JP2005021678A - Pad base for percutaneous admistration and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pad base for percutaneous admistration capable of administering the medicine to the inside of the skin without vibration, developed by solving the problem of a conventional micropatch method wherein a solid needle is punctured in the skin and vibrated by a vibrator to admister a medicine to the inside of the skin while widening the gap between the needle and the skin and a manufacturing method capable of easily obtaining the pad base. <P>SOLUTION: In the manufacturing method for the pad base for percutaneous admistration, one end of a metal fine wire is vertically immersed in a synthetic resin raw material solution to bond the synthetic resin raw material solution to the periphery of the metal fine wire and this coated metal fine wire is drawn out after the synthetic resin raw material solution is cured. By this method, the pad base wherein tubular fine needles 1, of which the outer walls are made thick toward the skirts thereof, are vertically provided to a pasting base material 2 on the surface on the side of the skin thereof is obtained. The medicine in the hollow part 3 of each of the fine needles 1 is injected in the skin to be percataneously administered to the inside of the skin. Each of the fine needles 1 is hardly broken because widened toward the skirt thereof. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a transdermal dosing pad base used when a drug acting on a living body is transdermally administered into a living body, a method for producing the same, and an injection needle. The pad base is a part responsible for transdermal administration of a drug in a transdermal drug pad, and the transdermal drug pad is a pad base covered with, for example, an adhesive sheet from the side opposite to the skin. Therefore, in use, the pad base surface should be affixed to the skin.

  The skin functions as a barrier that protects the body, and prevents foreign substances from entering the living body. In particular, the outer stratum corneum, which is in direct contact with foreign matter, plays a major role as a barrier. However, the gastrointestinal tract is the same in terms of direct contact with foreign matter in vitro, but the digestive tract has no barrier such as a stratum corneum like skin. It is composed of nutrient-absorbing cells that have the function of being taken up by the two, and in this respect both are greatly different.

  On the other hand, the skin also has a function of discharging out of the living body (insensitive steaming function). Thus, the skin is not a simple protective film, but is considered to be an organ having a regulating function through which a substance permeates. .

  By the way, as a method for administering a drug to a living body, intramuscular injection, oral administration, and administration from the colon by a suppository are known. However, paying attention to the skin function as described above, administration from the skin is important. Skin absorption methods have been proposed. According to this percutaneous absorption method, it is almost painless, administration of medication is easy and side effects are not likely to occur, and the quality of life (QOL) of patients is expected to improve dramatically from the convenience of administration form. . As transdermal drugs, nitroglycerin, isosorbide nitrate, estradiol, tulobuterol, nicotine, clonidine, scopolamine, fentanyl, lidocaine and the like have been developed.

  With the advent of the above-mentioned percutaneous absorption-type preparations, research on transdermal absorption of drugs has progressed, and it has been found that there are many drugs that cannot be absorbed percutaneously in any way.

  Therefore, electroporation (Electoroporation) used for gene transfer into cells as a next-generation transdermal absorption method, rather than simply spreading and absorbing drugs from the stratum corneum into the skin as before. This method is used to introduce a drug by momentarily opening a microscopic perforation in the skin, or a method such as iontophoresis (Iontophoreiss) to introduce a drug ionized using electrophoresis technology to the skin. Also, administration methods combining these were devised.

  In addition, as with electroporation, a micropatch (MicroPatch) method has been proposed in which a pad with countless small needles is applied to the skin and a drug is injected from the puncture site as a means to open a fine perforation in the skin. .

  The micropatch method will be described in more detail. The transdermal dosage pad used in this micropatch method includes a plurality of 10-50 μm thick and short solid needles (made of silicon, metal, or plastic) pointed in a pyramid shape, It is equipped with a reservoir that is a chemical solution tank. In use, the needle is stabbed into the skin, and the contact surface between the needle and the skin is shaken with a vibration device (100 MHz to 2000 MHz) to widen the gap. The drug solution from the reservoir is allowed to enter the skin from a very fine perforation site on the skin (for example, see Non-Patent Document 1).

  Insulin, morphine, α-interferon, parathyroid hormone, erythropoietin, etc. have been developed as drugs to be administered by this micropatch method (Altea Therapeutics, Atlanta, USA). Insulin has already been the first clinical trial. Research into practical use is in progress.

  As another administration method, a needleless injection method, which is in contrast to the above method, has also been proposed. Specifically, the injection solution is administered subcutaneously by applying high pressure to the injection solution, or the drug powder is directly used as a high-pressure gas. A method of using a high-pressure gas that is injected subcutaneously over the skin is proposed, and some of them have already been commercialized.

Although any of these administration methods has advantages and disadvantages, the micropatch method is an excellent method from the viewpoint that anyone does not need a dedicated device and can be used easily.
U.S. Patent No. 6,183,434

  As described above, the micropatch method punctures with a solid needle and injects a drug from the gap between the needle and the skin. Therefore, it is necessary to vibrate with a vibration device for this injection. Therefore, a simpler method is desired.

  Therefore, the present invention has been made paying attention to the circumstances as described above, and the purpose thereof is to provide a pad base for transdermal administration that can administer a drug into the skin without vibration in the micropatch method. It is to provide. Another object of the present invention is to provide a production method capable of easily obtaining such a pad base for transdermal administration.

  Moreover, in order to relieve pain in a normal injection needle, a thin one is required, but there is a concern that it will break if it is too thin, and if it breaks, there is a concern that it will remain in the skin and adversely affect the living body.

  Accordingly, an object of the present invention is to provide an injection needle that does not easily break the needle.

  The pad base for transdermal administration according to the present invention has a fine needle provided upright on the skin side surface of a base material for application to the skin, the fine needle being a hollow tubular body, and its outer wall is the application base. It is characterized by being thickened to spread out toward the material.

  Since the fine needle itself is a hollow tube as described above, the pad for transdermal administration having this pad base was affixed to the skin by filling the hollow portion with the administration medicine (liquid medicine, etc.). At this time, the fine needle pierces the skin, and the medicine in the fine needle is administered into the skin. In addition, since the fine needles are thickened to spread the hem, they are difficult to break, and there is little concern that the fine needles remain in the skin. As described above, according to the pad base for transdermal administration of the present invention, administration can be performed without performing the operation of shaking the contact surface between the needle and the skin to widen the gap as in the prior art. Is unnecessary, and the drug can be administered more easily.

  Then, the method according to the present invention capable of manufacturing the above-mentioned pad base for percutaneous administration comprises the step of immersing one end of a fine metal wire in a synthetic resin raw material solution in the vertical direction and surrounding the synthetic wire around the fine metal wire. After the resin raw material solution is adhered and the synthetic resin raw material solution is cured, the metal fine wire is drawn to form the tubular fine needle. Further, there may be a plurality of the fine metal wires, and a plurality of the fine needles may be formed. The “curing” includes a case where the solvent of the synthetic resin raw material solution evaporates and the raw material resin component is precipitated, a case where the liquid raw material resin component is reacted and solidified.

  Explaining the mechanism by which the fine needles that are thickened with the above method are obtained by the above method, for example, as a synthetic resin raw material solution, a synthetic resin is used that is dissolved in a solvent, and one end of a metal fine wire is attached to this. When the solvent is evaporated while immersed in the vertical direction, the liquid level of the raw material solution in the portion without the metal fine wire gradually decreases, and the raw material solution adheres to the original liquid level around the metal fine wire. It will remain, and will exhibit the shape of a hem spreading toward the said liquid level which fell. The synthetic resin cured by the evaporation of the solvent in this manner forms a tubular body (fine needle) having a hem spreading with the fine metal wire portion serving as a hole.

  When a thermoplastic resin is used as the synthetic resin, one end of the fine metal wire is immersed in the synthetic resin raw material solution that is a heat-melted resin, and the liquid level of the synthetic resin raw material solution is lowered at the portion of the fine metal wire. The shape is raised and cured in this state. In addition, as a method of attaching the synthetic resin raw material solution so that it rises around the metal thin wire, the method of raising the metal thin wire once deeply immersed in the synthetic resin raw material solution, the state where one end of the metal thin wire is immersed There are a method of vibrating the synthetic resin raw material solution to convey the solution to the surface of the fine metal wire, and a method of adjusting the viscosity of the synthetic resin raw material solution appropriately so that the solution naturally propagates. Then, after the resin is cured, when the metal fine wire is pulled out, the portion of the metal fine wire becomes a hole to form a tubular body (fine needle) that spreads at the bottom.

  Examples of the synthetic resin material in the synthetic resin raw material solution include polypropylene, polyurethane, aramid, fluorine-containing polyimide, and the like, and biodegradable resins are particularly preferable.

  If the fine needle is made of a biodegradable resin, the fine needle made of the biodegradable resin is decomposed in vivo even if the tip of the fine needle is missing and remains in the skin. And has little adverse effect on the living body. In addition, if the fine needle is made of a biodegradable resin and a drug to be administered, it is broken down in the living body even if it is lacking and remains in the skin as described above, and has almost no adverse effect on the living body. The drug is also administered when the fine needle itself is unwound (decomposes) by the living body.

  Biodegradable resins include polylactic acid, polyethylene succinate, polybutylene succinate adipate, polybutylene succinate carbonate, polycaprolactone, polyester amide, polyester carbonate, polyvinyl alcohol, polyhydroxybutyrate, mantriose, cellulose, acetic acid Cellulose, collagen, and mixtures thereof are recommended, and polylactic acid or a copolymer of lactic acid and glycolic acid is particularly preferable. For example, a lactic acid / glycolic acid copolymer has already been used as a pharmaceutical, and is hydrolyzed into lactic acid in the tissue and gradually disappears.

  Further, in the case of polylactic acid having a molecular weight of 100,000 to 500,000, the amount attached to the metal fine wire is appropriate in production, and the metal fine wire is easily drawn after the resin is cured, Since the quality of the finished film (tubular material) is also excellent, it is more preferable.

  As the synthetic resin raw material solution, a biodegradable resin added with an administration drug may be used.

  Further, the injection needle according to the present invention is characterized in that the outer wall of the needle portion of the injection needle is thickened so as to spread toward the connection portion with the syringe in the injection needle. Thus, since the outer wall of the needle portion is thickened so as to spread out, it is difficult to break, and there is little fear of remaining in the skin.

  According to the pad base for transdermal administration according to the present invention, since the fine needle is thickened so as to spread out at the bottom, it is difficult to break, and therefore there is little concern that the fine needle remains in the skin. Since the hollow portion of the fine needle can be filled with a medicine, the fine needle filled with the medicine can be punctured into the skin so that the medicine can be administered into the skin without using a vibration device or the like. is there.

  Further, according to the method for manufacturing a pad base for transdermal administration according to the present invention, the tubular fine needle is erected from the sticking base material, and the outer wall of the fine needle is widened toward the sticking base material. Can be easily manufactured.

  According to the injection needle according to the present invention, the needle portion is difficult to break, and there is little fear of remaining in the skin.

  Hereinafter, the pad base for transdermal administration and the method for producing the same according to the present invention will be described in detail with reference to the drawings showing examples. However, the present invention is not limited to the illustrated examples. The present invention can be implemented with appropriate modifications within a range that can be adapted to the gist of the present invention, and all of them are included in the technical scope of the present invention.

  First, an example of a method for producing a pad base for transdermal administration according to the present invention will be described.

  As a synthetic resin raw material solution, for example, a polylactic acid dissolved in chloroform is prepared. The raw material solution is poured into a shallow metal bat, and one ends of a plurality of fine metal wires are respectively immersed in the vertical direction so that the raw material solution adheres to the peripheral surface of the fine metal wires. Chloroform, which is a solvent, is removed by drying, thereby lowering the surface of the raw material solution with the raw material solution adhering to the peripheral surface of the fine metal wire, thereby curing polylactic acid. Thereafter, a thin metal wire is drawn from the cured polylactic acid and taken out from the metal bat.

  As a result, a transdermal drug pad base as shown in FIG. 2 [(a): sectional view showing a transdermal drug pad base according to an embodiment of the present invention, (b): top view of the pad base] can get. The obtained pad base has a large number of fine needles 1 erected on the base material 2, and the microneedles 1 have a bottomed cylindrical shape with an open skin surface, and the outer wall faces the base material 2. And thickened to spread the hem. In addition, the upper side in Fig.2 (a) becomes a sticking surface to skin. In FIG. 2, the fine needle 1 and the sticking base material 2 are drawn separately, but as can be understood from the above-described manufacturing method, these are manufactured by integral molding.

  Examples of the transdermal medication pad include a pad base covered with an adhesive sheet from the anti-skin surface side (the lower side in FIG. 2 (a)) of the pad base. Alternatively, there is a case where the drug is fed from the hollow portion and administered as in the case of injection by piercing the needle by pressing it against the skin without an adhesive.

  In use, the hollow portion 3 of the fine needle 1 is filled in advance so that the drug solution is sucked out from the drug solution container, and a transdermal drug pad provided with this pad base is applied to the skin. By applying pressure to the sticking substrate 2, the fine needle 1 is punctured into the living body, and the drug solution in the hollow portion 3 is injected into the living body from the tip of the fine needle 1. The drug to be filled in the tube (in the hollow portion 3) of the fine needle 1 may be liquid, cream, gel, suspension, or powder, and is not suitable for transdermal administration. Except for drugs, there is no substantial limitation.

  Further, the depth of the hollow portion 3 of the fine needle 1 may be deeper than shown in FIG. Specifically, as shown in (b) of FIG. 1 [sectional view for explaining the shape of the hollow portion of the fine needle], the height H of the fine needle 1 and the depth L of the hollow portion 3 are the same [ H = L (full hollow type: TYPE 2)], as shown in FIG. 1C, the hollow portion 3 reaches the middle of the thickness h of the pasting base material 2 [H <L <H + h (semi-penetrating type: TYPE 3). )], As shown in FIG. 1 (d), the hollow portion 3 may penetrate the sticking substrate 2 [H + h = L (full penetration type: TYPE4)]. In FIG. 2, as shown in FIG. 1A, the depth L of the hollow portion 3 is shallower than the height H of the fine needle 1 [H> L (semi-hollow type: TYPE 1)]. . However, it is difficult to define a boundary that clearly separates the fine needle 1 and the support portion 2 in the case where the fine needle 1 and the sticking base material 2 are formed by integral molding, but here, the curvature is infinite, that is, a planar portion is formed. The part below this plane as the boundary surface is referred to as the sticking substrate 2, and the part standing from here is referred to as the fine needle 1.

  The depth of the hollow portion 3 of each microneedle 1 in a pad base having a plurality of microneedles 1 may be the same as shown in FIG. 2 or may be combined with different depths. Moreover, like the above TYPE4 (FIG. 1 (d)), in the case where the hollow portion 3 penetrates the sticking base material 2 from the fine needle 1, a medicine container is provided on the anti-skin side surface of the sticking base material 2, The medicine may be supplied from here to continuously administer the medicine.

  As in the case of the injection needle according to one embodiment of the present invention, similarly to the above, one end of a metal fine wire is immersed in the vertical direction in the synthetic resin raw material solution to adhere the synthetic resin raw material solution around the metal thin wire. After the synthetic resin raw material solution is cured, the metal fine wire is preferably drawn to form a tubular needle portion. The outer wall of the needle portion of the injection needle obtained in this manner is widened.

<Examples 1-3>
As a mold material for forming fine needles, a stainless steel wire (metal fine wire) with a length of about 30 mm and a thickness of φ280 μm is inserted into a rubber plate in the form of a grid at 5 mm length and 6 width by 2 mm intervals. Was made. Next, the tip of the stainless steel wire of the above-mentioned mold material is brought into vertical contact with the bottom of the stainless steel dish, and 3 ml of a polylactic acid chloroform solution (synthetic resin raw material solution) having a molecular weight of 101,700 is placed on the stainless steel dish. Injected. This was allowed to stand, and chloroform was evaporated by natural drying. With this, the liquid level of the solution was lowered with the chloroform solution of polylactic acid adhering to the peripheral surface of the stainless steel wire to solidify the polylactic acid. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The polylactic acid concentration in the chloroform solution of polylactic acid was adjusted to 5, 6, and 7 wt%, and the pad bases obtained for each were designated as Examples 1, 2, and 3, respectively.

  All of Examples 1 to 3 described above were a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG.

<Examples 4 to 6>
Using the same fine needle mold as in Examples 1 to 3, the tip of the stainless steel wire of the mold was brought into contact with the bottom of the stainless steel dish vertically. Into the stainless steel dish, 3 ml of a polylactic acid chloroform solution having a molecular weight of 67,400 was poured and allowed to stand to dry naturally to solidify the polylactic acid. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The concentration of polylactic acid in the chloroform solution of polylactic acid was adjusted to 10, 11, and 12 wt%, and the pad bases obtained for each were designated as Examples 4, 5, and 6.

  Each of Examples 4 to 6 described above was a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG.

<Examples 7 to 9>
Using the same fine needle mold as in Examples 1 to 3, the tip of the stainless steel wire of the mold was brought into contact with the bottom of the stainless steel dish vertically. 3 ml of a polylactic acid chloroform solution having a molecular weight of 258,700 was poured into the stainless steel dish and allowed to stand and air-dried to solidify the polylactic acid. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The polylactic acid concentrations in the polylactic acid chloroform solution were adjusted to 1, 2, and 3 wt%, and the pad bases obtained for each were designated as Examples 7, 8, and 9, respectively.

  Each of Examples 7 to 9 described above was a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG.

<Examples 10 to 12>
The same fine needle mold material as in Examples 1 to 3 was used, and the tip of the stainless steel wire of the mold material was arranged so as to stand vertically with respect to the bottom while leaving a little space from the bottom surface of the stainless steel dish. To a chloroform solution of polylactic acid (molecular weight PLA) having a molecular weight of 101,700, 0.1 part by weight of polylactic acid (low molecular weight PLA) having a molecular weight of 10,000 is added, and 3 ml of the mixed solution is added to the stainless steel. The polylactic acid was solidified by pouring into a dish so that one end of the stainless steel wire was immersed and allowing to stand and air dry. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The concentration of polylactic acid in the chloroform solution of the above high molecular weight PLA was adjusted to 5, 6, and 7 wt%, and the pad bases obtained for each were designated as Examples 10, 11, and 12, respectively.

  Each of Examples 10 to 12 described above was a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG. A micrograph (magnification 40) of the fine needle in Example 10 obtained is shown in FIG. Moreover, the schematic diagram is shown in FIG.3 (b).

<Examples 13 to 15>
The same fine needle mold as in Examples 1 to 3 was used, and the tip of the stainless steel wire of the mold was arranged to stand vertically with a gap from the bottom of the stainless steel dish. To a chloroform solution of polylactic acid (high molecular weight PLA) having a molecular weight of 67,400, 0.1 part by weight of polylactic acid (low molecular weight PLA) having a molecular weight of 10,000 is added, and 3 ml of the mixed solution is added to the stainless steel. The polylactic acid was solidified by pouring into a dish and dipping one end of a stainless steel wire in the solution, allowing it to rise on the surface of the stainless steel wire, and allowing it to stand and air dry. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The concentrations of polylactic acid in the high molecular weight PLA chloroform solution were adjusted to 10, 11, and 12 wt%, and the pad bases obtained for the concentrations were designated as Examples 13, 14, and 15, respectively.

  Each of Examples 13 to 15 described above was a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG.

<Examples 16 to 18>
The same fine needle mold as in Examples 1 to 3 was used, and the tip of the stainless steel wire of the mold was arranged to stand vertically with a gap from the bottom of the stainless steel dish. To a chloroform solution of polylactic acid (high molecular weight PLA) having a molecular weight of 258,700, 0.1 part by weight of polylactic acid (low molecular weight PLA) having a molecular weight of 10,000 is added, and 3 ml of the mixed solution is added to the stainless steel. The solution was poured into a plate and immersed on one end of a stainless steel wire, and the solution was placed on a stainless steel wire and allowed to stand and air-dried to solidify polylactic acid. Thereafter, the stainless steel wire was pulled out and removed from the stainless steel dish to obtain a pad base for transdermal administration. The polylactic acid concentrations in the chloroform solution of the above high molecular weight PLA were adjusted to 1, 2, and 3 wt%, and the pad bases obtained for each were designated as Examples 16, 17, and 18, respectively.

  Each of Examples 16 to 18 described above was a pad base for transdermal administration having a plurality of fine needles having a shape as shown in FIG.

  The above Examples 1 to 9 are summarized in Table 1, and the above Examples 10 to 18 are summarized in Table 2, and the adhesion of a polylactic acid chloroform solution (synthetic resin raw material solution) to a stainless steel wire (metal thin wire); And each evaluation about the ease of drawing | extracting of the stainless steel wire after polylactic acid hardening is described.

  As described above, a pad base for transdermal administration having fine needles as shown in FIGS. 1C and 1D in Examples 1 to 18 can be obtained. In addition, since the pad bases (the pasting base material and the fine needles) of Examples 1 to 18 are all composed of polylactic acid, even if the fine needles break and remain in the skin during use, they are expected to be biodegraded. Is done.

  As can be seen from Tables 1 and 2 above, Examples 1 to 3 and 10 to 12 among the above examples from the viewpoint of the amount of polylactic acid adhered to the stainless steel wire, the film quality, and the ease of drawing the stainless steel wire. Is more preferable.

It is sectional drawing for demonstrating the shape of the hollow part of the fine needle in the pad base for transdermal medication which concerns on this invention. It is a figure showing the pad base for percutaneous medication concerning one embodiment of the present invention. (A) is the microscope picture of the fine needle in the pad base for transdermal administration of Example 10, (b) is the schematic diagram.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Fine needle 2 Base material 3 Hollow part

Claims (6)

A method for producing a pad base for transdermal administration in which fine needles are erected on the skin side surface of a base material for application to the skin,
One end of a fine metal wire is vertically immersed in the synthetic resin raw material solution to adhere the synthetic resin raw material solution around the metal fine wire, and after the synthetic resin raw material solution is cured, the metal fine wire is pulled out. A method for producing a transdermal dosing pad base, characterized in that the tubular fine needle is formed.   The method for producing a pad base for transdermal administration according to claim 1, wherein a plurality of the fine metal wires are formed and a plurality of the fine needles are formed. A pad base for transdermal administration in which fine needles are erected on the side of the skin of the base material for application to the skin,
A pad base for transdermal administration, wherein the fine needle is a hollow tubular body, and its outer wall is thickened so as to spread toward the pasting base material.   The pad base for transdermal administration according to claim 3, wherein the fine needle is composed of a biodegradable resin, or a biodegradable resin and a drug to be administered.   The pad base for transdermal administration according to claim 4, wherein the biodegradable resin is polylactic acid or a copolymer of lactic acid and glycolic acid.   An injection needle characterized in that the outer wall of the needle portion of the injection needle is thickened so as to spread toward the connection portion of the injection needle with the syringe.

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