuum is provided to be located below the tray. Conveyor device for continuous microneedle manufacturing. The method of claim 1, wherein the tray has a space in which air can remain, and has a pathway or hole in the upper plate through which air can pass through, and the depressurization or vacuum is performed. Conveyor device for continuous microneedle production, characterized in that the forming device forms a reduced pressure or vacuum inside the tray. The conveyor device for continuous microneedle production according to any one of claims 1 to 3, wherein the device for forming the reduced pressure or vacuum is a suction device. The conveyor apparatus for continuous microneedle manufacturing according to any one of claims 1 to 3, wherein the microneedle mold has a fine intaglio pattern. The porous material according to any one of claims 1 to 3, wherein the porous material is selected from the group consisting of PDMS (Poly dimethyl siloxane), PMHS (Polymethyl hydrosiloxane), porous silicon, porous polyurethane, and porous PMMA (Polymethyl methacrylate). Conveyor device for continuous microneedle manufacturing, characterized in that the polymer. The conveyor apparatus for continuous microneedle manufacturing according to any one of claims 1 to 3, wherein a plurality of molds are arranged on the tray. a) placing a microneedle mold made of a porous material on a tray;
b) putting the tray on a conveyor belt;
c) supplying and applying a microneedle blending solution to the mold;
d) filling the microcavities of the mold with a mixture solution by forming a reduced pressure or vacuum under the mold;
e) drying the moisture of the blended solution to prepare a microneedle; And
f) separating the prepared microneedle from the mold
It characterized in that it comprises a, a method of manufacturing a microneedle in a continuous process using a conveyor. The method of claim 8, further comprising the step of adhering a support including an adhesive between steps e) and f) to the prepared microneedle. 10. The method of claim 9, wherein the support is a skin adhesive patch.

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