WO2021193959A1 - Drug delivery device and method for producing same - Google Patents

Abstract

The present invention provides a drug delivery device having a needle that has less influence on the drug delivery ability and has sufficient mechanical strength for puncture. A microneedle 10 has: a needle 110 capable of holding a drug and having drug permeability; and a soluble/degradable material layer 120 formed on at least a portion of the surface of the needle 110 and made of a material that dissolves or decomposes under physiological conditions.

Description

Drug delivery device and its manufacturing method

The present invention relates to a drug delivery device having a needle capable of carrying a drug and a method for producing the same.

Microneedle is known as a device for percutaneously administering a drug. As disclosed in Patent Document 1, for example, the microneedles are provided as a patch in which a plurality of needles having a length of 1 mm or less carrying a drug to be administered are arranged in an array, and the needles are attached to the skin surface to attach the needles. The drug is configured to be delivered via. Therefore, the microneedle has a feature that the drug can be continuously administered in a minimally invasive manner for a long period of time.

Patent Document 1: International Publication No. 20/182099

However, the conventional microneedle has insufficient mechanical strength because the needle is very fine, and the needle may break or buckle when the needle is punctured into the skin. In order to prevent this, it is conceivable that the needle is made of a material having high mechanical strength, or the surface of the needle is coated with a material having high mechanical strength. However, in general, since a material having high mechanical strength has a dense structure, there is a possibility that the delivery ability of the drug may decrease, such as a decrease in the amount of the drug released from the needle.

One of the objects of the present invention is to provide a drug delivery device having a needle having sufficient mechanical strength for puncturing while suppressing the influence on the delivery ability of the drug and a method for producing the same.

The drug delivery device of the present invention comprises a needle capable of carrying a drug and having the permeability of the drug.
A soluble / degradable material layer formed of at least a part of the surface of the needle and composed of a material that dissolves or decomposes under physiological conditions.
Have.

The method for manufacturing a drug delivery device of the present invention
A method of manufacturing a drug delivery device having a drug-permeable needle.
Forming the needle and
To form a soluble / degradable material layer of a material that dissolves or decomposes under physiological conditions, at least on a portion of the surface of the needle.
including.

In the present invention, the "physiological condition" means an aqueous solution adjusted to have the same pH, temperature and ionic composition as in vivo. For example, the pH is preferably 1 to 9, more preferably 7 to 8, the temperature is preferably 30 to 40 ° C., and the ionic composition is preferably a sodium chloride concentration of 100 to 200 mM. In addition, "materials that dissolve or decompose under physiological conditions" and "soluble / degradable materials" are defined as "materials that dissolve or decompose over time" under physiological conditions (for example, in a state of being punctured subcutaneously). It means a material that can be decomposed and disappear.

According to the present invention, there is provided a drug delivery device having a needle having a needle having sufficient mechanical strength at the time of puncturing while suppressing the influence on the delivery ability of the drug and a method for producing the same.

It is a side view of the microneedle according to one Embodiment of this invention. It is an enlarged cross-sectional view of the needle of the microneedle shown in FIG. It is sectional drawing of one form of the microneedle which has a reservoir. FIG. 5 is a cross-sectional view of another form of microneedle having a reservoir. FIG. 5 is a cross-sectional view of yet another form of a microneedle having a reservoir. It is sectional drawing of one form of the mold used for manufacturing the microneedle shown in FIG. It is a confocal microscope image which shows the typical result obtained by the evaluation 1. It is a confocal microscope image and a graph which shows the representative result obtained by the evaluation 2. It is a graph which shows the typical result obtained by the evaluation 3. 3 is a fluorescence microscope image and a graph showing typical results obtained in Evaluation 4. It is a graph which shows the typical result obtained by the evaluation 5. It is a graph which shows the typical result obtained by the evaluation 6.

Referring to FIG. 1, a microneedle 10 according to an embodiment of the present invention, which has a base portion 100 and a plurality of needles 110 and is provided as a patch to be attached to the skin, is shown. The base portion 100 is a sheet-like portion that supports a plurality of needles 110, has mechanical strength capable of supporting these needles 110, and has flexibility enough to be deformed along the surface of the skin. ing. By supporting the plurality of needles 110 by the base portion 100, the plurality of needles 110 are configured as a needle array. The base portion 100 and the needle 110 may be made of different materials or may be made of the same material. When the base portion 100 and the needle 110 are made of the same material, they can be made at the same time. At least the needle 110 is permeable to the drug. Further, as shown in FIG. 2, a soluble / degradable material layer 120 that can function as a reinforcing structure of the needle 110 is formed on the surface of the needle 110.

Hereinafter, the microneedle 100 will be described in more detail.

[Drug]
Drugs that can be delivered using the drug delivery device according to the invention include, but are not limited to, proteins, peptides, nucleic acids, other high molecular weight polymers, low molecular weight compounds and the like. The drug may be a therapeutic agent for a disease, a prophylactic drug, a vaccine, a nutritional supplement, or the like. A particularly preferred drug is insulin. Various natural or modified insulins are available by purchase or synthesis of commercial products. As insulin, for example, Humarin (registered trademark) may be used. Humarin® is a human (genetically modified) insulin marketed by Eli Lilly and Company. As insulin preparations, various preparations including fast-acting type, intermediate type, and long-acting type have been developed, and they can be appropriately selected and used.

[Base part]
The base portion 100 is configured to have the mechanical strength necessary for the needle 110 to be punctured well into the skin against the elastic force of the skin when the plurality of needles 110 are punctured into the skin. , Can be composed of various materials. Examples of such materials include polymer materials, ceramic materials having a porous structure, and metal materials. Further, the base portion 100 is preferably made of a biocompatible material.

The base portion 100 can have a reservoir of the drug released from the needle 110. Having a reservoir allows the drug to be released over a long period of time (eg, 7 days). A microneedle capable of releasing a drug over a long period of time can be suitably used as an insulin delivery microneedle that administers insulin as a drug according to a blood glucose concentration.

The reservoir can be configured, for example, by forming the base portion 100 in a concave shape (cup shape) with an open upper surface. Alternatively, the base portion 100 may be formed of the same material as the needle 110, and the base portion 100 itself impregnated with the drug may be used as a reservoir. In this case, the base portion 100 and the plurality of needles 110 can be formed at the same time by integral molding. Further, in any case, it is preferable that the base portion 100 is made of a material that does not impede the continuity of the flow of the drug from the needle 110 to the base portion 100. The structure of the microneedle having a reservoir will be described in detail later.

The planar shape of the base portion 100 may be any shape such as a circular shape, an elliptical shape, and a polygonal shape, and may be, for example, a rectangular shape.

[needle]
(Dimensions, placement and shape)
The length of the needle 110 may be long enough for the needle 110 to reach the stratum corneum when the needle 110 is punctured into the skin, and may be preferably 5 mm or less, more preferably 1 mm or less. The number and arrangement of needles 110 may be arbitrary. For example, a plurality of needles 110 can be arranged in a matrix of M × N (M and N are integers of 1 to 30 respectively). As an example of specific arrangement, 10 × 12 needles 110 are arranged at a pitch of 500 μm in a rectangular region of 8 mm × 8 mm. The shape of the needle 110 may be arbitrary as long as it has a tip that can puncture the skin, and may be preferably a pyramid shape.

(component)
The needle 110 can contain any component, depending on the drug to be delivered, as long as it is permeable to the drug. Hereinafter, the components of the needle 110 that are preferable when the microneedle 10 is used as a device for delivering insulin as a drug according to the blood glucose concentration will be described.

The needle 110 can include a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit at least at the tip thereof. The gel composition is specifically obtained by copolymerizing a monomer mixture containing a phenylboronic acid-based monomer as described later, and as a result, a gel having a crosslinked molecular structure of the copolymer is obtained. Be done. In the present application, "monomer unit" means a structural unit in a (co) polymer derived from a monomer, and in the following description, "monomer" means "monomer unit". Sometimes used. The phenylboronic acid-based monomer has the following formula:

(In the formula, X represents a substituent, preferably F, and n represents an integer of 1 to 4.)
It means a monomer having a phenylboronic acid functional group represented by.

<Gel composition>
Insulin delivery microneedles utilize a mechanism by which the phenylboronic acid structure changes its structure depending on the glucose concentration, as described below.

Phenylboronic acid dissociated in water (hereinafter, may be referred to as "PBA" in the present specification) reversibly binds to a sugar molecule and maintains the above equilibrium state. When the glucose concentration is high, it binds and the volume expands, but when the glucose concentration is low, it contracts. When the needle 110 is punctured into the skin, this reaction occurs at the gel interface in contact with blood, and the gel contracts only at the interface to form a dehydration shrinkage layer, which the present inventors call a "skin layer". This property is used to control the release of insulin.

A gel composition that can be preferably used is a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit having the above-mentioned properties. The gel composition is not particularly limited, and examples thereof include those described in Japanese Patent No. 5696961.

The phenylboronic acid-based monomer used for preparing the gel composition is not limited, but is represented by, for example, the following general formula.

[In the formula, R is H or CH ₃ , F exists independently, n is either 1, 2, 3 or 4, and m is 0 or an integer greater than or equal to 1. ]

The above-mentioned phenylboronic acid-based monomer is a fluorinated phenylboronic acid in which hydrogen on the phenyl ring is replaced with 1 to 4 fluorines (hereinafter, may be referred to as "FPBA" in the present specification). It has a group and has a structure in which the carbon of the amide group is bonded to the phenyl ring. The phenylboronic acid-based monomer having the above structure has high hydrophilicity, and the phenyl ring is fluorinated, so that pKa can be set to 7.4 or less at the biological level. Furthermore, this phenylboronic acid-based monomer not only acquires sugar recognition ability in a biological environment, but also enables copolymerization with a gelling agent or a cross-linking agent described later due to an unsaturated bond, resulting in a glucose concentration. It can be a gel that depends on the phase change.

In the above phenylboronic acid-based monomer, when one hydrogen on the phenyl ring is substituted with fluorine, _{the introduction location of F and B (OH) 2} may be any of ortho, meta, and para. good.

In general, a phenylboronic acid-based monomer when m is 1 or more can have a lower pKa than a phenylboronic acid-based monomer when m is 0. m is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.

As an example of the above-mentioned phenylboronic acid-based monomer, there is a phenylboronic acid-based monomer in which n is 1 and m is 2, which is particularly preferable as a phenylboronic acid-based monomer 4- (2- (2-). Acrylamide ethylcarbamoyl) -3-fluorophenylboronic acid (4- (2-acrylamidoethylcarbamoyl) -3-fluorophenylboronic acid, AmECFPBA).

The gel composition can be prepared from a gelling agent having a property (biocompatibility) that does not cause toxic or adverse effects on biological functions in the living body, the above-mentioned phenylboronic acid-based monomer, and a cross-linking agent. .. The preparation method is not particularly limited, but is a monomer containing a gelling agent, a phenylboronic acid-based monomer, and a cross-linking agent, which are the main chains of the gel (copolymer), in a predetermined molar ratio. It can be prepared by mixing with the components and polymerizing the monomers. A polymerization initiator is used as needed for the polymerization.

It is preferable that insulin is contained in the gel composition in advance. For that purpose, insulin can be diffused into the gel by immersing the gel in an aqueous solution such as a phosphate buffered aqueous solution (PBS) containing insulin at a predetermined concentration. Next, the gel taken out from the aqueous solution is immersed in hydrochloric acid, for example, for a predetermined time to form a thin dehydration-shrinkable layer (called a skin layer) on the surface of the gel body, whereby the drug is encapsulated (loaded) in the needle 110. Can be made to.

The suitable ratio of the gelling agent, the phenylboronic acid-based monomer, and the cross-linking agent may be a monomer having a composition that can control the release of insulin according to the glucose concentration under physiological conditions. It varies depending on such factors, and is not particularly limited. The present inventors have already prepared gels by combining various phenylboronic acid-based monomers in various ratios with gelling agents and cross-linking agents, and have studied their behavior (for example, Japanese Patent No. 5622188). Please refer to). A person skilled in the art can obtain a gel having a suitable composition based on the description in the present specification and the technical information reported in the art.

The gel body formed by the copolymer obtained from the gelling agent, the phenylboronic acid-based monomer, and the cross-linking agent can expand or contract in response to the glucose concentration, and maintains the properties of pKa 7.4 or less. If it can be formed into a gel, the gel can be prepared by setting the charged molar ratio of the gelling agent / phenylboronic acid-based monomer to an appropriate value.

The gelling agent may be any biocompatible material that is biocompatible and can be gelled, and examples thereof include biocompatible acrylamide-based monomers. Specific examples thereof include N-isopropylacrylamide (NIPAAm), N, N-dimethylacrylamide (DMAAm), N, N-diethylacrylamide (DEAAm) and the like.

The cross-linking agent may be any substance that is also biocompatible and can cross-link the monomer. For example, N, N'-methylenebisacrylamide (MBAAm), ethylene glycol dimethacrylate (EGDMA), N, N'-methylenebismethacrylate (MBMAAm) and various other cross-linking agents can be mentioned.

In a preferred embodiment, the gel composition comprises N-isopropylmethacrylamide (NIPAAm), 4- (2-acrylamide ethylcarbamoyl) -3-fluorophenylboronic acid (AmECFPBA), and N, as shown below. It is obtained by dissolving N'-methylenebisacrylamide (MBAAm) in a solvent at an appropriate blending ratio and polymerizing it. The polymerization can be carried out at room temperature and under aqueous conditions.

As the solvent, any solvent in which the monomer is soluble can be used. Such solvents include, for example, water, alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), ionic liquids and combinations thereof. Among these, an aqueous methanol solution can be preferably used as a solvent.

A pregel solution in which a gelling agent, PBA and a cross-linking agent are dissolved in such a solvent is prepared and polymerized.

In the above gel composition, the phenylboronic acid-based monomer is copolymerized with the gelling agent and the cross-linking agent to form the gel body. Insulin can be diffused into this gel, and the surface of the gel body can be surrounded by a dehydration shrinkage layer. By applying this configuration to the needle 110, for example, the pKa is 7.4 or less, and when the glucose concentration becomes high under physiological conditions of a temperature of 35 ° C. to 40 ° C., the gel constituting the needle 110 expands. Along with this, the dehydration contraction layer disappears, and insulin in the gel can be released to the outside.

On the other hand, when the glucose concentration becomes low again, the expanded gel contracts and a dehydration contraction layer (skin layer) is formed again on the entire surface, and it is possible to suppress the release of insulin in the gel to the outside.

Therefore, such a gel composition can autonomously release insulin in response to glucose concentration.

A catalyst such as an initiator or an accelerator can be used for the polymerization. As the initiator, for example, ammonium persulfate (APS) can be used. As the accelerator, for example, tetramethylethylenediamine (TEMED) can be used. In this case, when 10 wt% ammonium persulfate 6.2 μl and tetramethylethylenediamine 12 μl were added to each 1 ml of the pregel solution and polymerized at room temperature, gelation was started within 10 minutes.

The gel composition may be a composite gel composition containing silk fibroin (SF) in addition to a copolymer containing a phenylboronic acid-based monomer unit. This composite gel composition is obtained by copolymerizing a monomer mixture containing a phenylboronic acid-based monomer in the presence of SF, and as a result, the molecules of SF are contained in the crosslinked molecular structure of the copolymer. Is distributed almost uniformly.

The SF contained in the compound gel composition can also be used for the base portion 100. SF imparts mechanical strength to the needle 110. The amount of SF (solid content weight) can be determined so that the mechanical strength of the microneedles is a suitable value, but of the monomer (phenylboronic acid-based monomer, gelling agent and cross-linking agent). It can be, for example, 10 to 90 parts by weight, preferably 24 to 60 parts by weight, and more preferably 40 to 60 parts by weight with respect to 100 parts by weight in total. The higher the weight fraction of SF with respect to the total number of monomers, the higher the mechanical strength of the composite gel composition. However, the higher the weight fraction of SF, the lower the monomer concentration. If the monomer concentration is too low, it becomes difficult to form a gel composition. Therefore, it is important to determine the weight fraction of SF with respect to the total amount of monomers within a range in which the formation of the gel composition is not inhibited.

In one preferred embodiment, the composite gel composition is N-isopropylmethacrylamide (NIPAAm), 4- (2-acrylamide ethylcarbamoyl) -3-fluorophenylboronic acid (AmECFPBA), N, N'-methylenebisacrylamide. It is obtained by dissolving (MBAAm) and SF in a solvent at an appropriate blending ratio to prepare a pregel solution, and polymerizing this solution. The pregel solution may optionally contain a gelling agent, PBA and a cross-linking agent. The polymerization is preferably carried out at room temperature and under aqueous conditions in order to avoid denaturation of SF.

Since SF has a property of easily gelling, when preparing a pregel solution, after dissolving a gelling agent, PBA, a cross-linking agent, etc. in a solvent, SF is added to the solution in the state of SF solution. Is preferable.

When an aqueous methanol solution is used as the solvent, an alcohol aqueous solution such that the volume% of methanol in the pregel solution before the addition of SF is, for example, 40% by volume can be used. In this case, the preferable volume% of methanol in the pregel solution after the addition of SF is 3% by volume to 30% by volume, more preferably 5% by volume to 20% by volume, and most preferably 8% by volume. Further, when an aqueous ethanol solution is used as the solvent, PBA has low solubility in ethanol. Therefore, it is preferable that the volume% is higher than that when the aqueous methanol solution is used, for example, the volume% of ethanol in the pregel solution before the addition of SF is 60% by volume.

The gel composition may contain a monomer having a hydroxyl group such as N-hydroxyethylacrylamide (NHEAAm). This gives a gel composition that is resistant to temperature changes. Such gel compositions include the following aspects:

The following general formula (1)

[In the formula, R is H or CH ₃ , F exists independently, n is either 1, 2, 3 or 4, and m is 0 or an integer greater than or equal to 1. ], And the following general formula (2)

[In the formula, R1 is H or CH ₃ , m is 0 or an integer of 1 or more, R ² is OH, a saturated or unsaturated C _1-6 alkyl group substituted with 1 or more hydroxyl groups, 1 Saturated or unsaturated C _{3-10 cycloalkyl group substituted with the above hydroxyl groups, C 3-12} containing 1 to 4 heteroatoms selected from NH, O and S substituted with one or more hydroxyl groups It is a heterocyclic group, a C _6-12 aryl group substituted with one or more hydroxyl groups, a monosaccharide group, or a polysaccharide group. ], A gel composition containing a monomer (hereinafter, also referred to as a hydroxyl-based monomer).

The monomer of the general formula (2) has a hydroxyl group in the molecule. Without being bound by any particular theory, this hydroxyl group increases the hydrophilicity of the gel, offsets the hydrophobicity of the boronic acid, and acts on the boronic acid in the gel to prevent excessive swelling of the gel. It is considered to have an effect. The upper limit of m is not particularly limited, but is, for example, 20 or less, preferably 10 or less, and more preferably 4 or less.

Examples of the above-mentioned hydroxyl-based monomer include a monomer in which R ¹ is hydrogen, m is 1, and R ² is OH, which is particularly preferable as the hydroxyl-based monomer N-. Hydroxyethyl acrylamide (N- (Hydroxyethyl) acrylamide, NHEAAm). In particular, by using ethyl instead of methyl for the side chain, there is an effect of increasing the degree of freedom of rotation of the side chain and significantly improving the efficiency of the cross-linking reaction between molecules (with the boronic acid side chain). Therefore, by using NHEAAm, it is possible to obtain an optimum gel that causes a phase change depending on the glucose concentration. In the example of other hydroxyl-based monomers, R ² may be, for example, a sugar derivative such as a catechol group or a glycolyl group. The monosaccharide can be, for example, glucose.

The hydroxyl group monomer represented by the general formula (2) is contained in the gel composition, for example, 1 mol or more, 5 mol% or more, 10 mol% or more, 15 mol% or more, 20 mol% or more, 25 mol% or more, 30 mol% or more. It can be contained in a proportion of 35 mol% or more, 40 mol% or more, 45 mol% or more, 50 mol% or more, or 60 mol% or more. Further, the hydroxyl group monomer represented by the general formula (2) is contained in the gel composition, for example, 90 mol% or less, 80 mol% or less, 70 mol% or less, 60 mol% or less, 50 mol% or less, 45 mol% or less, 40 mol. % Or less, 35 mol% or less, 30 mol% or less, 25 mol% or less, or 20 mol% or less. As a concentration range, the hydroxyl group monomer represented by the general formula (2) is contained in the gel composition, for example, from 10 mol% to 90 mol%, 15 mol% to 45 mol%, 20 mol% to 40 mol%, or 25 mol% to 25 mol%. The ratio may be in the range of 35 mol%. The concentration range can be specified by any combination of the above upper and lower limits. The preferred proportion of hydroxyl-based monomers is about 10 mol%. In addition, in this specification, the term "about" is used to refer to the range of 10% before and after the numerical value following it. That is, about 30 mol% means a range of 27 mol% to 33 mol%.

The gel composition comprises a gelling agent having a property (biocompatibility) that does not cause toxic or adverse effects on biological functions in the living body, the above-mentioned phenylboronic acid-based monomer, and the above-mentioned hydroxyl-based monomer. And a cross-linking agent. The method for preparing the gel is not particularly limited, but first, a gelling agent serving as the main chain of the gel, a phenylboronic acid-based monomer, a hydroxyl-based monomer, and a cross-linking agent are predetermined. It can be prepared by mixing at a charged molar ratio and allowing a polymerization reaction. A polymerization initiator is used as needed for the polymerization.

As the polymerization initiator, for example, an initiator known to those skilled in the art such as 2,2'-azobisisobutyronitrile (AIBN) and 1,1'-azobis (cyclohexanecarbonitrile) (ABCN) should be used. Can be done. The proportion of the polymerization initiator added to the gel composition can be, for example, about 0.1 mol%.

The polymerization reaction can be carried out, for example, using dimethyl sulfoxide (DMSO) as a reaction solvent, the reaction temperature can be, for example, 60 ° C., and the reaction time can be, for example, 24 hours. The conditions of can be appropriately adjusted by those skilled in the art.

Suitable forms of the gel composition containing the monomer having a hydroxyl group include, for example, N-isopropylmethacrylamide (NIPMAAm) as the gelling agent (main chain) and 4- (2) as the phenylboronic acid-based monomer. -Acrylamide ethyl carbamoyl) -3-fluorophenylboronic acid (AmECFPBA), N-hydroxyethyl acrylamide (NHEAAm) as a hydroxyl-based monomer, N, N'-methylenebisacrylamide (MBAAm) as a cross-linking agent, as a polymerization initiator Examples thereof include those prepared by adjusting 2,2'-azobisisobutyronitrile to a charged molar ratio of 62/27/11/5 / 0.1. By adjusting in this way, the temperature dependence in the vicinity of the normal blood glucose level (1 g / L) can be significantly reduced. However, not limited to this, the gel body that can be formed by the gel composition containing the gelling agent, the phenylboronic acid-based monomer, the hydroxyl-based monomer and the cross-linking agent can expand or contract in response to the glucose concentration. At the same time, if the desired temperature tolerance can be exhibited, a gel is prepared by setting the charged molar ratio of the gelling agent / phenylboronic acid-based monomer / hydroxyl-based monomer / cross-linking agent to various other values. You may. For example, the gel composition is N-isopropylmethacrylamide (NIPMAAm), 4- (2-acrylamide ethylcarbamoyl) -3-fluorophenylboronic acid (AmECFPBA), N-hydroxyethylacrylamide (NHEAAm), N, N'-. It may be prepared by polymerizing methylenebisacrylamide (MBAAm) at a charged molar ratio of 62/27/11/5 (mol%).

[Soluble / Degradable Material Layer]
The soluble / degradable material layer 120 is made of a material that dissolves or decomposes under physiological conditions (hereinafter, also referred to as a soluble / degradable material). By forming the soluble / degradable material layer 120 on the surface of the needle 110, the mechanical strength of the needle 110 can be reinforced. By reinforcing the mechanical strength of the needle 110, it is possible to prevent damage such as breakage or deformation of the needle 110 when the needle 110 is punctured into the skin. Further, since the soluble / degradable material layer 120 is made of a material that dissolves or decomposes under physiological conditions, the soluble / degradable material layer 120 dissolves or decomposes over time when the needle 110 is punctured into the skin. It decomposes and disappears from the surface of the needle 110. Therefore, it can be said that the release characteristics of the drug from the needle 110 are hardly affected by the formation of the soluble / degradable material layer 120. After at least the soluble / degradable material layer 120 has disappeared from the surface of the needle 110, the drug is released as if the soluble / degradable material layer 120 had not been formed.

(Material of soluble / degradable material layer)
The soluble / degradable material constituting the soluble / degradable material layer 120 is not particularly limited as long as it is biocompatible and dissolves or decomposes under physiological conditions. Such materials include, for example, polyvinyl alcohol (PVA), hyaluronic acid, polylactic acid, polyethylene glycol, cellulose, starch, alginic acid, chitosan, collagen, albumin, poly (3-hydroxyalkanoate), polyethylene succinate, poly. Examples thereof include glycolic acid, poly (ε-caprolactone), polyethylene terephthalate, polyester carbonate, polyacid anhydride, polycyanoacrylate, polyorthoester, polyphosphazene and silk fibroin (SF). Among these, PVA has high mechanical strength, and since it has high viscosity among polymers, it can be crystallized by heat treatment to further improve the mechanical strength. Therefore, the microneedle 10 as in this embodiment is used. Suitable as a soluble / degradable material layer 120 for the needle 110 of. When PVA is used as the soluble / degradable material, it is preferable to appropriately select the saponification degree and molecular weight of PVA.

(Strength of needle with soluble / degradable material layer formed)
The mechanical strength per needle 110 is preferably 0.6 N or more, more preferably 0.7 N or more, so that the needle 110 is not damaged when the needle 110 is punctured into the skin. However, it is not necessary to give the needle 110 an excessive mechanical strength, and the mechanical strength per needle 110 may be 0.8 N or less.

(Thickness of soluble / degradable material layer)
The thickness of the soluble / degradable material layer 120 is one of the parameters affecting the mechanical strength of the needle 110. There is an appropriate range for the thickness of the soluble / degradable material layer 120. If the soluble / degradable material layer 120 is too thin, the mechanical strength of the needle 110 may not be sufficient. Considering this, the thickness of the soluble / degradable material layer 120 is preferably 12 μm or more, more preferably 15 μm or more. On the other hand, if the thickness of the soluble / degradable material layer 120 is too thick, the needle 110 may be deformed due to the tension of the soluble / degradable material layer 120 when the soluble / degradable material layer 120 is formed. Further, if the soluble / degradable material layer 120 is too thick, it takes a long time for the soluble / degradable material layer 120 to disappear after the needle 110 is punctured into the skin. Considering these facts, the thickness of the soluble / degradable material layer 120 is preferably 24 μm or less, more preferably 21 μm or less.

(Region of forming soluble / degradable material layer)
Regarding the region forming the soluble / degradable material layer 120, in FIG. 2, the soluble / degradable material layer 120 is formed in all the regions on the surface of the needle 110. However, since it is the tip of the needle 110 that is most easily damaged when the needle 110 is punctured into the skin, the soluble / degradable material layer 120 may be formed only in the region on the tip side of the needle 110. .. Alternatively, when the needle 110 is punctured, stress tends to be concentrated at the root of the needle 110, so that the soluble / degradable material layer 120 may be formed only in the region on the root side of the needle 110. In which region the soluble / degradable material layer 120 is formed can be determined according to the size and shape of the needle 110 and the like. Further, when the soluble / degradable material layer 120 is formed on the root side of the needle 110, the soluble / degradable material layer 120 expands to the region around the needle 110 on the surface of the base portion 100 on which the needle 110 protrudes. May be formed. By doing so, the effect of reinforcing the root of the needle 110 by the soluble / degradable material layer 120 is further improved.

(Method of forming soluble / degradable material layer)
The method for forming the soluble / degradable material layer 120 on the surface of the needle 110 is not particularly limited. For example, by applying a soluble / degradable material solution in which a soluble / degradable material is dissolved in a solvent to the desired area of the needle 110, and then drying the soluble / degradable solution (removing the solvent). , Soluble / degradable material layer 120 can be formed on the surface of the needle 110. The method of applying the soluble / degradable material solution may be arbitrary, and for example, a dip coating method, a spray coating method, a spin coating method and the like can be used. Among these, the dip coating method can easily form the soluble / degradable material layer 120 having a uniform thickness even in a relatively wide area, and therefore the soluble / degradable material layer 120 on the surface of the needle 110. It is one of the methods that can be preferably used for the formation of.

(Drug release control by soluble / degradable material layer)
The release of the drug can be controlled by adjusting the thickness of the soluble / degradable material layer 120. For example, by forming the soluble / degradable material layer 120 with a thickness that inhibits the release of the drug, the drug can be released after a certain period of time has passed since the needle 1110 was punctured. The time at which release of the drug begins can be controlled by the thickness and solubility / degradability of the soluble / degradable material layer 120.

[Structure of microneedle with reservoir]
Some forms of the structure of the microneedle having a reservoir will be described with reference to FIGS. 3A-3C.

In the form shown in FIG. 3A, the reservoir 101 is formed in a space formed by forming the base portion 100 in a concave shape (cup shape) and sealing the open upper surface of the base portion 100 with a sheet 102. For bonding the sheet 102, for example, a water resistant adhesive 103 can be used. The sheet 102 is not particularly limited, but from the viewpoint of water resistance and flexibility, for example, a silicone sheet having a thickness of 0.3 mm can be used. The drug can be filled into the reservoir 101 via the sheet 102 by syringe injection.

In the form shown in FIG. 3B, the reservoir 101 is sealed with an adhesive 103, for example, with a sheet 102 made of silicone, as in the case shown in FIG. 3A. However, the base portion 100 is formed in a stepped manner having a flange 100b on the open end side of the reservoir 101. Further, the sheet 102 hangs over the flange 100b toward the bottom surface 100a having the needle 110, and covers the base portion 100 also in the height direction of the base portion 100. The adhesive 103 is applied between the base portion 100 and the sheet 102 at the hanging portion of the sheet 102 over the entire circumference of the base portion 100.

According to such a structure, the sheet 102 can be adhered to the base portion 100 with a larger adhesive area as compared with the structure shown in FIG. 3A, and the reservoir 101 can be sealed more effectively. As a result, the leakage of the drug from between the base portion 100 and the sheet 102 can be effectively prevented. Moreover, the expansion of the area of the microneedle can be minimized.

The overhang amount A of the flange 100b can be, for example, 0.2 mm. The thickness B of the flange 100b can be, for example, 0.1 mm, and the height C from the flange 100b to the bottom surface of the base portion 100 can be, for example, 0.2 mm.

Also in this embodiment, the planar shape of the microneedle may be any shape such as a quadrangle or a circle. Further, the outer shape of the flange 100b and the shape of the bottom surface 100a of the base portion 100 on which the needle 110 is arranged may be the same or different. From the viewpoint of suppressing deformation during manufacturing of the microneedles, it is preferable that the outer shape of the flange 100b and the shape of the bottom surface 100a are both circular.

When it is permissible to increase the area of the microneedles, as shown in FIG. 3C, the overhanging amount of the flange 100b is increased, and the sheet 102 is adhered on the upper surface of the flange 100b via the adhesive 103. It is also possible to increase the adhesive area.

[Formation of base and needle]
The base portion 100 and the needle 110 can be formed using a mold-based micromolding technique. Since the needle 110 can be formed integrally with the base portion 100, it is preferable to use a mold 200 having a cavity 201 formed in a shape in which the needle and the base portion are combined as shown in FIG.

By using such a mold 200, the base portion 100 and the needle 110 can be formed in one step. However, when the material constituting the base portion 100 and the material constituting the needle 110 are different, first, a solution in which the material constituting the needle 110 is dissolved in a solvent is poured into a portion corresponding to the needle 110 of the mold 200. This is dried (removing the solvent) to form the needle 110. The solution can be poured and dried in multiple steps. Next, a solution in which the material constituting the base portion 100 is dissolved in a solvent is poured into a mold 200, and this is dried. The obtained molded body is taken out from the mold 200. Thereby, the base portion 100 and the needle 110 integrally formed can be obtained.

Since the needle 110 has a very fine structure, it is important to fill the tip of the needle 110 with the solution when forming the needle 110. Therefore, it is preferable to carry out centrifugation or vacuum treatment before drying the solution.

A centrifuge can be used for centrifugation. More specifically, the mold 200 into which the solution is poured is placed in a falcon tube and centrifuged using a centrifuge. As a result, the solution can be filled up to the tip of the mold 200. The needle 110 can then be formed by placing the mold 200 in a desiccator and drying the solution.

The vacuum treatment can be performed, for example, by forming the mold 200 with a porous material, placing the mold 200 under reduced pressure to remove air in the mold 200, and then pouring the solution into the mold 200. As a result, the solution can be filled up to the tip portion of the needle 110. As the porous material constituting the mold 200, for example, polydimethylsiloxane (PDMS) can be used.

There is no significant difference in the form of the needle 110 obtained by either the centrifugal treatment or the vacuum treatment, and both the centrifugal treatment and the vacuum treatment can be used in the present invention.

[Evaluation of microneedles]
Next, the evaluation of the microneedle in which the soluble / degradable material layer is formed on the surface of the needle will be described. In the following evaluation, the soluble / degradable material layer is formed of polyvinyl alcohol (PVA), and the soluble / degradable material layer is referred to as a PVA layer.

(Evaluation 1) Formation of soluble / degradable material layer <Experimental method>
N-Isopropylacrylamide (NIPAAm), 4- (2-acrylamide ethylcarbamoyl) -3-fluorophenylboronic acid (AmECFPBA) and N-hydroxyethylacrylamide (NHEAAm), N, N'-methylenebisacrylamide (MBAAm), respectively. Dissolve in a mixed solvent of methanol and water (methanol / water = 4/6, v / v) and mix at a ratio of NIPAAm / AmECFPBA / NHEAAm / MBAAm = 57.7 / 10.2 / 22.6 / 5.00. To obtain a mixed solution. Ammonium peroxodisulfate (APS, concentration: 100 mg / mL, addition amount: 4 μL) and tetramethylethylenediamine (TEMED, addition amount: 4 μL) were added to the obtained mixed solution (100 μL) to obtain a reaction solution (pregel solution). rice field. The obtained reaction solution (40 μL) was poured into a microneedle mold (number of needles: 10 × 10, needle arrangement area: 8 mm × 8 mm, needle length: 700 μm), and the mold into which the reaction solution was poured was centrifuged at 2200 g for 3 minutes. The treatment was then performed and the reaction solution was dried after the polymerization reaction. A series of processes from pouring the reaction solution into the mold to drying was repeated three times, and finally, the dried product was taken out from the mold to prepare a molded body in which the needle and the base portion made of the gel composition were integrated. ..

A PVA aqueous solution (PVA concentration: 100 mg / mL, PVA saponification degree: 99% or more, PVA molecular weight: 130 to 230 kDa, ultimate viscosity: 59 mL / The PVA solution was applied to the surface of the needle by immersing it in g) and taking it out. After the applied PVA solution was dried, heat treatment was performed at 130 ° C. for 1 hour. This was washed with pure water and then dried at room temperature to prepare microneedles having a PVA layer formed on the surface of the needle (Sample 1-1). Further, a sample (Sample 1-2) in which a series of steps starting from immersion for forming the PVA layer on the needle was repeated twice and a sample (Sample 1-3) in which the series process was repeated three times were prepared and subjected to immersion. The difference depending on the number of times the PVA solution was applied was confirmed.

<Result>
Each of the obtained samples was observed by fluorescence microscopy using a confocal microscope. Representative results obtained in Evaluation 1 are shown in FIG. The fluorescence intensity was increased by increasing the number of times the PVA solution was applied to the needle, suggesting that PVA was introduced on the surface of the needle and that the amount of PVA was increased by increasing the number of times of application. However, in this experiment, the shape of the needle changed when the number of times the PVA solution was applied was 3, suggesting that the optimum amount of PVA exists.

(Evaluation 2) Thickness of soluble / degradable material layer <Experimental method>
Cy5-NHS was added as a fluorescent label to the PVA solution used in Evaluation 1 (1 equivalent, concentration: 25 mg / mL, solvent: DMSO) and reacted at 35 ° C. overnight to synthesize Cy5-labeled PVA. In the same manner as in Evaluation 1, microneedles having a PVA layer formed on the surface of the needle were produced. In this evaluation as well, as in Evaluation 1, three types of microneedles (Sample 2-1 and Sample 2-2 and Sample 2-3) were prepared in which the number of times the PVA solution was applied was changed from 1 to 3 times. For each of the produced microneedles, Cy5 on the surface of the needle was observed by fluorescence microscopy and used as an index of the thickness of the PVA layer.

<Result>
Representative results obtained in Evaluation 2 are shown in FIG. 6 (a) to 6 (c) are confocal microscope images in the vicinity of the needles of Sample 2-1 and Sample 2-2 and Sample 2-3, respectively. FIG. 6D is a graph of the thickness of the PVA layer of each sample estimated from the thickness of the Cy5 region observed by the microscope image. From the graph of FIG. 6D, the thickness of the PVA layer increased as the number of times the PVA solution was applied increased, suggesting that the thickness of the PVA layer also increased as the number of times the PVA solution was applied increased.

(Evaluation 3) Mechanical strength of the needle on which the soluble / degradable material layer was formed <Experimental method>
A microneedle having a PVA layer formed on the surface of the needle was produced in the same manner as in Evaluation 1 except that no fluorescent label was added to the PVA solution used in Evaluation 1. In this evaluation, in addition to the three types of microneedles (Sample 3-1 and Sample 3-2, Sample 3-3) in which the number of times the PVA solution was applied was changed from 1 to 3 as in Evaluation 1, the PVA solution was used. A microneedle (sample 3-0) to which the above was not applied was also prepared.

The mechanical strength of the needle of each sample was measured with a bond tester (universal bond tester manufactured by Daige Co., Ltd., model number: 5000). Specifically, the microneedle is fixed to a bond tester, the stainless probe is set at a position 200 μm from the root of the needle under vacuum, and then the yield stress of the needle is measured by moving the stainless probe horizontally, and the yield stress is measured. The value was used as an index of the mechanical strength of the needle.

<Result>
Representative results obtained in Evaluation 3 are shown in FIG. From FIG. 7, since the yield stress of the needle having the PVA layer formed was higher than that of the needle without the PVA layer, it was suggested that the mechanical strength of the needle was improved by forming the PVA layer. In addition, no significant difference was observed between the sample 3-2 to which the PVA solution was applied twice and the sample 3-3 to which the PVA solution was applied three times. Considering the results obtained from Evaluation 2, it was suggested that the thickness of the PVA layer is preferably in the range of 15 to 21 μm from the viewpoint of mechanical strength.

(Evaluation 4) Solubility / Degradability Solubility of material layer <Experimental method>
A microneedle was prepared by applying the Cy5-labeled PVA solution twice in the same manner as in Evaluation 2. The needle portion of the prepared microneedle was immersed in phosphate buffered saline (PBS) and observed by fluorescence microscopy. In addition, the fluorescence intensity of free Cy5 in PBS was measured with a fluorometer (manufactured by Thermo Fisher Scientific Co., Ltd., product name: NanoDrop 3300) to quantify the disappearance of PVA from the needle surface.

<Result>
The representative result obtained by the evaluation 4 is shown. FIG. 8A is a fluorescence microscope image immediately after immersion in PBS, 5 minutes and 30 minutes after immersion in PBS, in order from the left. FIG. 8B is a graph showing the change in fluorescence intensity of free Cy5 in PBS with time. From (a) of FIG. 8, it can be seen that the fluorescence derived from Cy5 disappears from the needle surface 30 minutes after being immersed in PBS. From this, it can be seen that the rapid dissolution of the PVA layer under physiological conditions was suggested. In addition, the fluorescence intensity of free Cy5 in PBS increased with the passage of time, suggesting excellent solubility of the PVA layer under physiological conditions.

(Evaluation 5) Glucose response ability <Experimental method>
In order to evaluate the glucose response ability with and without the PVA layer, 2 was prepared in the same manner as Sample 3-0 (number of PVA solution coatings: 0 times) and Sample 3-2 (number of PVA solution coatings: 2 times) in Evaluation 3. Insulin storage containers were attached to each type of microneedle. Specifically, a silicon sheet (thickness: 0.3 mm) was bonded to the microneedle using a water-repellent epoxy resin, and FITC-labeled insulin (130 mg / L) was injected into the microneedle using a syringe.

For each of the obtained microneedles with an insulin storage container, by HPLC method (mobile phase: glucose-containing PBS (100, 500 mg / dL, pH 7.4), flow rate: 1 mL / min, Ex / Em = 490/520 nm). Fluorescence from FITC-labeled insulin released from the microneedles was measured.

<Result>
The representative results obtained by the evaluation 5 are shown in FIG. In FIG. 9, A is a graph showing a FITC-labeled insulin release pattern from a microneedle without a PVA layer, and B is a graph showing a FITC-labeled insulin release pattern from a microneedle coated with a PVA layer. Is a graph showing a glucose concentration pattern. Comparing A and B, there was almost no change in insulin release behavior with or without the PVA layer, suggesting rapid disappearance of the PVA layer and insulin release in response to glucose concentration.

(Evaluation 6) Glucose response ability in agarose gel that mimics the intradermal environment <Experimental method>
Agarose was dissolved in glucose-containing PBS (concentration: 100 mg / dL) at 1 wt% and heated in a microwave oven (600 W) for 1 minute. Then, the solution was added to a 3D culture observation device (cube type, dimensions: 10 mm × 10 mm × 10 mm) to prepare an agarose gel. As the microneedle, a PVA layer-coated microneedle prepared in the same manner as in Evaluation 3 was used. FITC-labeled insulin was added to the microneedles, and the microneedles to which FITC-labeled insulin was added were attached to the surface of the agarose gel, and the fluorescence intensity derived from FITC in the PBS solution was measured. A fluorometer (manufactured by Thermo Fisher Scientific Co., Ltd., product name: NanoDrop 3300) was used for measuring the fluorescence intensity.

<Result>
Representative results obtained by evaluation 6 are shown in FIG. No increase in fluorescence intensity derived from FITC was observed in PBS (glucose (−)) containing no glucose. On the other hand, in glucose-containing PBS (glucose (+)), the fluorescence intensity derived from FITC increased. This suggests that insulin was released by sensing the glucose concentration even in a network structure such as an agarose gel.

10 Microneedle 100 Base 110 Needle 120 Soluble / Degradable Material Layer

Claims (11)

1. A needle that can carry a drug and has the permeability of the drug,
   A soluble / degradable material layer formed of at least a part of the surface of the needle and composed of a material that dissolves or decomposes under physiological conditions.
   Drug delivery device with.
2. The drug delivery device according to claim 1, wherein the material that dissolves or decomposes under the physiological conditions is polyvinyl alcohol.
3. The drug delivery device according to claim 1 or 2, wherein the soluble / degradable material layer has a thickness of 15 to 21 μm.
4. The drug delivery device according to any one of claims 1 to 3, further comprising a base portion that supports the needle.
5. The drug delivery device according to claim 4, wherein the base portion has a reservoir of the drug carried by the needle.
6. The drug delivery device according to any one of claims 1 to 5, wherein the needle comprises a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit.
7. The drug delivery device according to any one of claims 1 to 6, wherein the drug delivery device is a microneedle.
8. A method of manufacturing a drug delivery device having a drug-permeable needle.
   Forming the needle and
   To form a soluble / degradable material layer of a material that dissolves or decomposes under physiological conditions, at least on a portion of the surface of the needle.
   A method of manufacturing a drug delivery device, including.
9. The method for producing a drug delivery device according to claim 8, wherein the material that dissolves or decomposes under the physiological conditions is polyvinyl alcohol (PVA).
10. Forming the needle
    Pour the pregel solution containing the monomer mixture containing the phenylboronic acid-based monomer into the mold, and
    By polymerizing the monomer mixture in the pregel solution in the mold, a molded product composed of a gel composition can be obtained.
    Taking out the molded body from the mold and
    The method for manufacturing a drug delivery device according to claim 8 or 9.
11. The method for manufacturing a drug delivery device according to any one of claims 8 to 10, further comprising carrying the drug on the needle.

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