Patent Application
20090234301
1. Field of the Invention
The present invention relates to a microneedle, a method for producing the microneedle, a microneedle array using the microneedle and a method for producing the microneedle array.
2. Description of the Related Art
Conventionally, for administration of a drug through the skin, the mucous membrane, or a like biological surface, usually, a liquid or gel drug is often applied. Although an application of a drug on a biological surface is a noninvasive method, the applied drug is easily removed by sweating, external contact, and the like. Further, when the administration is continued for a long period of time, a safety problem such as dermopathy may be caused. Further, when the subject drug has a large molecular weight, is water soluble, etc., such a drug is hardly absorbed into the body even if applied on a biological surface, and percutaneous administration thereof has thus been difficult.
In order to solve these problems, a microneedle array having a large number of 50 μm to 100 μm high microneedles provided on a substrate has been proposed (see, e.g., JP-T-2005-503194) (the term “JP-T” as used herein means a published Japanese translation of PCT patent Application 2005-503194).
Although the method of administering a drug directly into the body tissue using a microneedle array having a desired drug applied to the surface of microneedles is not a perfectly noninvasive method, this seldom stimulates the sense of pain and is less invasive to the patient because microneedles have a small diameter and only reach the dermis or the like which is a region at a relatively shallow depth in the body tissue. Further, the drug can be administered in the state that the microneedles run through the epidermis and the horny layer, and this accordingly gives the advantage that drugs heretofore difficult to percutaneously administrate can also be administered.
The above microneedles are excellent in the puncturing ability as they are formed on a silicon single crystal substrate, however, there is a problem in that when the microneedles break, the residues remain in the skin.
An example of producing a needle shape with a degradable polymer, such as polylactic acid, has also been proposed. In such a case, however, because of the high aspect ratio, air in the tip of a needle-forming portion of a mold remains to cause a problem in the shape reproducibility.
The present invention was accomplished in view of the above background. An object thereof is to provide a production method for molding a microneedle and a microneedle array which do not obtain blunt needle tips at the time of molding, do not undergo hydrolysis, thus maintaining a stable molecular weight, do not suffer from coloring, and have excellent shape stability; and also to provide products therefrom.
An aspect of the invention is a method for producing a microneedle, comprising feeding a resin fluid to a forming mold having a needle-forming portion with an opening diameter of 50 to 200 μm and a depth of 100 to 500 μm, for example a depth of 100 to 450 μm, charging the fed resin fluid into the needle-forming portion, and cooling and solidifying the charged resin fluid. The feeding, the charging, and the cooling and solidification are performed under reduced pressure or vacuum. Another aspect of the invention is a method for producing a microneedle, comprising feeding resin to a forming mold having a needle-forming portion with an opening diameter of 50 to 200 μm and a depth of 100 to 500 μm, for example a depth of 100 to 450 μm, fluidizing the fed resin to give a resin fluid, charging the resin fluid into the needle-forming portion, and cooling and solidifying the charged resin fluid, the feeding, the heating and melting, the charging, and the cooling and solidification being performed under reduced pressure or vacuum.
A microneedle array according to a first embodiment of the invention is explained with reference to
As shown in
The needle portions 4 and the sheet portion 5 are made of medical-grade polylactic acid (PLA), a biocompatible material. The needle portions 4 have a bottom diameter φ of 50 μm to 200 μm and a height h of 100 μm to 500 μm. In consideration of the balance between the degree of penetration of a drug applied to the surface and the degree of invasion due to the stimulation of the sense of pain, it is more preferable that the bottom diameter φ be within the range of 80 μm to 120 μm, and the height h be within the range of 200 μm to 400 μm. Further, as in
A method for producing the microneedle array 1 is explained with reference to
First, on the conveyor belt 12, a mold 17 for forming the microneedle 2 is installed. As shown in
Next, a solution or a cutting block of medical-grade PLA 19, a product of Birmingham Polymers Inc., is fed onto the mold 17 from the nozzle 14. At this time, the temperature of the heater 13a is set at the melting point (hereinafter referred to as “Tm”) of PLA 19 or higher.
As moving on the conveyor belt 12, the mold 17 is heated with the heater through the belt, whereby the PLA 19 is heated to the temperature range (° C.) expressed by the equation (1) below and is spread out over the entire surface of the mold 17 to obtain the shape of the large number of needle portions 4 integrated at the sheet portion 5 (microneedle formation process). At this time, the temperature of the heater 13b is set at the Tm of PLA.
Tm+X (X is 2 or more and less than 50, and preferably 2 or more and less than 10) (1)
Subsequently, the mold 17 moves on the conveyor belt 12, and a substrate 3 is installed on the mold 17 from the substrate feeder 15. Although the substrate 3 is made of PMMA as mentioned above, a copolymer of butyl acrylate and methacrylate or the like is also suitable. Further, other plastic materials are also usable. In addition, alumina and metal, which are porous materials, may also be used. At this time, the temperature of the heater 13c is set at a temperature higher than the Tm of PLA by about 20° C., and is adjusted to be in the temperature range of the equation (1) when PLA reaches the heater 13c.
At least the processes from the feeding of PLA onto the mold to the formation of microneedle are to be performed under reduced pressure or vacuum.
The integrated substrate 3 and mold 17 are pressurized by the roll 16 and thus closely adhered, and, as shown in
Subsequently, while moving on the conveyor belt 12, the temperature of the substrate 3 and the mold 17 are gradually lowered to about 70° C. by the heaters 13d and 13e. After cooling, the substrate 3 integrated with the microneedle 2 is removed from the mold 17, and is punched into a desired shape, thereby giving the microneedle array 1 of this embodiment. To the surface of the needle portions 4 of the obtained microneedle array 1, insulin, estradiol, or a like hormone drug, nitroglycerin, or a like desired drug is applied in the form of a spray or a gel to form a drug layer. Thus, the microneedle array 1 can be used in transcutaneous administration of the drug.
According to the microneedle array 1 of the invention, the needle portions 4 are sufficiently adhered to the substrate 3 made of PMMA at the sheet portion 5, and thus have sufficient strength to resist plastic deformation even under a load of 5 kgf/cm2 or less. Accordingly, when puncturing through the skin or a like biological surface, the needle portions satisfactorily reach the body tissue without plastic deformation. Further, the needle portions do not break in the body tissue. Even if they break, PLA that forms the needle portions 4 is decomposed in the body and disappears, and this thus causes no harm to the patient.
Further, because only the microneedle 2 is made of medical-grade PLA, as compared with the case where the entire microneedle array (i.e., the microneedle 2 and the substrate 3) is made of medical-grade PLA, the amount of the expensive medical-grade PLA to be used can be reduced by about 50% to about 80%. Accordingly, in comparison with conventional microneedle arrays, the manufacturing cost can be greatly reduced, while maintaining comparable performance.
Further, because the substrate 3 is made of flexible PMMA, it sufficiently follows the change in skin shape, and there is no need to worry about the separation of the microneedle 2 from the substrate 3, etc.
The microneedle 2 of this embodiment may have slots 21 formed on the surface thereof, as shown in
Further, as shown in
Accordingly, this allows further extension of the drug releasing time. The drug layer 22 may be provided inside the substrate 3, as shown in
Although in the method for producing a microneedle array of this embodiment, a method in which production is performed while the mold and the substrate are moved has been explained, a microneedle array may be produced by heating of a fixed mold, feeding PLA or a like biocompatible material thereto from micro-nozzles provided above the mold in correspondence with needle-forming portions to form a microneedle, and thermally fusing it with a substrate.
Next, a second embodiment of the invention is explained with reference to
A method for producing the microneedle array 31 of this embodiment is explained with reference to
First, a substrate 3 made of PC is installed on the conveyor belt 42. Next, medical-grade PLA 19, which has been heated to the melting temperature or higher, is fed to the surface of the first roll 43 from the nozzle 45. At this time, the first roll 43 has also been heated with a non-illustrated heater or the like to the PLA 19 melting temperature or higher. As the first roll 43 rotates, melted PLA 19 approaches the conveyor belt 42. During this process, the knife edge 46 removes excessive PLA 19 from the surface of the first roll 43. For this reason, the sheet portion 5 that is present in the microneedle 2 in the first embodiment is not formed in this embodiment.
When the substrate 3 moves on the conveyor belt 42, and is inserted between the first roll 43 and the second roll 44, PLA 19 melted on the surface of the first roll 43 is transferred to the surface of the substrate 3 to form microneedles 34, and, at the same time, the substrate 3 and the microneedles 34 are thermally fused. At this time, the second roll 44 is heated by a non-illustrated heater or the like to a temperature lower than the PLA 19 melting temperature by about 20° C.
After passing between the first roll 43 and the second rolls 44, the substrate 3 is naturally cooled by ambient air while moving on the conveyor belt 42. The thus-obtained substrate 3 having the microneedles 34 is punched into a desired shape and size, thereby giving the microneedle array 31 of this embodiment.
According to the microneedle array 31 of this embodiment, because the sheet portion 5 that is present in the first embodiment is not present in the microneedle 32, the amount of the medical-grade PLA to be used can be further reduced, thereby enabling reduction of manufacturing cost.
Although the microneedles 34 of this embodiment have a flat bottom, the microneedles 34 may each have an anchor portion 35 that digs into the substrate as shown in
Further, in the method for producing a microneedle array of this embodiment, although explained is the case where the substrate 3 is in the form of a sheet, the substrate may also be a continuous film. Further, by adjusting the distance between the knife edge 46 and the first roll 43, it is also possible to form a microneedle provided with a sheet portion, as in the first embodiment.
Next, a third embodiment of the invention is explained with reference to
A method for producing the microneedle array 51 of this embodiment is explained with reference to
The mold 63 is formed by machining a mold produced by almost the same method as that of the first embodiment into a desired shape and size, however, unlike the above mold 17, the mold 63 has a large number of protruding portions 65 formed thereon for forming the communicating holes 56 in the sheet portion 55.
First, as shown in
Tg+Y<T<Tm+50 (Tg is the glass transition temperature, and Y is 2 or more and less than 50, and preferably 20 or more) (2)
Subsequently, as shown in
After the press plate 64 is raised, the mold 63 is removed from the outer frame 62. Then, as shown in
According to the microneedle array 51 of this embodiment, because of the communicating holes 56 formed in the sheet portion 55, the drug is released through the communicating holes 56 without being influenced by the behavior of the microneedles 54 in the body tissue, and thus, stably released into the body tissue through the holes formed in the biological surface by the puncture of the microneedles 54. Accordingly, drug release can be controlled more stably.
When the amount of charged drug is not large, it is also possible to form the drug layer 57 only in the communicating holes 56, as shown in
Although examples of a two-layer structure of a microneedle and a substrate have been explained above, the invention may be structured so that, as shown in
A method for producing a microneedle array of this embodiment is explained with reference to
According to the microneedle array 64 of this embodiment, because the microneedle array 64 is formed of a single layer, the number of manufacturing processes can be reduced, and the productivity can be improved.
As shown in the third embodiment, it is also possible to provide the mold with protruding portions to form communicating holes in the microneedle.
Embodiments of the invention have been explained thus far. However, the technical scope of the invention is not limited to the above embodiments, and various modifications may be made without deviating from the spirit of the invention.
For example, although the microneedle is made of medical-grade PLA in the above embodiments, insofar as the medical grade is satisfied, PLGA, chitin, chitosan, hyaluronic acid, collagen, glucose, cellulose, magnesium alloy, and other biocompatible materials may also be used. Further, the microneedle may also be made of a mixed material of the above biocompatible materials and the drug. In such a case, the drug is released by dissolution of the microneedle in the body tissue.
Further, although the substrate is made of PMMA in the above embodiments, as mentioned above, a copolymer of butyl acrylate and butyl methacrylate polycarbonate, polyurethane, polypropylene, and other resin materials, metals, ceramics, and the like may also be used. In addition, PLA and like materials of a grade lower than the medical grade are also usable. In view of the conformability with the change in shape of the biological surface, the substrate is preferably made of a highly expansible resin material. Further, it is also possible that a plurality of layers made of the above various materials be integrated to form a substrate.
Further, although the substrate and the microneedle are adhered by thermal fusion in the above embodiments, they may be adhered by plasma welding. Further, although the substrate and the microneedle are formed by compression molding in the above embodiment, a common plastic molding technique, such as injection molding or the like, may be used instead to form the substrate and the microneedle.
According to the invention, molding is performed under reduced pressure or vacuum, and therefore, a sharp microneedle tip can be obtained. Further, since hydrolysis reaction is suppressed, reduction in the molecular weight is made less prone to occur and maintaining the strength of the microneedle is made possible. In addition, the suppression of reactions can avoid the problem of coloring.
While vacuuming, PLA on a mold was heated to 210° C. The PLA was charged into needle-forming portions, and then cooled and solidified at normal temperature over 1 hour, thereby molding a microneedle array. For the molding of microneedles, the apparatus shown in
The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and the tip portions of all the microneedles on the microneedle array had the same shape.
PLA on a mold was heated to 210° C. without vacuuming. The PLA was charged into needle-forming portions, and then cooled and solidified at normal temperature over 1 hour, thereby molding a microneedle array. For the molding of microneedles, the apparatus shown in
The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, rounded tip portions were observed in 80 needles out of every 800. The microneedles varied in shape and height.
Chitin was dissolved in chloroform to give a resin fluid. The resin fluid was fed onto the mold, and vacuuming was performed while increasing the temperature to 60° C. After 1 hour, at the time when the organic solvent chloroform evaporated, the temperature was lowered to normal temperature, whereby only a chitin molded product was left on the mold. A chitin microneedle array was thus obtained. For the molding of microneedles, the apparatus shown in
The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and all the microneedle tip portions on the microneedle array had the same shape.
Chitin was dissolved in chloroform to give a resin fluid. The resin fluid was fed onto the mold, and charged into the mold while increasing the mold temperature to 60° C.
After 1 hour, the temperature was lowered to normal temperature, thereby molding a microneedle array. For the molding of the microneedle array, the apparatus shown in
The obtained microneedle array contained the organic solvent chloroform remaining therein, and thus was unusable for puncturing through a biological surface.
Chitosan, a protein preparation, and water were mixed to give a resin fluid. The resin fluid was fed onto the mold, and the mold was heated to 40° C. Vacuuming was performed, and the mold was maintained at 40° C. and left to stand for 1 hour in this state. Subsequently, the temperature was lowered to normal temperature, whereby only a chitosan molded product was left on the mold. A chitosan microneedle array was thus obtained. For the molding of the microneedle array, the apparatus shown in
The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and all the microneedle tip portions on the microneedle array had the same shape.
Chitosan, a protein preparation, and water were mixed to give a resin fluid. The resin fluid was fed onto the mold. The mold was heated to 40° C. and left to stand for 10 hours in this state. After 10 hours, the mold temperature was lowered to normal temperature, and molding was thus performed. For the molding of microneedles, the apparatus shown in
In Comparative Example 3, solidification into the microneedle array shape took time ten times longer than time required when vacuuming was included.
The invention can be used as a microneedle array for medical applications.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-315371 | Nov 2006 | JP | national |
This is a Continuation Application of PCT Application No. PCT/JP2007/072555, filed Nov. 21, 2007. PCT Application No. PCT/JP2007/072555 is based on and claims the benefit of priority from the Japanese Patent Application number 2006-315371, filed on Nov. 22, 2006; the entire contents of which are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/JP2007/072555 | Nov 2007 | US |
| Child | 12453783 | US |
