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EP-3398645-B1 - METHOD FOR PREPARING A MICROSTRUCTURE FOR PERCUTANEOUS ABSORPTION

EP3398645B1EP 3398645 B1EP3398645 B1EP 3398645B1EP-3398645-B1

Inventors

  • KWON, SOON CHANG
  • PARK, SANG JIN
  • KIM, JAE SOO

Dates

Publication Date
20260513
Application Date
20161222

Claims (10)

  1. A method for manufacturing a microstructure, the method comprising: (a) supplying a biodegradable polymer or an adhesive into a micro-mold; (b) injecting the biodegradable polymer or adhesive into a hole of the micro-mold; (c) drying the biodegradable polymer or adhesive; and (d) separating the dried biodegradable polymer or adhesive from the micro-mold to form a microstructure, wherein the microstructure has a triple structure comprising a cone at a distal tip, a first truncated cone positioned below the cone, and a second truncated cone positioned below the first truncated cone, wherein aspect ratio (w:h), configured of the diameter (w) of the bottom surface and the height (h) of the microstructure, is 1:5 to 1:2, characterized in that a plurality of microstructures are arranged in a hexagonal shape, and in that the injecting is carried out by applying a pressure of not less than 80 kPa and not more than 101 kPa inside the micro-mold for 10-30 minutes.
  2. The method of claim 1, wherein step (c) is carried out (i) at room temperature for 36-60 hours, (ii) at 40-60°C for 5-16 hours, or (iii) at 60-80°C for 2-4 hours.
  3. The method of claim 1, wherein, in step (a), the solid content of the biodegradable polymer is 1-30 %(w/v) on the basis of the entire composition of the microstructure.
  4. The method of claim 1, wherein the plurality of microstructures are arranged at intervals (p) of 250-1500 µm.
  5. The method of claim 1, wherein the biocompatible polymer is at least one polymer selected from the group consisting of hyaluronic acid (HA), carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), pullulan polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, ethylene-vinyl acetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefin, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxypropyl cellulose (HPC), cyclodextrin, copolymers of monomers forming these polymers, and cellulose.
  6. The method of claim 1, wherein the adhesive is at least one material selected from the group consisting of silicone, polyurethane, hyaluronic acid, a physical adhesive (Gecko), a polyacrylic material, ethylcellulose, hydroxymethyl cellulose, ethylene vinyl acetate, and polyisobutylene.
  7. The method of claim 1, wherein the height of the microstructure is 80-1500 µm.
  8. The method of claim 1, wherein the diameter (t) of the distal tip is 2-20 µm.
  9. The method of claim 1, wherein the microstructure further comprises a metal, a polymer, or an adhesive.
  10. The method of claim 1, wherein the microstructure further comprises a drug, a cosmetic ingredient, or a combination thereof other than the biodegradable polymer and the adhesive.

Description

Technical Field The present application relates to a microstructure for transdermal absorption and a method for manufacturing the same. More specifically, the present invention relates to a method for manufacturing of a biodegradable microstructure including a biocompatible polymer or an adhesive. Background Art The drug delivery system (DDS) corresponds to a series of technologies that deliver drugs to target sites, such as cells or tissues, by controlling the absorption and release of the drugs, and encompasses a transdermal penetration type delivery system enabling local applications of drugs, in addition to a general oral absorption. There have been continuous studies about efficient and safe administration of pharmaceutical substances, such as drugs. Of these, the injection therapy has problems in that administration is cumbersome, some patient may be painful, and there is a limit in controlling the drug release rate besides the temporary injection of drugs. In order to supplement these disadvantages of the injection therapy, studies have been advanced on microstructures (microneedles) having a much smaller size and causing less pain compared with syringe needles, and studies have been being conducted in several fields of drug delivery, blood collection, biosensors, skin care, and the like. As a method for manufacturing microneedles of the prior art, there are U.S. Pat. No. 6,334,856, "MICRONEEDLE DEVICES AND METHODS OF MANUFACTURE AND USE THEREOF" and Korea Patent Registration No. 10-0793615, "BIODEGRADABLE SOLID MICRONEEDLES AND MANUFACTURING METHOD THEREFOR". The above patents disclose that microneedles are manufactured by injecting a biodegradable viscous material in a micro-mold manufactured using a curable polymer, followed by drying and de-molding (molding technique), or microneedles are manufactured by coating a biodegradable viscous material for forming biodegradable solid microneedles, drawing and drying the coated biodegradable viscous material on a frame that is patterned in pillars, and then cutting the drawn biodegradable viscous material (drawing technique). However, the biodegradable polymer microstructures manufactured by the above methods of the prior art have a problem in that the microstructures are bent or crushed due to relatively low mechanical strength when penetrating the skin. Especially, when a polymer derivative with high elasticity is used as a raw material to manufacture microstructures through a molding technique or a drawing technique, structures with desired shapes are uniformly not produced and the mechanical strength of the microstructure necessary for skin penetration cannot be satisfied. EP 2,664,323A discloses an array of microprotrusions which are formed by providing a mold with cavities corresponding to the negative of the microprotrusions, casting atop the mold a first solution comprising a biocompatible material and a solvent, removing the solvent, casting a second solution atop the first cast solution, removing the solvent from the second solution, and demolding the resulting array from the mold. JP 4-985025B discloses a microneedle chip aggregate which is constituted by arranging a large number of microneedle chips. By arranging a large number the microneedle chips, the microneedle chips can be formed into a sheet/tape shape to be produced/kept/transported. The hyaluronic acid used in the present invention is a biodegradable polymer, and in the structures manufactured using the hyaluronic acid, the smaller molecular weight facilitates the formation of structures and induces lower viscosity, and the larger molecular weight induces higher mechanical strength but higher viscosity. Due to these characteristics, low-molecular weight hyaluronic acid is used as a raw material for the microstructure. However, microstructures using low-molecular weight hyaluronic acid may be easily broken or bent when penetrating the skin. Meanwhile, carboxymethyl cellulose (CMC), which is a cellulose derivative, is mainly used as a thickening agent in pharmacology, and is a biodegradable polymer with various molecular weights. Meanwhile, the microstructures of the prior art are not suitable for skin penetration since the angle at the tip portion is too large, or even though the angle of the tip portion has a range that is easy to penetrate skin, the diameter is continuously enlarged from the tip portion toward the bottom surface, and thus only a very limited percent of the height of the entire structure is allowed to penetrate the skin due to the resistance of the skin per se. A structure with a low aspect ratio (w:h, h/w) is difficult to penetrate the skin, and a structure with a high aspect ratio is easy to penetrate the skin, but may be broken or bent due to relatively low mechanical strength when penetrating the skin. Moreover, a microstructure of the prior art has a structure such that it is hard for the microstructure to overcome the elasticity and restoring force of the skin p