JP2011224308A - Microneedle welding method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a microneedle array holding medicine only on the tip end of the microneedle, and to provide a manufacturing method of the microneedle array.SOLUTION: The microneedle array holding medicine only on the tip end of the microneedle is manufactured by a microneedle welding method with features of: (a) making the microneedle array using a biodegradable polymer as the material; (b) making a solution of the medicine to be attached on the tip end of the microneedle array; (c) dipping the tip end of the microneedle array into the solution; (d) drawing up the microneedle array from the solution; and (e) drying the microneedle array. By this method, when the medicine solution is made to be aqueous solution, the biodegradable polymer is made to be water soluble, and the biodegradable polymer other than the medicine is solved into high concentration to heighten the viscosity in aqueous solution, since the attached medicine is integrally made with the microneedle, the medicine is prevented from peeling off alone upon stabbing.

Description

  The present invention relates to a microneedle welding method for imparting a modifying effect and / or a functional effect to a skin surface layer and / or a skin stratum corneum.

  Oral administration and transdermal administration are often used as methods for administering a drug into a human body. Injection is a typical transdermal method of administration. However, injection is an unacceptable technique for many people who must bother the hands of specialists such as doctors and nurses, can be painful, and can also be infected with AIDS or hepatitis B. . On the other hand, a transdermal administration method using a microneedle array without causing pain has recently attracted attention (Non-Patent Document 1).

During the transdermal administration of a drug, the stratum corneum acts as a barrier for drug permeation, and simply applying the drug to the skin surface does not necessarily provide sufficient permeability. On the other hand, by perforating the stratum corneum using a fine needle, that is, a microneedle, the drug administration efficiency can be significantly improved over the coating method. A microneedle array is a large number of microneedles integrated on a substrate. Microneedle patches are products that are easy to use by adding various tapes to the microneedle array, such as adhesive tape for attaching the microneedle array to the skin and a cover sheet for maintaining sterility until use. .
Here, the tape refers to a film in which an adhesive is applied.

Initially, metal or silicon was used as a material for the microneedle. A method of piercing the skin with a stainless needle, allowing a drug solution to flow through it and absorbing the drug from the hole (Patent Document 1), or a method of coating the drug on the surface of the stainless needle and inserting the drug ( Patent Document 2) has been proposed. Furthermore, it has also been proposed to inject a drug solution simply by using a hollow microneedle in which the injection needle is miniaturized (Patent Document 3).
However, the chemical solution casting method has poor drug uptake efficiency or sterilization, and the coating method peels off the coated drug at the time of insertion and the drug uptake efficiency is low, and the microinjection needle method has a complicated structure There were disadvantages such as.

If a microneedle is made using a substance that disappears by metabolism in the body, such as sugar, as a material of the microneedle, no accident will occur even if the needle breaks and remains in the skin. Moreover, if the drug is contained in the carbohydrate, the inserted microneedle is dissolved in the body, so that the drug can be easily administered intracutaneously or subcutaneously (Patent Document 4). .
In particular, when a microneedle made of a biosoluble polymer material such as hyaluronic acid or collagen is applied to the skin, moisture in the skin diffuses into the needle portion, and the needle portion inserted into the skin swells and then dissolves. Anti-wrinkle action is expressed by diffusion of hyaluronic acid and collagen into the skin due to dissolution of the needle, or drugs and valuable substances previously dissolved in the needle are released into the skin (Patent Documents 5 and 6).

  A microneedle array made of a biosoluble polymer substance is often manufactured using a template (Patent Document 5). A microneedle pattern is formed by a lithography method using a photosensitive resin and then transferred to create a mold having a microneedle-forming recess. A microneedle array can be obtained by casting a microneedle material onto this mold and then heating to evaporate the moisture, and then separating the solidified material from the mold.

  Some drugs contained in the microneedle array are very expensive or only a small amount can be obtained. When such a precious drug is contained in a material and a microneedle array is prepared by a conventional method, the drug is contained not only in the microneedle part but also in the substrate part. When this microneedle array is inserted into the skin, the drug contained in the microneedle part is taken into the body and diffuses, but the drug present in the substrate part is discarded without being used, and the utilization efficiency of expensive drugs is low. Result.

  Several attempts to efficiently use expensive drugs are already known. In addition to the method of coating the microneedle surface (Patent Document 2), which is also used for metal microneedles, the method of attaching a drug to the tip of the microneedle (Patent Document 7) or the microneedle is centrifuged while it is soft A method of collecting a drug at the needle tip (Patent Document 8) has been reported. The method of Patent Document 7 for attaching the drug to the tip is characterized in that the drug is heated to about 100 ° C. and dissolved to adhere to the tip of the microneedle. This Patent Document 7 also teaches that the sharpness of the tip of the microneedle can be maintained if it is slowly pulled up from a highly viscous solution.

Japanese Patent Laid-Open No. 3-151982 JP 2008-029710 A Special Table 2002-517300 JP 2003-238347 A JP 2009-238772 A JP 2010-029634 A JP 2006-346127 A Special table 2009-507573

Gon Ei, Fumio Kamiyama “The Path to Microneedle Product”, Pharmacology, The Pharmaceutical Society of Japan, September 2009, Vol. 69, No. 4, p. 272-276.

The problem to be solved by the present invention is to solve the problems of the prior art and provide a new method for effectively using expensive drugs.
Although the method for attaching the drug to the tip of the microneedle is simple, if the drug is heated to 100 ° C. or higher, an expensive and valuable drug is often thermally decomposed. Therefore, warming should be avoided when attaching the drug to the microneedle tip.
Further, in the conventional method in which the drug simply adheres to the tip of the microneedle, it is necessary to solve the problem that the adhered part is broken or peeled off when the microneedle is inserted into the skin, and the drug is not sufficiently taken up.

The microneedle welding method according to the present invention made to solve the above problems is as follows.
a) Create a microneedle array using biodegradable polymer as a raw material,
b) preparing a drug solution to be attached to the tip of the microneedle array;
c) immersing the tip of the microneedle array in the solution;
d) pulling the microneedle array out of the solution;
e) drying the microneedle array;
A microneedle array having a drug attached to the tip is manufactured.

In order to efficiently attach the drug to the tip of the microneedle array, the microneedle array material and the drug solution are preferably compatible.
Therefore, if the drug is made water-soluble, a water-soluble biodegradable polymer is used as a raw material, and the biodegradable polymer is previously contained in an aqueous solution of the drug, the drug is integrated with the biodegradable polymer. Is taken into the tip of the microneedle. This is because the tip portion is partially dissolved when the tip portion of the microneedle is immersed in the drug solution. If integrated in this way, the drug is completely taken into the body without being peeled off when the microneedle is inserted.
Here, “integral” means that there is no clear boundary surface between the tip of the original microneedle and the newly attached portion. At the border, the drug appears to have a concentration gradient. A method characterized by such integration is called a welding method.

  At this time, the concentration of the biodegradable polymer in the aqueous solution is preferably increased to increase the viscosity of the aqueous solution. If the microneedle is lowered from the upper part of the aqueous solution and its tip is immersed in the aqueous solution and then slowly pulled up, the viscous solution pulls the thread, and the sharpness of the tip of the microneedle is maintained even after drying.

The drug referred to in the present invention includes all substances that cause some effect when taken into the body.
When the drug dissolves only in the organic solvent, a microneedle can be prepared using a biodegradable polymer that dissolves in the organic solvent, and the same procedure can be used.

  It is appropriate to use this method when an expensive drug or a drug that is difficult to obtain in large quantities is to be transdermally administered to the human body. For inexpensive drugs and drugs that can be obtained in large quantities, the drug may be mixed with the microneedle material from the beginning and a microneedle may be prepared from the mixed material according to a conventional method.

  Examples of drugs suitable for the purpose of the present invention include bioactive peptides and derivatives thereof, nucleic acids, oligonucleotides, various antigen proteins, bacteria, virus fragments, and the like. Examples of the physiologically active peptides and derivatives thereof include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1 → 34), insulin, secretin, oxytocin, angiotensin, β-endorphin, glucagon, vasopressin, Somatostatin, gastrin, luteinizing hormone releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone releasing hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone, prolactin, interferon, interleukin, G- Examples include CSF, glutathione peroxidase, superoxide dismutase, desmopressin, somatomedin, endothelin, and salts thereof.Examples of the antigen protein include HBs surface antigen and HBe antigen.

  As the microneedle material of the present invention, water-soluble polymer substances such as hyaluronic acid, collagen, dextrin, dextran, and chondroitin are suitable for water-soluble drugs. It is also possible to improve the physical properties of microneedles by blending these polymers with low-molecular substances. If various tapes such as adhesive tapes and bar sheets are added to the microneedle array manufactured as described above to make the product easy to use, a microneedle patch having a drug only at the tip is obtained.

In this method, since the drug is dissolved in a solvent and adhered to the tip of the microneedle, it is not necessary to heat the drug. Many useful drugs decompose by heating at about 100 ° C., and it has been difficult to apply the conventional method, but this method has no weak point.
If the microneedle tip is immersed in a solution containing both the drug and the microneedle material, and the drug is taken into the microneedle, the interface between the original part and the newly attached part disappears, and the microneedle is integrated. It becomes the target. When integrated, only the drug does not fall off when the microneedle is inserted into the skin.
By holding an expensive and precious drug only at the tip portion of the microneedle, the waste of the drug can be prevented and the drug can be used economically and effectively.

Schematic of the microneedle welding method of the present invention.

  A schematic diagram of the microneedle welding method of the present invention is shown in FIG. Since FIG. 1 is a schematic diagram, only one microneedle is described, but actually a microneedle array having a large number of microneedles is used.

FIG. 1A shows a state before the microneedle is brought into contact with the aqueous drug solution. (B) has shown the state which dropped the microneedle and immersed the microneedle in the drug aqueous solution. Although not clear in the figure, the surface of the tip of the microneedle is dissolved by the solution. (C) has shown the state at the time of starting pulling up microneedle slowly. When the drug solution has a high viscosity, the thread is pulled in this way. (D) has shown the state which pulled up further and cut the thread | yarn. If the microneedle in this state is dried, the microneedle is obtained by integrally attaching the drug to the tip.
Although it is not clear in this figure, in (c) and (d), the boundary part between a microneedle front-end | tip part and an adhesion part mixes, and there is no clear boundary surface.

  Next, examples of the present invention will be described in detail with reference to the drawings. However, the present invention is not limited to the examples.

  The microneedle array of the present invention was manufactured using a template. After the frustoconical microneedle pattern is formed by the lithography method of irradiating the photosensitive resin with light, the frustoconical microneedle forming recess is formed by transferring the frustoconical microneedle pattern by electroforming. Used molds.

The concave portions for forming microneedles have a truncated cone shape with a root diameter of 0.16 mm, a tip diameter of 0.04 mm, and a depth of 0.8 m, and are arranged in a grid at intervals of 0.6 mm, and 144 per cm ^2. Individually formed. The concave portion for forming the microneedle is formed in a circular shape having a diameter of 30 mm.

Hyaluronic acid aqueous solution layer is a high molecular weight hyaluronic acid having a weight average molecular weight of 100,000 (from Kibun Food Chemical Co., Ltd., trade name “FUH-SU”, derived from culture) 13.5 parts by weight and a low molecular weight hyaluron having a weight average molecular weight of 10,000. An aqueous hyaluronic acid solution (I solution) obtained by dissolving 1.5 parts by weight of an acid (trade name “Hyaloligo”, culture origin) by 85 parts by weight of water was cast on a mold.
Next, heating was performed to evaporate the moisture in the hyaluronic acid aqueous solution layer, and then it was peeled from the mold. Next, a 1% liquid paraffin / ethyl alcohol solution was sprayed on the microneedles, and then the ethyl alcohol was evaporated to obtain a microneedle array.

  Separately, bovine insulin (manufactured by Nacalai Tesque) was dissolved in a hydrochloric acid aqueous solution having a pH of 2.5 to obtain a 0.006 g / ml aqueous solution. 1 ml of the obtained aqueous solution was added to the above 1 solution to obtain an insulin / hyaluronic acid aqueous solution.

  The tip portion of the microneedle array was immersed in the obtained insulin / hyaluronic acid aqueous solution for 5 seconds and then taken out and air-dried to obtain a tip portion insulin-concentrated microneedle array.

  Microscopic observation of the obtained microneedle array revealed that the tip of the needle was swollen as shown in FIG. 1- (d), but it was observed that the needle and insulin-containing hyaluronic acid were completely integrated.

  When the obtained microneedle array was lightly pressed against the abdomen of the hairless rat, the microneedle 4 was easily pierced into the skin, and after 60 minutes, the intracutaneous portion was dissolved in the skin and did not retain its shape. When the peeled substrate was observed with a microscope, the microneedle was 100% dissolved and did not remain at all.

  The microneedle patch according to the present invention is expected to be widely used in the fields of medicine and beauty.

Claims (7)

a) Create a microneedle array using biodegradable polymer as a raw material,
b) preparing a drug solution to be attached to the tip of the microneedle array;
c) immersing the tip of the microneedle array in the solution;
d) pulling the microneedle array out of the solution;
e) drying the microneedle array;
A microneedle welding method for manufacturing a microneedle array with a drug attached to the tip. 2. The microneedle welding method according to claim 1, wherein the tip of the microneedle array and the drug solution have compatibility.   The microneedle welding method according to claim 1 or 2, wherein the drug solution is an aqueous solution, and the biodegradable polymer is water-soluble.   The drug solution is an aqueous solution, and the biodegradable polymer is water-soluble. In addition to the drug, the biodegradable polymer is dissolved in a high concentration in the aqueous solution, and the viscosity of the aqueous solution is adjusted. The microneedle welding method according to claim 1, 2, or 3, wherein the height is kept high. The microneedle welding method according to claim 1, 2, 3, or 4, wherein the needle length of the microneedle has a length of 100 to 1,000 microns.   The drug is selected from PTH, interferon, insulin, various antigenic proteins, and virus fragments, and the biodegradable polymer is selected from hyaluronic acid, dextrin, dextran, polyvinylpyrrolidone, polyvinyl alcohol, and carboxymethylcellulose. The microneedle welding method according to any one of claims 1, 2, 3, 4, 5 and 6, characterized in that it is a seed or more.   A microneedle array, wherein a mixture of a microneedle material and a drug is integrally welded to a tip of a microneedle.