JP2005152180A - Microneedle for insulin administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a means capable of easily supplying insulin to a dermal layer or a subcutaneous tissue.
SOLUTION: An insulin or an insulin preparation is contained in a fine needle 2 whose main component material is a mixture of maltose and dextran or trehalose. Insulin is administered into the body by inserting a part or all of the fine needle 2 into the skin and dissolving or remaining it. Since the material of the fine needle 2 remaining in the skin is a carbohydrate, it is harmless to the human body. Since the substrate 1 is also made of natural carbohydrate, it is easy and safe to dispose after use.
[Selection] Figure 1

Description

  The present invention relates to a microneedle which is a jig for giving an effect of administering insulin or an insulin preparation simply, safely and efficiently in the dermal layer or subcutaneous tissue.

  Conventionally, in the treatment of diabetes and the like, the technique of administering insulin is performed by a doctor using a syringe equipped with a needle made of a metal material or an inorganic material that achieves an equivalent effect, or by a doctor's guidance. The patient himself was administered subcutaneously with a pen-type insulin syringe.

In addition, for patients with type 1 diabetes who are depleted of insulin secretion and pregnant women who need insulin treatment, continuous subcutaneous insulin infusion therapy (CSII) in which insulin is continuously infused subcutaneously using a small portable syringe pump In any case, the method is similar in that the needle is punctured subcutaneously. These methods are described in detail in publicly known literature (Japanese clinical 60 volume, extra number 9, pages 279-309, 2002).
Japanese Clinical Volume 60, Special Issue 9, pp. 279-309, 2002

However, in the case of administration by a syringe, the control of the needle penetration depth is artificial for each doctor or patient's own technique, and injection is performed for each person who performs the injection or for each administration. In some cases, the needle penetration depth was different. In addition, in a solution intended to penetrate deep into the skin, it depends on a penetration phenomenon such as diffusion, so that it is difficult to reliably control the penetration depth.
Moreover, the thickness of the needle used at present is the thinnest, and the outer diameter is about 0.3 mm. If injection is frequently made at the same site, the injection site is hardened, resulting in poor absorption of insulin. What happens is a clinical problem.

There are cartridge type and disposable type pen type insulin syringes, but the cartridge type has been reported to have problems such as blood backflow into the cartridge, complicated operation, and failure. On the other hand, the disposable type also has a large cost problem.
Special disposal is also required for the disposal of used needles.

Furthermore, since the means for insulin administration is an injection needle, it is accompanied by mental pain in use, and the mental burden of insulin administration by subcutaneous injection cannot be ignored in daily life.
Further, when using CSII, there is a risk of infection pump failure, injection tube trouble, infection due to contamination of the needle insertion site.
The solution to these problems is highly desired in today's growing population of diabetics.

The invention according to the present application has been made to solve the above-described problems, and the object of the invention is to improve the convenience, safety and efficiency in the administration action and the disposal of the administration means. It is to realize a jig that can be safely disposed of without requiring any special treatment.
Another object of the invention according to the present application is to provide a jig that can administer insulin under mental distress greatly reduced compared to the prior art.

As a result of intensive research and development by the present inventors in order to achieve the above object, the inventors have invented a fine functional microneedle made from naturally occurring sugars and insulin or insulin preparations. Realized the technology to achieve the above-mentioned purpose, which was difficult.
In addition, functional microneedles can be industrially produced through an easily feasible and efficient manufacturing method.

  The first invention according to the present application has a polygonal cross-sectional shape that fits in a circle having a side of 0.1 μm or more and a diameter of 1000 μm or less, and a length of 100 μm or more and 5 mm or less in the shape of a pyramid or prism. A needle or a conical or cylindrical fine needle having a circular cross-sectional shape with a diameter of 0.1 μm to 1000 μm and a length of 100 μm to 5 mm, the fine needle being a main component material Is a mixture of maltose and dextran or trehalose, and is a microneedle characterized by containing insulin or an insulin preparation.

  The second invention according to the present application has a polygonal cross-sectional shape that fits in a circle having a side of 0.1 μm or more and a diameter of 1000 μm or less, and a pyramid or prism shape having a length of 300 μm or more and 3 mm or less. Or a conical or cylindrical fine needle having a circular cross-sectional shape with a diameter of 0.1 μm or more and 1000 μm or less and a length of 300 μm or more and 3 mm or less. It is a microneedle characterized in that the component material is a mixture of maltose and dextran or trehalose and contains insulin or an insulin preparation.

  Further, according to a third invention of the present application, a constricted portion is provided in an intermediate portion of the fine needle, and the portion containing the insulin or insulin preparation is easily foldable in the constricted portion, so that the portion containing the insulin or insulin preparation The microneedle according to the first or second invention, wherein the microneedle remains in a subcutaneous tissue.

  Furthermore, the fourth invention according to the present application provides a step which is divided into a thin upper needle and a thick lower needle at an intermediate portion of the fine needle, and the insulin or insulin preparation is easily broken at the step portion. The microneedle according to the first or second invention described above, wherein the portion containing the lysine remains in the dermis layer or subcutaneous tissue.

  The fifth invention according to the present application is characterized in that a capillary cavity is provided along the central axis of the fine needle, and the insulin or insulin preparation can be contained in the capillary cavity. It is a microneedle as described in any one of 1-4 inventions.

  Further, a sixth invention according to the present application is the multi-microneedle according to any one of the first to fifth inventions, wherein a plurality of the fine needles are provided on a substrate.

  In addition, according to a seventh aspect of the present invention, in any one of the first to fifth aspects, the ratio of the dextran mixed with the maltose is 1% or more and 10% or less in terms of a weight percent concentration. Or a microneedle according to any one of the above.

  According to the present invention, insulin can be administered into the body by inserting part or all of a microneedle into the skin and dissolving or remaining in the dermal layer or subcutaneous tissue. As a result, unlike administration with an injection needle, insulin can be reliably supplied to a desired location in the dermis layer of the skin or subcutaneous tissue, which is much more effective than conventional insulin supply.

In addition, since the shape of the fine needle can be sufficiently miniaturized using conventional techniques, it is possible to administer insulin safely and simply in a painless state or in a state with very little pain.
Furthermore, since the remaining microneedle material is a carbohydrate, it is harmless to the human body, and is easier and safer to dispose of after use than conventional injection needles.

  In recent years, the number of diabetic children has increased due to the aging of diabetes. For children, insulin administration with microneedle, which is nearly painless, is a much more convenient administration method than conventional administration devices. is there.

Insulin is administered by microneedles. A fine needle made of a material in which insulin or an insulin preparation is mixed into a naturally occurring sugar is lightly pressed against the skin to enter the inside, leaving insulin in the dermal layer or subcutaneous tissue. To do.
Since the constituent material of the microneedle is a carbohydrate, the microneedle dissolves in the body and is extremely safe. As the microneedles dissolve, insulin is absorbed into the body from the blood vessels in the tissue.
By designing the structure of the microneedle in various ways, it is possible to leave it in a state of painlessness or very little pain intended for the skin dermis layer or subcutaneous tissue. In addition, by configuring a plurality of microneedle structures, it is possible to control the residual amount of insulin even with a single skin inoculation, and the efficiency is sufficiently improved.

  An outline of the structure of such a microneedle is shown in FIG. FIG. 1 is a perspective view showing an example of a microneedle. In the microneedle, a thin needle 2 is erected on the upper surface of a rectangular parallelepiped substrate 1. Since the substrate 1 becomes a part to be held by hand when the microneedle is inserted into the affected area, it is desirable that the substrate 1 has a size that can be easily held by hand.

  In FIG. 1, the fine needle 2 has a long triangular pyramid shape with one side of the root portion being 300 μm and a height of 1 mm. Although illustration is omitted in the present application, the shape of the fine needle 2 is not limited to a triangular pyramid shape, and may be a polygonal pyramid shape such as a quadrangular pyramid or a conical shape. Further, it may be a polygonal columnar shape or a cylindrical shape having a triangular shape or more, and may be a shape in which only the tip of the prism / cylindrical shape is sharply sharpened. The cross-sectional shape of the pyramid or prism does not need to be a regular polygon, and the cross-sectional shape of a cone or cylinder does not need to be a perfect circle.

  The fine needle 2 is a part to be inserted into a human skin, and an extremely thick shape is not preferable because it is painful. Therefore, the fine needle 2 is a pyramid or prism shape having a polygonal cross-sectional shape that fits in a circle having a side of 0.1 μm or more and a diameter of 1000 μm or less, or a conical shape having a circular cross-section having a diameter of 0.1 μm or more and 1000 μm or less. A cylindrical shape is desirable. The circular cross-sectional shape with a diameter of 1000 μm or less includes an elliptical cross-sectional shape that fits in a circle with a diameter of 1000 μm or less.

  When the length of the fine needle 2 is less than 100 μm, the tip does not reach the skin dermis layer. Therefore, it is necessary to have a length of 100 μm or more from the viewpoint of an appropriate supply of insulin to the skin dermis layer or subcutaneous tissue. On the other hand, when the length is longer than 5 mm, the supplied insulin is not harmful to the human body, but there is a possibility that extreme pain is caused by the insertion of the fine needle 2. Therefore, for the purpose of supplying insulin to the skin dermis layer or subcutaneous tissue, the thickness is desirably 5 mm or less. In particular, since it is sufficient that insulin can be supplied to blood vessels existing in the range of 300 μm to 3 mm from the most epithelium, the length of the fine needle 2 is 300 μm to 3 mm from the viewpoint of appropriate supply of insulin and reduction of pain. It is further desirable that

As disclosed in Japanese Patent Application Laid-Open No. 2003-238347, a constricted portion is provided in the middle portion of the microneedle, and the tip of the microneedle containing insulin or an insulin preparation is easily broken at the constricted portion. It may be a structure remaining in the subcutaneous tissue. In addition, the microneedle is composed of two stages with different diameters in the middle part, divided into a thin upper needle on the tip side and a thick lower needle on the root side, and it can be easily broken at this step part to contain insulin or insulin preparations A structure in which only the upper needle that remains in the skin dermis layer or the subcutaneous tissue may remain. Further, in addition to the above structure, a capillary cavity may be provided along the central axis of the microneedle, and insulin or an insulin preparation may be included in the cavity.
JP 2003-238347 A

  As the material for the substrate 1 and the fine needle 2, natural carbohydrate is used which is solid at room temperature and can secure fluidity by heating. In particular, it is desirable to add maltose to dextran which is easy to process. Insulin is known to undergo a Maillard reaction and change properties when mixed with heated carbohydrates. In this respect, maltose is easy to process, and the heating time for changing to a fluid state is very short. Therefore, the occurrence of a Maillard reaction when insulin is mixed can be suppressed.

  Maltose is a natural carbohydrate suitable for microfabrication such as microneedles, but maltose alone has low viscosity during flow and weak strength when solidified. Actually, microneedles processed only with maltose have low strength and are inappropriate as fine needles to pierce the skin. Therefore, in the present invention, a small amount of dextran is added to maltose to improve the strength of the fine needle.

  Since dextran has a higher viscosity than maltose, the addition of dextran to maltose makes it sticky during flow and increases the strength when solidified. From the viewpoint of strength, it is desirable to add 1% or more of dextran at a weight percent concentration with respect to maltose. Further, from the viewpoint of processing, it is desirable that the dextran to be added is 10% or less by weight percent concentration with respect to maltose. If more dextran is added, the viscosity is too high when pouring fluid maltose into the mold, making it difficult to pour into the mold details.

  Therefore, it can be said that it is desirable to add 1% or more and 10% or less of dextran in a weight percent concentration with respect to maltose in terms of both processing and strength. After both maltose and dextran are inserted into the human body, they are dissolved by hydrolysis and absorbed into the body, and are harmless to the human body.

  The fine needle 2 is further mixed with powdered insulin or an insulin preparation. Insulin may be evenly mixed with the saccharide base, or may be unevenly distributed at the tip of the fine needle 2.

  Conventionally, in the field of micromachines, a process technology capable of performing high-precision machining of μm size or less has already been established. In the present invention, this technique is applied to realize a skin insertion jig mechanism of nm to μm size. The jig can be processed using a conventional ultraviolet lithography technique. These existing techniques are used to machine the inverted shape of the microneedle pattern.

  In this way, a microneedle mold was prepared, and a microneedle was prepared by pouring or casting a material mixed with an appropriate amount of insulin or insulin preparation into a natural carbohydrate heated to an appropriate temperature to ensure fluidity. Form. Specifically, insulin or an insulin preparation is mixed and stirred in a state where a small amount of dextran is added to maltose heated to 110 ° C. or less, and poured into a mold. According to this method, insulin or an insulin preparation is evenly mixed throughout the fine needle 2. When the fine needle 2 and the substrate 1 are formed at the same time, they are poured into the mold of the substrate 1 at the same time, so that insulin or an insulin preparation is mixed in the substrate 1. There is no need to mix insulin. Therefore, a mixture of a saccharide and insulin or an insulin preparation may be poured into the portion of the fine needle 2 of the template, and only a carbohydrate not containing insulin may be poured into the portion of the substrate 1 of the template.

  In the step of mixing insulin, a necessary amount of insulin or an insulin preparation can be poured into a desired portion of a needle that is poured into a sugar and shaped in advance into an appropriate shape. In this way, insulin can be unevenly distributed at the tip of the fine needle 2.

  FIG. 2 is a perspective view showing an example of a microneedle having a plurality of fine needles. The microneedle of the present embodiment employs a comb-like structure provided with a large number of fine needles 2 in order to reliably provide a large amount of insulin or insulin preparation at a time. As shown in FIG. 2, the microneedle has a structure in which a plurality of fine pyramid-shaped needles 2 having a height of 1 mm are provided on a rectangular parallelepiped substrate 1 having a total length of 1 cm. One side of the root portion of the fine needle 2 is 300 μm, and the pitch between the needles is 0.5 mm. In this structure, twelve fine needles 2 arranged in a straight line can be produced on the substrate 1. The manufacturing method of the microneedle and the shape and material of the fine needle 2 are the same as in the first embodiment.

  By holding the portion of the substrate 1 opposite to the side where the fine needle 2 is provided and pressing the fine needle 2 lightly onto the skin, the insulin mixed in the fine needle 2 can be inserted into the skin. The function of can be demonstrated.

  FIG. 3 shows a combination of a plurality of comb-like structures in FIG. 2 and fine needles 2 arranged in a matrix. By arranging the matrix in this manner, the residual amount of insulin in the skin dermis layer or subcutaneous tissue can be controlled, and convenience in use is also improved.

This matrix structure can be manufactured by forming a plurality of comb-like structures in FIG. 2 and combining them. Moreover, it can also form in a lump by forming the inversion shape of a matrix structure as a casting_mold | template.
[Example of use]

  The amount of insulin or insulin preparation mixed is determined according to a request from the medical side. For example, when expressed by the unit UPS defined by the United States Pharmacopoeia, insulin 28 UPS = 1 mg. In the case of an adult diabetic patient, the dose of insulin is 10 Unit to 100 Unit. In the case of 100 Unit administration, it is divided into 3 to 4 times a day. Therefore, it is only necessary that approximately 300 μg to 1 mg of insulin can be absorbed by one administration. In Example 1 described above, the fine needle 2 may be processed so as to contain 300 μg to 1 mg of powdered insulin. Moreover, in the said Example 2, what is necessary is just to process so that 30-100 micrograms of powdery insulin may be contained per fine needle.

Insulin mixed in the fine needle 2 by holding the part opposite to the side where the fine needle 2 of the microneedle shown in Example 1 or Example 2 is provided by hand and pressing the fine needle 2 lightly on the skin Is inserted into the body. After the insulin is administered, the fine needle 2 is dissolved or broken and remains in the body, so that only the substrate 1 remains.
When the substrate 1 is discarded, it can be discarded as it is if the substrate 1 is made of only carbohydrates. If insulin is also mixed into the substrate 1, if it is put into boiling hot water, it quickly decomposes and dissolves, so it can be discarded. Thus, in the present application, natural carbohydrate is used as a base, and the disposal work of the substrate 1 is extremely easy.

  Although the present application describes an example based on a carbohydrate obtained by adding a small amount of dextran to maltose, trehalose can also be used as a base material. In particular, trehalose is a saccharide that does not easily undergo a Maillard reaction with insulin when heated. The fine needle made of trehalose has sufficient strength, dissolves easily when inserted into the skin, and is harmless to the human body.

  Further, the surface of the saccharide microneedles used in the present invention is not particularly limited, but a structure that can be made water-repellent and can prevent moisture permeation and can prevent softening due to moisture in the atmosphere is preferable.

  It is well known that there are a significant number of diabetic patients who need insulin today. For patients who require daily insulin administration, the current administration by injection is painful, and it tends to be difficult to inject the injection at the same site due to skin alteration.

  According to the present invention, insulin can be administered into the body by inserting part or all of a microneedle into the skin and dissolving or remaining in the dermal layer or subcutaneous tissue. Therefore, there is no troublesome operation with a pen-type insulin syringe and troubles as seen in the syringe. Moreover, the puncture site of the microneedle is not different from normal tissue and does not leave any scar. As a result, unlike administration with an injection needle, insulin can be reliably delivered to a desired location in the dermis layer of the skin or subcutaneous tissue under certain conditions, so that it is much more effective than conventional insulin delivery. Is. Furthermore, since the material of sugar is the main component, the cost can be significantly reduced by mass production.

In addition, since the shape of the fine needle can be sufficiently miniaturized using conventional techniques, it is possible to administer insulin safely and simply in a painless state or in a state with very little pain.
Furthermore, since the remaining microneedle material is a carbohydrate, it is harmless to the human body, and is easier and safer to dispose of after use than conventional injection needles.

  In recent years, the number of diabetic children has increased due to the aging of diabetes. For children, insulin administration with microneedle, which is nearly painless, is a much more convenient administration method than conventional administration devices. is there.

It is a perspective view which shows an example of the single microneedle in this invention. It is a perspective view which shows an example of the microneedle which has several thin needles. It is a perspective view which shows the state which combined several comb-shaped structures and has arrange | positioned the thin needle in the matrix form.

Explanation of symbols

1 ... Substrate 2 ... Fine needle.

Claims (7)

A polygonal cross-sectional shape that fits in a circle with a side of 0.1 μm or more and a diameter of 1000 μm or less, a pyramid or prismatic fine needle with a length of 100 μm or more and 5 mm or less, or a diameter of 0.1 μm or more A circular needle having a circular cross-sectional shape of 1000 μm or less and a length of 100 μm or more and 5 mm or less,
The microneedle is characterized in that the main component material is a mixture of maltose and dextran or trehalose, and contains insulin or an insulin preparation. A polygonal cross-sectional shape that fits in a circle with a side of 0.1 μm or more and a diameter of 1000 μm or less, a pyramid or prismatic fine needle with a length of 300 μm or more and 3 mm or less, or a diameter of 0.1 μm or more A circular needle having a circular cross-sectional shape of 1000 μm or less and a length of 300 μm to 3 mm,
The microneedle is characterized in that the main component material is a mixture of maltose and dextran or trehalose, and contains insulin or an insulin preparation. A constriction is provided in the middle of the fine needle,
The microneedle according to claim 1 or 2, wherein the portion containing the insulin or the insulin preparation remains in the dermis layer or the subcutaneous tissue by being easily broken at the constricted portion. A step is provided in the middle of the fine needle to divide it into a thin upper needle and a thick lower needle,
The microneedle according to claim 1 or 2, wherein the portion containing the insulin or insulin preparation remains in the dermis layer or subcutaneous tissue by being easily folded at the stepped portion. A capillary cavity is provided along the central axis of the fine needle,
The microneedle according to any one of claims 1 to 4, wherein the insulin or insulin preparation can be encapsulated in the capillary cavity.   The multi-microneedle according to any one of claims 1 to 5, wherein a plurality of the thin needles are provided on a substrate.   6. The microneedle according to claim 1, wherein a ratio of the dextran mixed with the maltose is 1% or more and 10% or less by weight percent concentration.

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