JP2023037496A - Drug delivery device and method for producing the same - Google Patents

Abstract

To provide a drug delivery device that includes a needle having sufficient mechanical strength, with reduced influence on drug delivery, and also has sufficient mechanical strength for puncturing.SOLUTION: A microneedle 10 has a base part 100 and at least one needle 110 supported by the base part 100. The base part 100 and the needle 110 comprise a porous body comprising a polymer, and a gel composition that is filled in the gap portion of the porous body, can carry a drug and has permeability for the drug.SELECTED DRAWING: Figure 1

Description

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

A microneedle is known as a device for transdermally administering a drug. Microneedles, for example, as disclosed in Patent Document 1, are provided as a patch in which a plurality of needles with a length of 1 mm or less carrying a drug to be administered are arranged in an array, and are attached to the skin surface to release the needles. A drug is configured to be delivered via. Therefore, microneedles have the characteristic of being able to continuously administer drugs over a long period of time in a minimally invasive manner.

WO2019/182099

When attaching a microneedle-type drug delivery device to the skin, it is necessary to press the device firmly against the skin so that the needle penetrates the skin sufficiently. However, in conventional microneedle type drug delivery devices, mainly due to insufficient strength of the base portion (reservoir portion), it has been difficult to pressurize when puncturing. In addition, conventional microneedles lack mechanical strength because the needles are very fine, and the needles may break or buckle when the needles puncture the skin. In order to prevent this, it is conceivable to configure the needle with a material having high mechanical strength, or to coat the surface of the needle with a material having high mechanical strength. However, since materials with high mechanical strength generally have a dense structure, there is a possibility that the delivery performance of the drug may be lowered, for example, the amount of drug released from the needle may be decreased.

The present invention provides a drug delivery device in which the needle has sufficient mechanical strength to suppress the effect on delivery of the drug and has sufficient mechanical strength to facilitate pressurization during puncture. One of the objects is to provide a manufacturing method thereof.

The drug delivery device of the present invention comprises a base portion,
at least one needle supported by the base;
has
The base portion and the needle each include a porous body made of a polymer, and a gel composition capable of supporting a drug and permeable to the drug, which is filled in voids of the porous body. .

A method for manufacturing a drug delivery device of the present invention is a method for manufacturing a drug delivery device having a base and at least one needle supported by the base, comprising:
a step of molding a porous body made of a polymer using a mold having cavities corresponding to the base portion and the needle;
a step of filling a void portion of the porous body with a gel composition capable of supporting a chemical solution and having permeability for the chemical solution;
have

(Definition of terms)
As used herein, "physiological conditions" means an aqueous solution adjusted to pH, temperature and ionic composition equivalent to those 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 ion composition is preferably sodium chloride concentration of 100 to 200 mM.
Also, the term "about" is used herein to refer to a range of 10% around the numerical value that follows. That is, about 30 mol % means a range of 27 mol % to 33 mol %.

ADVANTAGE OF THE INVENTION According to the present invention, there is provided a drug delivery device in which the needle has sufficient mechanical strength while suppressing the effect on delivery of the drug and has sufficient mechanical strength when punctured, and a method for manufacturing the same. be.

1 is a schematic cross-sectional view of a microneedle according to one aspect of the invention; FIG. FIG. 2 is a cross-sectional view of one embodiment of a mold used to manufacture the microneedles shown in FIG. 1; 2 is an optical micrograph showing the moldability of needles when microneedles were produced by changing the PES concentration and the benzene concentration in Evaluation 1. FIG. 10 is a high-cost photomicrograph showing the moldability of needles when microneedles were produced by changing the benzene concentration in Evaluation 2. FIG. 4 is a scanning electron micrograph of the porous polymer material in evaluation 3. FIG. 1 is an optical micrograph of a polymer porous/gel composition composite microneedle according to evaluation 4. FIG. 10 is a graph showing the mechanical strength of needles measured in evaluation 5. FIG. Fig. 10 is a photograph of the skin surface of a mouse after application of polymer porous/gel composition composite microneedles in Evaluation 6; 10 is a graph showing drug release properties in Evaluation 7. FIG.

Referring to FIG. 1, there is shown a microneedle 10 according to one embodiment of the present invention having a base portion 100 and a plurality of needles 110 and provided as a patch to adhere to the skin. 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 to the extent that it can be deformed along the skin. . By supporting the plurality of needles 110 on the base portion 100, the plurality of needles 110 are configured as a needle array. Needle 110 comprises a gel composition that is capable of carrying the drug to be delivered by the microneedle 10 and is permeable to the drug.

The microneedle 10 will be described in more detail below.

[Drug]
Drugs that can be delivered using the drug delivery device of the present invention include, but are not limited to, proteins, peptides, nucleic acids, other macromolecular polymers, low molecular weight compounds, and the like. A drug may be a therapeutic agent for a disease, a prophylactic agent, a vaccine, a nutritional supplement, or the like. A particularly preferred drug is insulin. Various natural insulins or modified insulins are available commercially or by synthesis. As insulin, for example, Humalin (registered trademark) may be used. Humalin® is a human (genetically-recombinant) insulin marketed by Eli Lilly and Company. Various types of insulin preparations have been developed, including rapid-acting, intermediate-acting, and sustained-acting types, and can be selected and used as appropriate.

[Base part and needle]
The base part 100 and the needle 110 have a polymer porous material responsible for mechanical strength and a gel composition responsible for drug loading and release. The gel composition resides in the voids to fill the voids of the polymeric porous body, thereby configuring the base portion 100 and the needle 110 as one piece without boundaries. The planar shape of the base portion 100 may be any shape such as circular, elliptical, and polygonal, and may be rectangular, for example. The polymer porous body and gel composition are described in detail below.

(Polymer porous body)
The porous polymer body provides mechanical strength to the base portion 100 such that bending of the base portion 100 due to the reaction force received from the skin when the needle 110 is punctured (also referred to as piercing) into the skin is suppressed. , the needle 110 provides mechanical strength to suppress breakage and buckling when puncturing the skin.

Examples of polymers constituting the polymer porous body include polyethersulfone (PES), polyethylene, polypropylene, polyethylene glycol, polypropylene glycol, polylactic acid, and cellulose. For example, when PES is used, a firm gel is formed by π-π interaction and phase separation, and gaps in a co-continuous structure can be formed. A polymer porous body using polyethersulfone can be obtained, for example, as follows. First, a polyethersulfone solution (polymer solution ) is prepared. To the prepared polyethersulfone solution is added a poor solvent such as benzene, toluene, xylene, tetrahydrofuran, water, methanol, ethanol, hexane, pentane, diethyl ether, ethyl acetate, etc., in which the starting polymer has low solubility. As a result, the organic solvent is extracted into the poor solvent and the poor solvent diffuses into the polyethersulfone solution, causing phase separation between a layer having a high raw material polymer concentration and a layer containing little raw material polymer. After that, by removing both the good solvent and the poor solvent by washing with methanol or the like, a polymer porous body is obtained. It is also possible to obtain a porous polymer body without adding a poor solvent by performing phase separation at a low temperature such as 4°C. It is considered that this is because phase separation is induced by precipitation of the starting polymer at low temperatures.

The polymer concentration when preparing the polymer solution and the poor solvent concentration when adding the poor solvent can be appropriately determined depending on the polymer to be used, the poor solvent to be used, the phase separation conditions, and the like. For example, if the polymer is polyethersulfone, the antisolvent is benzene, and the phase separation temperature is room temperature, the preferred polymer concentration is about 15 to about 25 wt% (eg, about 20 wt%), and the preferred antisolvent concentration is is about 20 to about 35 wt% (eg, about 25 wt%). Here, the polymer concentration is wt % of the polymer in the polymer solution to which the good solvent is added, and the poor solvent concentration is vol % of the poor solvent in the polymer solution to which the good solvent and the poor solvent are added.

A polymer sintered body obtained by sintering polymer particles can also be used as the polymer porous body. Polyethylene (PE) can be mentioned as a polymer used for the polymer sintered body. The particle size is not limited as long as it does not affect the moldability of the base portion 100 and the needle 100 . For example, preferred particle size ranges include an average particle size of 10 μm or more, or 20 μm or more, and an average particle size of 300 μm or less, 200 μm or less, 100 μm or less, or 60 μm or less.

The porosity of the porous body can be arbitrarily determined according to the mechanical strength required for the base portion 100 and the amount of drug that the base portion 100 should retain. For example, the preferred porosity range may be 20% or more, 30% or more, or 40% or more, and may be 80% or less, 70% or less, or 60% or less.

The polymeric porous body may be coated with a polymer having hydrophilic groups. This improves the fillability of the gel composition into the voids of the polymer porous body, resulting in enhanced formability of the base portion 100 and the needles 110 . When the polymer is polyethersulfone, coating with a polymer having a hydrophilic group can be performed, for example, by irradiating the porous polymer body with plasma and adding acrylic acid diluted with methanol to the porous polymer body after plasma irradiation. By graft-polymerizing acrylic acid, a polyacrylic acid film is formed on the surface of the polyethersulfone, and hydrophilicity can be imparted to the porous polymer material. Contaminants on the surface of the polyethersulfone are removed (washed) by the plasma treatment, and the molecular chains of the surface layer are partially cut by the collision of radicals formed by the plasma with the surface of the polyethersulfone. new functional groups are generated (surface modification).

Having the base portion 100 and the needle 110 have a porous polymer body allows the porous body to be used as a drug reservoir and release the drug over an extended period of time (eg, 7 days). A microneedle that can release 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 the blood glucose concentration.

(Gel composition)
The gel composition can contain optional components so long as it is permeable to the drug, depending on the drug to be delivered. A gel composition that is preferable when the microneedle 10 is used as a device for delivering insulin as a drug according to blood glucose concentration will be described below.

（式中、Ｘは置換基を示し、好ましくはＦであり、ｎは１～４の整数を表す。）
で表されるフェニルボロン酸官能基を有する単量体を意味する。 A preferred gel composition of this type is a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit. 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". may also be used. A phenylboronic acid-based monomer is represented by the following formula:

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

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

Phenylboronic acid dissociated in water (hereinafter sometimes referred to as “PBA” in this specification) reversibly binds to sugar molecules and maintains the above equilibrium state. When the glucose concentration is high, it binds and expands in volume, but when the glucose concentration is low, it contracts. With the needle 110 pierced into the skin, this reaction occurs at the gel interface in contact with the blood, causing the gel to shrink only at the interface to form a dehydrated shrink layer that we call the "skin layer." This property is utilized for insulin release control.

A gel composition that can be suitably used is a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit having the properties described above. The gel composition is not particularly limited, but includes, for example, those described in Japanese Patent No. 5,696,961.

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

［式中、ＲはＨまたはＣＨ_３であり、Ｆは独立に存在し、ｎが１、２、３または４のいずれかであり、ｍは０または１以上の整数である。］

[wherein R is H or _CH3 , F is independently present, n is either 1, 2, 3 or 4, and m is 0 or an integer greater than or equal to 1]. ]

The above phenylboronic acid-based monomer is a fluorinated phenylboronic acid in which hydrogen on the phenyl ring is substituted with 1 to 4 fluorine atoms (hereinafter sometimes referred to as "FPBA" in this specification) 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 since the phenyl ring is fluorinated, the pKa can be set to 7.4 or less, which is the biological level. Furthermore, this phenylboronic acid-based monomer not only acquires the ability to recognize sugars in a biological environment, but also enables copolymerization with gelling agents and cross-linking agents, which will be described later, due to unsaturated bonds, and increases glucose concentration. It can result in a gel that undergoes a phase change depending on it.

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

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

An example of the above phenylboronic acid-based monomer is a phenylboronic acid-based monomer in which n is 1 and m is 2, which is particularly preferred as a phenylboronic acid-based monomer of 4-(2- Acrylamidoethylcarbamoyl)-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 vivo, the above phenylboronic acid-based monomer, and a cross-linking agent. . The preparation method is not particularly limited, but a monomer containing a gelling agent, a phenylboronic acid-based monomer, and a cross-linking agent, which will be the main chain of the gel (copolymer), at a predetermined molar ratio It can be prepared by mixing the components and polymerizing the monomers. A polymerization initiator is optionally used for the polymerization.

It is preferred that insulin is already included in the gel composition. For this purpose, insulin can be diffused into the gel by immersing the gel in an aqueous solution such as phosphate buffer solution (PBS) containing insulin at a predetermined concentration. Next, the gel taken out of the aqueous solution is immersed in, for example, hydrochloric acid for a predetermined period of time to form a thin dehydration shrinkage layer (called a skin layer) on the surface of the gel body, thereby encapsulating (loading) the drug in the needle 110. can be made

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

A gel body formed by a copolymer obtained from a gelling agent, a phenylboronic acid-based monomer, and a cross-linking agent can swell or contract in response to glucose concentration while maintaining a pKa of 7.4 or less. If it is possible to form a gel, the gel can be prepared by setting the charging 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 capable of gelling, and examples thereof include biocompatible acrylamide-based monomers. Specific examples include N-isopropylacrylamide (NIPAAm), N,N-dimethylacrylamide (DMAAm), N,N-diethylacrylamide (DEAAm) and the like.

Also, the cross-linking agent may be any substance that similarly has biocompatibility and can cross-link the monomers. N'-methylenebismethacrylamide (MBMAAm) and various cross-linking agents are included.

In one preferred embodiment, the gel composition comprises N-isopropylmethacrylamide (NIPAAm), 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), and N, It is obtained by dissolving N'-methylenebisacrylamide (MBAAm) in a solvent in an appropriate compounding ratio and polymerizing it. Polymerization can be carried out under ambient and aqueous conditions.

Any solvent that can dissolve the monomer can be used as the solvent. Such solvents include, for example, water, alcohols, dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), ionic liquids and combinations of one or more thereof. Among these, a methanol aqueous solution can be preferably used as a solvent.

A pre-gel solution is prepared by dissolving a gelling agent, PBA and a cross-linking agent in such a solvent, and polymerization is carried out.

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 in this gel, and the surface of the gel body can be surrounded by a dehydration contraction layer. By applying this configuration to the needle 110, under physiological conditions such as a pKa of 7.4 or less and a temperature of 35° C. to 40° C., the gel forming the needle 110 expands when the glucose concentration increases. Along with this, the dehydration contraction layer disappears, and the insulin in the gel can be released to the outside.

On the other hand, when the glucose concentration becomes low again, the swollen gel shrinks and a dehydrated shrink layer (skin layer) is formed again on the entire surface, thereby suppressing release of insulin in the gel to the outside.

Such gel compositions are therefore capable of autonomous release of insulin in response to glucose concentration.

Catalysts such as initiators and accelerators can be used in the polymerization. As an initiator, for example, ammonium persulfate (APS) can be used. Tetramethylethylenediamine (TEMED), for example, can be used as an accelerator. In this case, 6.2 μl of 10% by weight ammonium persulfate and 12 μl of tetramethylethylenediamine were added to each 1 ml of pregel solution, and polymerization was carried out at room temperature. Gelation started within 10 minutes.

The gel composition may be a composite gel composition containing silk fibroin (SF) in addition to a copolymer containing phenylboronic acid-based monomer units. This composite gel composition is obtained by copolymerizing a monomer mixture containing a phenylboronic acid-based monomer in the presence of SF. are distributed almost uniformly.

The SF contained in the composite gel composition can also be used in the base portion 100. SF imparts mechanical strength to needle 110 . The amount of SF (solid content weight) can be determined so that the mechanical strength of the microneedle has a suitable value. 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, relative to 100 parts by weight in total. The higher the weight fraction of SF with respect to the total monomers, the higher the mechanical strength of the composite gel composition. However, the higher the SF weight fraction, the lower the monomer concentration. If the monomer concentration is too low, it becomes difficult to form a gel composition, so it is important to determine the weight fraction of SF with respect to the total monomers within a range that does not inhibit the formation of the gel composition.

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

Since SF has the property of easily gelling, when preparing the pre-gel solution, the gelling agent, PBA, cross-linking agent, etc. are dissolved in a solvent, and then SF is added to the solution in the form of an SF solution. It is preferable to

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

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

［式中、ＲはＨ又はＣＨ_３であり、Ｆは独立に存在し、ｎが１、２、３又は４のいずれかであり、ｍは０又は１以上の整数である。］で表されるフェニルボロン酸系単量体、及び下記一般式（２）

［式中、Ｒ１はＨ又はＣＨ_３であり、ｍは０又は１以上の整数であり、Ｒ^２はＯＨ、１以上の水酸基で置換された飽和若しくは不飽和のＣ_１－６アルキル基、１以上の水酸基で置換された飽和若しくは不飽和のＣ_３－１０シクロアルキル基、１以上の水酸基で置換されたＮＨ、Ｏ及びＳより選ばれる１～４個のヘテロ原子を含有するＣ_３－１２複素環式基、１以上の水酸基で置換されたＣ_６－１２アリール基、単糖基、又は多糖基である。］で表される単量体（以下、ヒドロキシル系単量体ともいう。）を含むゲル組成物。 General formula (1) below

wherein R is H or _CH3 , F is independently present, n is either 1, 2, 3 or 4, and m is 0 or an integer greater than or equal to 1; ] and a phenylboronic acid-based monomer represented by the following general formula (2)

[wherein R1 is H or _CH3 , m is 0 or an integer of 1 or more, ^R2 is OH, a saturated or unsaturated _C1-6 alkyl group substituted with one or more hydroxyl groups, 1 saturated or unsaturated C _3-10 cycloalkyl group substituted with one or more 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. ] (hereinafter also referred to as a hydroxyl-based monomer).

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

Examples of the above hydroxyl-based monomers include monomers in which R ¹ is hydrogen, m is 1, and R ² is OH, which are particularly preferred as hydroxyl-based monomers. Hydroxyethylacrylamide (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 remarkably improving the efficiency of the intermolecular cross-linking reaction (with the boronic acid side chain). Therefore, by using NHEAAm, an optimum gel can be obtained that undergoes a phase change depending on the glucose concentration. In addition, in other examples of hydroxyl-based monomers, ^R2 may be a sugar derivative such as a catechol group or a glycolyl group. A monosaccharide can be, for example, glucose.

The hydroxyl-based monomer represented by the general formula (2) contains, in the gel composition, It can be contained at a ratio 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-based monomer represented by the general formula (2) is, 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 in the gel composition. % or less, 35 mol % or less, 30 mol % or less, 25 mol % or less, or 20 mol % or less. As the concentration range, the hydroxyl-based monomer represented by the general formula (2) is contained in the gel composition, for example, 10 mol% to 90 mol%, 15 mol% to 45 mol%, 20 mol% to 40 mol%, or 25 mol% to The ratio may be within the range of 35 mol %. Concentration ranges can be specified by any combination of the above upper and lower limits. A preferred proportion of hydroxyl-based monomers is about 10 mol %.

The gel composition comprises a gelling agent having a property (biocompatibility) that does not cause toxic or adverse effects on biological functions in vivo, the above phenylboronic acid-based monomer, and the above-described hydroxyl-based monomer. and a cross-linking agent. The method for preparing the gel is not particularly limited. It can be prepared by mixing at a charged molar ratio and allowing a polymerization reaction to occur. A polymerization initiator is optionally used for the polymerization.

As the polymerization initiator, for example, 2,2'-azobisisobutyronitrile (AIBN), 1,1'-azobis (cyclohexanecarbonitrile) (ABCN) and other known initiators to those skilled in the art can be used. can be done. The proportion of 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 dimethylsulfoxide (DMSO) as a reaction solvent, the reaction temperature can be, for example, 60° C., and the reaction time can be, for example, 24 hours. can be adjusted as appropriate by those skilled in the art.

A preferred embodiment of the gel composition containing a monomer having a hydroxyl group includes, for example, N-isopropylmethacrylamide (NIPMAAm) as a gelling agent (main chain) and 4-(2 -acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), N-hydroxyethylacrylamide (NHEAAm) as a hydroxyl-based monomer, N,N'-methylenebisacrylamide (MBAAm) as a cross-linking agent, and polymerization initiator For example, 2,2'-azobisisobutyronitrile is adjusted to a charging molar ratio of 62/27/11/5/0.1. By adjusting in this way, the temperature dependence in the vicinity of the normal blood sugar level (1 g/L) can be greatly reduced. However, not limited to this, a gel body that can be formed by a gel composition comprising a gelling agent, a phenylboronic acid-based monomer, a hydroxyl-based monomer, and a cross-linking agent can swell or shrink in response to glucose concentration. In addition, if the desired temperature resistance can be exhibited, gels can be prepared by setting the charging molar ratio of gelling agent/phenylboronic acid-based monomer/hydroxyl-based monomer/crosslinking agent to various other numerical values. may For example, the gel composition contains N-isopropylmethacrylamide (NIPMAAm), 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), N-hydroxyethylacrylamide (NHEAAm), N,N'- It may be prepared by polymerizing methylene bisacrylamide (MBAAm) at a charge molar ratio of about 62/about 27/about 11/about 5 (mol %).

Another preferred form of the gel composition containing a monomer having a hydroxyl group includes, for example, N-isopropylmethacrylamide (NIPMAAm) as a gelling agent (main chain) and 4-( 2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA), N-(2-hydroxyethyl)acrylamide (NHEAAm) as a hydroxyl-based monomer, N,N'-methylenebis(acrylamide) (MBAAm) as a cross-linking agent ) is added to the solvent at a charge molar ratio of, for example, about 60.7/about 10.7/about 23.8/about 4.8, and polymerized using a reduction initiator as a polymerization initiator. It may be prepared. For example, the gel composition may be prepared by preparing NIPMAAm, AmECFPBA, NHEAAm, and MBAAm at molar ratios of 55-65 mol %, 8-12 mol %, 20-25 mol %, and 2-8 mol %, respectively. As a reducing initiator, for example, ammonium persulfate (APS) can be used. By using a reducing initiator, a relatively loose gel composition is formed with excellent drug release behavior. Accelerators such as tetramethylethylenediamine (TEMED) can also be used in combination with the polymerization. As the solvent, for example, a solution in which water and methanol are mixed at a volume ratio of 4/6 can be used.

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

[Formation of base portion and needle]
Base portion 100 and needle 110 may be integrally formed using micromolding techniques using a mold. As the mold, for example, a microneedle mold 200 as shown in FIG. 2 can be used. Microneedle mold 200 can have a cavity (recess) 201 corresponding to the combined shape of base portion 100 and needle 110 (see FIG. 1).

An example of a method for manufacturing microneedles using such a microneedle mold 200 will be described below, taking as an example the case where the polymer porous body is composed of polyethersulfone. First, polyethersulfone is dissolved in an organic solvent (for example, DMF) to a predetermined concentration to obtain a polyethersulfone solution, which is injected into the cavity 201 of the microneedle mold 200. After that, the solution is injected into the microneedle mold. A non-solvent (e.g., benzene) is added to the polyethersulfone solution to a predetermined concentration, which is allowed to stand for a period of time sufficient for phase separation of the polyethersulfone solution, then removed from the microneedle mold 200, and methanol is added. The microneedle-shaped porous polymer body is thus obtained, and the obtained porous polymer body can be subjected to a hydrophilic treatment.

On the other hand, for the gel composition, a solution (pre-gel solution) is prepared by dissolving a monomer mixture containing the monomers constituting the gel composition in a solvent, and this is added to the porous polymer body. By adding the pre-gel solution, the pre-gel solution penetrates into the voids of the porous polymer body, and the voids are filled with the pre-gel solution. By polymerizing the monomer mixture by an appropriate method, the pregel solution becomes a gel composition in a state in which the voids of the polymer porous body are filled. As a result, the microneedle 10 is manufactured by combining the polymer porous material and the gel composition, and in which the base portion 100 and the needle 110 are configured as one portion without a boundary.

Addition of the pre-gel solution to the porous polymer body can be performed, for example, by immersing the porous polymer body in the pre-gel solution and then pulling the porous polymer body out of the pre-gel solution. After the porous polymer material is extracted from the pre-gel solution, the voids of the porous polymer material are filled with the gel composition by polymerizing the monomer mixture to form a structure in which the porous polymer material and the gel composition are combined ( microneedles) can be obtained.

As for filling the cavity 201 with the polyethersulfone solution (and the pregel solution), the needle 110 has a very fine structure. It is important to fill the solution to the tip of the part. Therefore, it is preferable to perform centrifugation or vacuum treatment before polymerizing the solution.

A centrifuge can be used for centrifugation. More specifically, the solution-filled microneedle mold 200 is placed in a falcon tube and centrifuged using a centrifuge. Thereby, the solution can be filled up to the tip of the cavity 201 .

The vacuum treatment is, for example, forming the microneedle mold 200 with a porous material, placing the microneedle mold 200 under reduced pressure to remove the air in the microneedle mold 200, and then pouring the solution into the microneedle mold 200. can be done by Thereby, the solution can be filled up to the tip of the portion of the cavity 201 corresponding to the needle 110 . Polydimethylsiloxane (PDMS), for example, can be used as the porous material forming the microneedle mold 200 .

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

[Evaluation of microneedles]
Next, evaluation of microneedles will be described.

(Evaluation 1) Moldability of Needle with Polyethersulfone <Experiment 1>
Polyethersulfone (PES) was added to 30 wt % of N,N-dimethylformamide (DMF) and dissolved at 110° C. to prepare a PES solution. The prepared PES solution was further diluted with DMF to a predetermined concentration. The diluted PES solution was injected into a microneedle mold 200 made of polydimethylsiloxane (PDMS) and having a base and a cavity 201 corresponding to the needle as shown in FIG. After that, benzene was added to the diluted PES solution injected into the microneedle mold 200 so that the benzene concentration reached a predetermined concentration, and the solution was allowed to stand at room temperature for 24 hours to obtain a molded body. The obtained molding was washed with methanol together with the microneedle mold 200 to remove benzene, and then taken out from the microneedle mold 200 . A microneedle consisting of only a polymer porous body in which a base portion and a needle are integrally formed was produced.

A plurality of types of microneedles were produced by variously changing the PES concentration and the benzene concentration in the PES solution diluted with DMF through the series of treatments described above. The PES concentrations were 15 wt%, 20 wt% and 25 wt%, and the benzene concentrations were 20 vol%, 25 vol%, 30 vol% and 35 wt%.

<Results>
For each microneedle produced, the shape of the needle was observed using an optical microscope. A micrograph of each microneedle is shown in FIG. As a result of shape observation, microneedles with high moldability were obtained at a PES concentration of 20 wt %. It is believed that this is because low-concentration PES is disadvantageous for gelation, while high-concentration PES has high viscosity, and the PES solution does not permeate to the tip of the portion of the cavity corresponding to the needle of the microneedle mold 200. be done. In addition, microneedles with high moldability were obtained at a benzene concentration of 25 wt %. This is because a low concentration of benzene cannot induce phase separation, while a high concentration of benzene causes phase separation before the PES solution penetrates to the tip of the cavity corresponding to the microneedle needle, and the PES solution This is thought to be due to the precipitation of

(Evaluation 2) Effect of presence or absence of benzene on needle moldability <Experiment 2-1>
Polyethersulfone (PES) was added to 30 wt % of N,N-dimethylformamide (DMF) and dissolved at 110° C. to prepare a PES solution. The prepared PES solution was further diluted with DMF so that the PES concentration was 20 wt %. The diluted PES solution was injected into a microneedle mold 200 made of polydimethylsiloxane (PDMS) and having a base and a cavity 201 corresponding to the needle as shown in FIG. After that, the microneedle mold 200 injected with the PES solution was allowed to stand at 4° C. for 24 hours to obtain a molded body. The obtained molded body is washed with methanol together with the microneedle mold 200 to remove benzene, and then taken out from the microneedle mold 200 to obtain microneedles consisting only of a porous polymer body integrally formed with a base portion and a needle. made.

<Experiment 2-2>
After injecting the PES solution into the microneedle mold 200 in Experiment 2-1, benzene was added so that the benzene concentration reached a predetermined concentration, and the mixture was allowed to stand at 4° C. for 24 hours in the same manner as in Experiment 2-1. A microneedle was produced. Two benzene concentrations, 5 vol % and 15 vol %, were used.

<Results>
For each microneedle produced, the shape of the needle was observed using an optical microscope. A micrograph of each microneedle is shown in FIG. As a result of shape observation, microneedles with high formability were obtained even at a benzene concentration of 0%. It is believed that this is because phase separation is induced by precipitation of the polymer under low temperature conditions.

(Evaluation 3) Porosity of porous polymer material <Experiment 3>
In Experiment 1, microneedles produced with a PES concentration of 25 wt % and a benzene concentration of 20 vol % were subjected to surface observation using a scanning electron microscope.

<Results>
A scanning electron micrograph is shown in FIG. As a result of surface observation with a scanning electron microscope, a porous structure was formed, suggesting that phase separation by benzene was efficiently induced.

(Evaluation 4) Moldability of polymer porous/gel composition composite microneedles <Experiment 4>
Polyethersulfone (PES) was added to 30 wt % of N,N-dimethylformamide (DMF) and dissolved at 110° C. to prepare a PES solution. The prepared PES solution was further diluted with DMF so that the PES concentration was 25 wt %. The diluted PES solution was injected into a microneedle mold 200 made of polydimethylsiloxane (PDMS) and having a base and a cavity 201 corresponding to the needle as shown in FIG. After that, benzene was added to the diluted PES solution injected into the microneedle mold 200 so that the benzene concentration was 20 vol %, and the mixture was allowed to stand at room temperature for 24 hours to obtain a molded body composed of a porous polymer body. The obtained molding was washed with methanol together with the microneedle mold 200 to remove benzene, and then taken out from the microneedle mold 200 .

The molded body taken out from the microneedle mold 200 was irradiated with plasma to modify the surface of the molded body. Thereafter, the molding was immersed in an acrylic acid solution diluted with methanol to a concentration of 5% acrylic acid, and reacted at 60° C. for 1 hour to impart hydrophilicity to the molding. A plasma dry cleaner (PDC210) manufactured by Yamato Scientific Co., Ltd. was used for plasma irradiation, and irradiation was performed for 15 minutes at an output of 300 W.

Thereafter, the molded body was washed with methanol, and a pregel solution (monomer concentration: 3M, cross-linking agent density: 5%) was added to the molded body to polymerize the pregel solution. A microneedle composed of a composite of a porous polymer body and a gel composition, in which a base part and a needle are integrally formed by drying the pregel solution after polymerization of the pregel solution (porous polymer/gel composition composite microneedle) was made.

A pre-gel solution was prepared as follows. N-isopropylacrylamide (NIPAAm) as a gelling agent, 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AmECFPBA) as a phenylboronic acid-based monomer, and N-hydroxyethyl as a hydroxyl-based monomer Acrylamide (NHEAAm) and N,N'-methylenebisacrylamide (MBAAm) as a cross-linking agent were respectively dissolved in a mixed solvent of methanol and water (methanol/water = 4/6, v/v), and NIPAAm/AmECFPBA/NHEAAm was obtained. /MBAAm=57.7/10.2/22.6/5.00 to obtain a mixed solution. Ammonium persulfate (APS) as an initiator and tetramethylethylenediamine (TEMED) as an accelerator were added to the resulting mixed solution to obtain a pregel solution.

<Results>
The shape of the fabricated porous polymer/gel composition composite microneedles was observed using an optical microscope. A micrograph of the microneedles in this experiment is shown in FIG. As a result of shape observation, it was confirmed that the shape of the needle was maintained even in the polymer porous body filled with the gel composition.

(Evaluation 5) Mechanical properties of polymer porous/gel composition composite microneedles <Experiment 5>
The mechanical strength of the needles of the polymer porous/gel composition composite microneedles prepared in the same manner as in Experiment 4 was measured using a bond tester (manufactured by Daisi Co., Ltd., universal type bond tester, model number: 5000). Specifically, the microneedle is fixed to a bond tester, a stainless steel probe is set at a position 200 μm from the root of the needle under vacuum, and then the stainless steel probe is moved horizontally to measure the yield stress of the needle. The value was used as an index of the mechanical strength of the needle.

<Reference experiment 5-1>
In Experiment 4, microneedles were produced by injecting a pre-gel solution into the microneedle mold 200, omitting a series of steps for obtaining a molded body made of a porous polymer body and the subsequent treatment with an acrylic acid solution. In other words, in this experiment, microneedles made only of the gel composition were produced. The mechanical strength of the produced microneedles was measured in the same manner as in Experiment 5.

<Reference experiment 5-2>
In Experiment 4, a microneedle was produced by omitting the composite of the gel composition and the molding made of the porous polymer material. In other words, in this experiment, a microneedle made of only a porous polymer material was produced. The mechanical strength of the produced microneedles was measured in the same manner as in Experiment 5.

<Results>
The measurement results of Experiment 5, Reference Experiment 5-1 and Reference Experiment 5-2 are shown graphically in FIG.
In the graph, "Naked MNs", "PES MNs" and "Hybrid MSs" are the results from Reference Experiment 5-1, Reference Experiment 5-2 and Experiment 5, respectively. From the graph, Experiment 5 showed a higher maximum stress than Reference Experiments 5-1 and 5-2. It was suggested that the

(Evaluation 6) Skin penetration of polymer porous/gel composition composite microneedles <Experiment 6>
A polymer porous/gel composition composite microneedle prepared in the same manner as in Experiment 4 was applied to the skin of a mouse for 1 minute, and trypan blue staining was performed to visualize skin penetration.

<Results>
FIG. 8 shows a photograph of the mouse skin surface after application of the polymer porous/gel composition composite microneedles. Microneedle-derived holes were confirmed on the mouse skin surface by trypan blue staining. From this, it was confirmed that the polymer porous/gel composition composite microneedles have excellent skin-penetrating properties.

(Evaluation 7) Drug release property of polymer porous/gel composition composite microneedle <Experiment 7>
100 μL of FITC-labeled insulin solution was added to polymer porous/gel composition composite microneedles prepared in the same manner as in Experiment 4, and allowed to stand at room temperature for 24 hours. After that, the polymer porous/gel composition composite microneedle to which the FITC-labeled insulin solution was added was placed in a low glucose solution (100 mg/dL) or a high glucose solution (500 mg/dL), and the released FITC-labeled insulin was , using a fluorometer (manufactured by Thermo Fisher Scientific, product number: NanoDrop3300).

<Results>
The detection results are shown graphically in FIG. From the graph it can be seen that higher concentrations of FITC-labeled insulin were detected in the high glucose solution than in the low glucose solution. This suggested that the polymer porous/gel composition composite microneedles could carry insulin while maintaining gel properties.

10 Microneedle 100 Base Part 110 Needle 200 Microneedle Mold 201 Cavity

Claims (13)

a base;
at least one needle supported by the base;
has
The base portion and the needle each include a porous body made of a polymer, and a gel composition capable of supporting a drug and permeable to the drug, which is filled in voids of the porous body. ,
Drug delivery device. 2. The drug delivery device of claim 1, wherein said polymer is polyethersulfone. 3. The drug delivery device according to claim 2, wherein the porous body is coated with a polymer having hydrophilic groups. 4. The drug delivery device according to claim 3, wherein the polymer with hydrophilic groups is polyacrylic acid. The drug delivery device according to any one of claims 1 to 4, wherein the gel composition is a gel composition containing a copolymer containing a phenylboronic acid-based monomer unit. 1. A method of making a drug delivery device having a base and at least one needle supported by said base, comprising:
a step of molding a porous body made of a polymer using a mold having cavities corresponding to the base portion and the needle;
a step of filling a void portion of the porous body with a gel composition capable of supporting a chemical solution and having permeability for the chemical solution;
A method of manufacturing a drug delivery device comprising: the polymer is polyethersulfone,
The step of molding the porous body includes:
preparing a polyethersulfone solution by dissolving the polyethersulfone in an organic solvent;
adding benzene to the polyethersulfone solution;
phase-separating the benzene-added polyethersulfone solution;
including,
7. A method of manufacturing a drug delivery device according to claim 6. 8. The method of manufacturing a drug delivery device according to claim 7, wherein the step of preparing the polyethersulfone solution includes preparing the polyethersulfone solution so that the polyethersulfone concentration is 15-25 wt %. The method for manufacturing a drug delivery device according to claim 7 or 8, wherein the step of adding benzene includes adding the benzene so that the benzene concentration is 20 to 35 vol%. The method for manufacturing the drug delivery device according to any one of claims 6 to 9, further comprising coating the porous body with a polymer having a hydrophilic group before the step of filling the gel composition. . The step of coating the porous body includes:
irradiating the porous body with plasma;
adding acrylic acid to the porous body after plasma irradiation;
graft polymerizing the acrylic acid;
11. A method of manufacturing a drug delivery device according to claim 10, comprising: The step of filling the gel composition,
preparing a pre-gel solution in which a monomer mixture containing monomers constituting the gel composition is dissolved in a solvent;
adding the pre-gel solution to the porous body such that the pre-gel solution fills the voids of the porous body;
After adding the pre-gel solution to the porous body, polymerizing the monomer mixture;
The method for manufacturing the drug solution delivery device according to any one of claims 6 to 11, comprising 13. The method of manufacturing a drug delivery device according to claim 12, wherein the monomer mixture contains a phenylboronic acid-based monomer.

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