Patent Application
20110152792
The present invention relates to a microneedle array made of a water-soluble thread-forming polymer as the base made on a porous platform, in which a target substance is held in the acral portion of the base, and a production method thereof.
Microneedles are under study as a pharmaceutical technology to improve the bioavailability of drugs having a very low bioavailability even for transdermal administration. Microneedles are fine needles that do not give pain even when inserted into the skin. As the materials for microneedles, in addition to the metals used as the conventional injection needles, microneedles made of materials such as silicon have been developed (Non-Patent Documents 1 and 2).
These microneedle arrays have the same hollow structure as injection needles, and are used for the injection of drug solution. Furthermore, self-dissolving type microneedle arrays having biosoluble substance as the base are also developed. In addition, self-dissolving type microneedles having a biosoluble substance as a base are also being developed. Where the target substance is held in the base and is administered into the epiderm followed by the self-dissolution of the base when it is inserted into the skin. For example, Patent Documents 1 to 3 and 40 to 43 disclose a self-dissolving type microneedles made of maltose as the base. There are also many known patents relating to devices and instruments for injecting a drug via microneedles, as well as the materials, shape, production method and the like of microneedles (Patent Documents 4 and 7 to 50).
The present inventor has filed a patent application directed to a microneedle having a base made of a water-soluble thread-forming polymer as a microneedle for overcoming the drawbacks of the above-described microneedles having a base made from maltose (Patent Document 5). That invention is directed to increasing the skin permeability of drugs which would not be expected to have a sufficient effect under conventional transdermal administration due to their low skin permeability, like polymeric drugs such as recombinant protein drugs, vaccines, and genetic DNA and water-soluble drugs having poor/low transdermal absorbability.
Here, the expression “water-soluble drugs having poor/low transdermal absorbability” refers to drugs which exhibit a bioavailability value of several percent or less during transdermal absorption. More specifically, this expression refers to aminoglycoside antibiotics, peptide antibiotics such as vancomycin, and vitamin C and the like.
Further, the present inventor has filed a patent application directed to an industrial production method of a microneedle array having a water-soluble thread-forming polymeric substance such as chondroitin sulfate, dextran, hyaluronic acid and the like as a base (Patent Document 6). In addition, the present inventor has also invented a multi-layer microneedle (Patent Document 51).
In addition, the present inventor invented a method for producing a microneedle array having, for example, 100 microneedles having a length of about 500 μm and a bottom portion diameter of about 300 μm in 10 rows×10 columns on a one square centimeter chip by using a polymer such as a vaccine antibody and a peptide/protein drug such as insulin as a target substance, and chondroitin sulfate, dextran, hyaluronic acid and the like as a base (Patent Document 52).
Non-Patent Document 1: D. K. Armini and C. Lui, Microfabrication technology for polycaprolactone, a biodegradable polymer, Journal of Micromechanics and Microengineering, 2000, Vol. 10, p.80-84
Non-Patent Document 2: M. R. Prausnitz, Microneedles for transdermal drug delivery, Advanced Drug Delivery Reviews, 2004, Vol. 56, p.581-587
A microneedle array was prepared by filling into a female mold produced using a silicone resin and the like a target substance as a viscous solution or a suspension using a base, and then using a substrate made from paper and the like to dry and cure the filled solution or suspension. However, to develop a microneedle array as a pharmaceutical preparation, steps such as a sterilization step or the like must be carried out. Therefore, there is a need for a substrate which has better productivity and is suited to pharmaceutical production processes such as sterilization.
Since such a microneedle array is formed with tiny needles densely packed together, when pulling the microneedle array out from the female mold during production, although the needles are adhered to the substrate, some of them can remain stuck to the female mold. For a microneedle array having in its acral portion a target substance to be inserted into a human body as a pharmaceutical, the drug dose included per microneedle array unit, specifically, the number of needles, needs to be correctly determined. Therefore, there has been the problem that when pulling out from the female mold, if the predetermined number of needles is not formed on the substrate of the microneedle array, that microneedle array cannot be used as a pharmaceutical preparation.
Further, there has also been the problem that when pulling out from the female mold, if the substrate is not removed vertically from the female mold, the microneedles can break.
It is an object of the present invention to provide a substrate suitable for a pharmaceutical preparation when producing a microneedle array containing a target substance. Especially, it is an object of the present invention to provide a substrate which can be released with the microneedles firmly fixed thereto when pulling out from a female mold, a microneedle array using this substrate, and a production method thereof.
As a result of extensive research to resolve the above-described problems, the present inventor was successful in producing a microneedle array by using a water-soluble thread-forming polymer as a base, and using a substrate which is suited for, after inserting a target substance and the base into a female mold for microneedle production, efficiently drying and curing while the target substance and the base are still inserted in the female mold and being released from the female mold, thereby completing the present invention.
More specifically, the substrate for a microneedle array according to the present invention having at least one flat face is characterized by
having a protrusion on an opposite face of the flat face, and
being formed from a porous material which has a porosity of which direction is directed from the flat face to the opposite face of the flat face.
Further, the substrate is characterized by including a water-insoluble fibrous polymer and an adhesive polymer.
In addition, the fibrous polymer includes at least one of crystalline cellulose, ethyl cellulose, cellulose acetate and derivatives thereof, and chitin and derivatives thereof.
Still further, the adhesive polymeric substance includes at least one of a carboxy vinyl polymer, a carboxymethyl cellulose sodium, a polyvinyl alcohol, and a hydroxy propyl cellulose.
Moreover, the porous material may be a porous polymer resin. Further, this porous polymer resin includes at least one of polyethylene, poly(methyl methacrylate), polyvinyl chloride, acrylonitrile, chlorinated polyethylene-styrene, polyoxyethylene, and polypropylene. In addition, the porous material may be a porous metal.
Still further, the microneedle array according to the present invention is characterized by comprising:
any of the above-described porous substrates;
a protruding base portion made of a thread-forming polymer material which is fixed to the substrate; and
a target substance portion provided on a acral portion of the protruding base portion.
Moreover, a method for producing a microneedle array according to the present invention, comprises the steps of:
filling a target substance and the like into a female mold;
further filling a base into the female mold;
pressing a porous substrate against the female mold to dry and cure; and
peeling the female mold from the substrate.
When removing the base remaining on the surface of the female mold with a squeegee after filling the base into the female mold, the method may further comprise a step of coating a glue on the substrate before the step of pressing the substrate to dry and cure. Further, the glue may be coated on the side faces of the substrate in addition to the surface thereof.
The step of pressing the substrate against the female mold to dry and cure may be carried out under a reduced-pressure environment. Usually, the method is carried out under a room temperature to low-temperature environment.
A microneedle array serving as a pharmaceutical preparation has to be produced using a pharmaceutical additive or undergo sterilization and the like during the production process. If the substrate of the present invention is used, after filling a female mold for microneedle array production with a viscous base dense solution or viscous suspension including a target substance, the solution can be dried and cured while the substrate is still pressed against the female mold, and then it is peeled from the female mold. Consequently, a microneedle array can be efficiently produced.
Further, since the microneedle array is produced using a thread-forming polymer as a base or as a glue in a porous substrate, during drying and curing, the base of the thread-forming polymer diffuses into the porous substrate, so that the microneedles are solidly fixed to the substrate by an anchor effect. Consequently, when peeling the substrate from the female mold, the substrate can be pulled out with all of the needles still fixed to the substrate.
In addition, since a protrusion is provided on the rear face of the porous substrate, the surface area of the rear face increases, which makes the drying and curing easier. Moreover, by gripping the protrusion on the rear face of the porous substrate with a jig, the substrate can be vertically removed from the female mold. This allows breaking of the microneedles when peeling the substrate from the female mold to be avoided. Consequently, a microneedle array can be produced formed with all of the planned microneedles arranged on the substrate.
The substrate for a microneedle array used in the present invention is a water-insoluble porous substrate. Therefore, after a water-soluble thread-forming polymer base containing a target substance is filled to the female mold of the microneedle array, the substrate can be dried and cured while pressing the substrate against the female mold.
Further, the porous substrate used in the present invention may be formed by molding a water-insoluble material. In addition, a porous filter produced from a known polymer resin or metal may also be used. The porous substrate of the present invention used in the microneedle array can be reliably peeled from the female mold with the needles fixed to the substrate by an anchor effect as a result of diffusing and curing the base made of a thread-forming polymeric substance during drying in the substrate. Therefore, it is enough for the “porosity” of the substrate of the present invention to be at a level which allows a thread-forming polymer to diffusee and be dried.
Preferably, the water-insoluble material (also referred to as “water-insoluble polymer”) is a tablet produced using cellulose acetate, crystalline cellulose, ethyl cellulose, cellulose derivatives, and chitin and derivatives thereof. These substances may also be called a “ fibrous polymer”.
In addition, preferably, the porous polymer resin material is polyethylene, poly (methyl methacrylate), polyvinyl chloride, acrylonitrile-chlorinated polyethylene-styrene, polyoxyethylene, or polypropylene. In addition, the substrate of the present invention using a porous polymer may have been solidified to an extent that it has porosity by pressure molding of these polymers.
The shape of the substrate is not specifically limited, but a plate-shape having at least one flat face is preferred. This is because to adhere the microneedles, which were formed by flowing a substance into the female mold, to the flat face and remove them, a force is uniformly applied to all of the microneedles, so that no microneedles are left behind.
A protrusion is formed on a rear side of the flat face of the substrate of the present invention. The substrate pressed against the female mold has to be pulled out vertically upwards with respect to the female mold. This is because if the substrate is pulled out at an angle, the microneedles can bump into an edge of the concave portion of the female mold, and the needle portions can be damaged. Therefore, if a protrusion which can be gripped during removal is provided on the rear side of the substrate, the substrate can be easily pulled out from the female mold in a vertical direction.
Further, by forming a protrusion on the rear face of the substrate, the surface area of the rear face increases, so that drying and curing are easier when the substrate is pressed against the female mold.
The shape of the protrusion is not specifically limited. The protrusion may be formed only in the center of the substrate, or formed from one edge of the substrate to the other edge. Further, the protrusion may be formed by forming a concavity on the rear face of the substrate.
Preferably, the base made of a water-soluble thread-forming polymer is at least one substance selected from the group consisting of thread-forming polysaccharides, proteins, polyvinyl alcohols, carboxy vinyl polymers, and sodium polyacrylate. One kind of such a substance may be used, or a combination of a plurality of kinds may be used.
Preferably, the thread-forming polysaccharide is at least one substance selected from sodium chondroitin sulfate, dextran, dextran sulfate, hyaluronic acid, cyclodextrin, hydroxypropyl cellulose, alginic acid, agarose, pullulan, and glycogen, and derivatives thereof.
Preferably, the above-described thread-forming protein is at least one substance selected from serum albumin, serum a acidic glycoprotein, collagen, and gelatin, and derivatives thereof.
The method for holding the target substance in the base is not specifically limited, and various methods may be applied. For example, by including the target substance as a supermolecule in the base, the target substance may be inserted into the female mold while held in the base. Then, using the substrate of the present invention, the solvent may be absorbed and evaporated to dry and cure the base to produce a microneedle array. Another method is to charge a target substance which has been micropulverized and formulated in dissolved base, and fill the resultant product as a suspension into the female mold. Then, using the substrate of the present invention, the solvent may be absorbed and evaporated to dry and cure the base so that a microneedle array can be released.
Preferably, the target substance is an active substance used in drugs and cosmetics.
Preferably, such a drug can be classified as a vaccine antigen, a peptide, a protein, a nucleic acid, or a polysaccharide.
Target substances in the field of cosmetics include substances for the purpose of prevention and treatment of skin whitening, anti-aging and the like.
The length of the microneedles constituting the microneedle array is not specifically limited, but is preferably about 200 to 700 micrometers, and more preferably about 300 to 600 micrometers.
The area of the substrate is not specifically limited, but is preferably about 25 square centimeters, more preferably about 5.0 square centimeters, and even more preferably about 2.0 to 1.0 square centimeters. Further, the thickness is also not specifically limited, but is preferably about 5 millimeters, and more preferably about 3 to 1 millimeters.
Next, the method for producing the microneedle array according to the present invention will be described using the drawings. The microneedle array according to the present invention is formed by filling into a female mold having a needle shape, in order, a dense solution comprising a mixture of a target substance and a base, and a viscous base dense solution, then drying and curing, and transferring the dried and cured product to a substrate. It is preferred that the female mold is a material which is not soluble in a polar solvent. This is because the microneedle array according to the present invention is based on the assumption that it will be used in a pharmaceutical, and the target substance and the base often dissolve in a polar solvent (in particular water).
The target substance filled in the acral portions of the needles does not have to include a base. Further, the base to be mixed with the target substance does not have to be the same kind of base as that which is filled after the target substance and the like is filled. In addition, in the present specification, the target substance may be a substance which has a pharmacological effect, a complex thereof, or a mixture with a substance which can become a base.
It is preferred that the female mold is a material which can be easily worked. This is because, as described above, the microneedle array has a size of about a few hundred micrometers, and thus a concavity of such a size has to be formed in the female mold. Specifically, a polymer resin such as silicone and the like, and a rubber can be preferably employed. A needle-like concavity having a depth of about 500 μm and a surface opening diameter of about 300 μm is formed in the female mold. This is because the female mold is used for forming a tiny needle-like structure having a height of about 500 μm and a bottom-face diameter of about 300 μm.
Further, this concavity is built, for example, at a density of about 100 concavities of 10 rows×10 columns on a one square centimeter chip. Since a microneedle array is often provided as a sheet several square centimeters in size, the concavities at the above-described concavity density are formed for each surface area corresponding to one microneedle array unit . A region in which concavities are not formed may be formed around the periphery thereof. This is because many microneedle arrays can be produced with one female mold. In addition, this is because the number of needles to be planted per microneedle array can be determined, thereby allowing the amount of included target substance to be correctly set.
Next, the viscous solution of the thread-forming base is coated on the female mold. As illustrated in
In
Next, the whole structure is dried in a state in which the substrate 25 is pressed against the female mold 11 (
If the substrate 25 is dried while still being pressed against the female mold 11, the solvent is sucked upward from the surface of the porous substrate in contact with the female mold, and the solvent in the base and the target substance evaporates from the opposite face thereof. Specifically, the porosity of the substrate contributes to the drying and curing of the needles in the female mold. Further, as illustrated in
Further, a protrusion 24 formed on the rear face of the substrate increases the surface area of the rear face. Specifically, the protrusion 24 provides the substrate for a microneedle array with the property of easier drying and curing.
Further, a plurality of these protrusions may be formed on the rear face of the substrate. A plurality of protrusions increases the surface area of the rear face, so that the microneedles in the female mold can be easily dried and cured.
Further, the protrusion 24 on the rear face of the substrate can also be utilized as a gripping portion for lifting the substrate vertically upward when peeling the substrate from the female mold.
As illustrated in
The present invention will now be described using the following examples. However, these examples are in no way intended to limit the invention.
Cellulose acetate for a tablet was placed in a mortar of a single punch tableting machine, and a tablet substrate having a diameter of 1.5 cm was produced at a pressing force of about 10 kN. A resin mold having, per square centimeter block, a hundred to several hundred inverted cone-shaped pores with a depth of about 500 microns and an opening diameter of about 300 microns was prepared as a female mold. Further, degassed purified water was charged into ovalbumin serving as a model antigen, hyaluronic acid, and evans blue to produce a viscous dense solution. Then, this viscous dense solution was coated onto the holes of the female mold.
Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force. Further, purified water was added to sodium chondroitin sulfate to prepare a viscous dense solution. This viscous dense solution was coated on the female mold, and the cellulose acetate substrate produced by tableting machine was then covered thereon. The whole female mold was rotated using the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be removed while stuck to the substrate, so that a microneedle array could be obtained.
Crystalline cellulose was placed in a single punch tableting machine, and a tablet substrate having a diameter of 1.5 cm was produced at a pressing force of about 10 kN. Then, in the same manner as in Example 1, a viscous dense solution was prepared by dissolving ovalbumin serving as a model antigen, sodium chondroitin sulfate C, and evans blue in purified water, and this viscous dense solution was coated onto the holes of the female mold. Residual matter on the female mold was removed. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
Purified water was added to hyaluronic acid to prepare a viscous solution. This viscous solution was coated on the female mold, and the substrate produced by tableting was covered thereon. The whole female mold was rotated while applying centrifugal force with the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be peeled off while stuck to the substrate, so that a microneedle array was obtained.
Chitin was placed in a single punch tableting machine, and a tablet substrate having a diameter of 1.5 cm was produced at a pressing force of about 12 kN. Then, in the same manner as in Example 2, a viscous dense solution containing ovalbumin serving as a model antigen was coated onto the holes of the female mold. Residual matter on the female mold was removed. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
The sodium chondroitin sulfate dense solution used in Example 1 was coated on the female mold, and the substrate was covered thereon. The whole female mold was rotated while applying centrifugal force with the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be peeled off while stuck to the substrate, so that a microneedle array was obtained.
A square filter having a length of 1.5 cm and a width of 1.5 cm was produced by cutting a porous sheet made of polyethylene. Degassed purified water was added to insulin (produced by the inventor), evans blue, and sodium chondroitin sulfate, and the resultant solution was thoroughly dissolved and mixed to produce a viscous dense solution.
In the same manner as in Example 1, the viscous dense solution containing insulin was coated onto the holes of the female mold. Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force. The female mold was further centrifuged to perform drying and curing. A viscous dense solution produced by adding purified water to sodium chondroitin sulfate was coated on the female mold, and a porous substrate made of polyethylene was covered thereon. The whole female mold was rotated using the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array was obtained.
A square filter having a length of 1.5 cm and a width of 1.5 cm was produced by cutting a porous sheet made of poly (methyl methacrylate). Degassed purified water was added to human growth hormone, lissamine green, and sodium chondroitin sulfate, and the resultant solution was thoroughly dissolved and mixed to produce a viscous dense solution. In the same manner as in Example 1, the viscous dense solution containing human growth hormone was coated onto the holes of the female mold. Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
The female mold was further centrifuged to perform drying and curing. A viscous dense solution produced by adding purified water into sodium chondroitin sulfate was coated on the female mold, and a porous substrate made of poly(methyl methacrylate) was covered thereon. The whole female mold was rotated while applying centrifugal force with the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array was obtained.
A square filter having a length of 1.5 cm and a width of 1.5 cm was produced by cutting a porous sheet made of polyvinyl chloride. Desmopressin was dissolved in a phosphate buffer having a pH of 6.5. Further, evans blue and sodium chondroitin sulfate were added and dissolved to produce a viscous dense solution. In the same manner as in Example 1, the viscous dense solution containing desmopressin was coated onto the holes of the female mold. Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
The same viscous dense solution of sodium chondroitin sulfate that was used in Example 5 was coated on the female mold, and a porous substrate made of polyvinyl chloride was covered thereon. The whole female mold was rotated while applying centrifugal force with the table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array could be obtained.
A square filter having a length of 1.5 cm and a width of 1.5 cm was produced by cutting a porous sheet made of a chlorinated polyethylene-styrene resin. An erythropoietin injection (trade name: Espo, 24,000 IU/mL, Kyowa Hakko Kirin Co., Ltd.) and degassed purified water were added to evans blue and high-molecular-weight dextran, and the resultant mixture was dissolved to produce a viscous dense solution. In the same manner as in Example 1, the viscous dense solution containing erythropoietin was coated onto the holes of the female mold. Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
Degassed purified water containing polyethylene glycol 400 in a 0.1% concentration was added to high-molecular-weight dextran to produce a viscous dense solution. This viscous dense solution was coated on the female mold, and a porous substrate made of chlorinated polyethylene-styrene resin was covered thereon. This structure was left overnight while pressing the porous substrate on the female mold to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array could be obtained.
In the same manner as in Example 1, a viscous dense solution produced by adding degassed purified water into ovalbumin used as a model antigen, hyaluronic acid, and evans blue was coated onto the holes of a female mold having, per square centimeter block, a hundred to several hundred inverted cone-shaped pores with a depth of about 500 microns and an opening diameter of about 300 microns. Residual matter on the female mold was removed. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force.
A dense solution produced by adding purified water to sodium chondroitin sulfate was coated on the female mold, and an acrylic plate having a thickness of 3 mm and a size of 1.5 cm×1.5 cm was covered thereon. The resultant structure was left for a whole day at room temperature which sandwiched with a clip. Alternatively, the whole female mold was rotated for 2 hours by a table-top centrifugal machine. However, in either case the drying and curing was insufficient. Although the acrylic sheet was peeled from the female mold, the microneedle array could not be released.
The experiment was carried out in the same manner as in Comparative Example 1, except that a sheet made of polypropylene having a thickness of 0.75 mm was used instead of the acrylic plate. However, similar to Comparative Example 1, when an attempt was made to release the microneedle array from the female mold, the microneedle array could not be released.
Comparing Examples 1 to 7 with Comparative Examples 1 and 2, when a non-porous substrate was used such as an acrylic plate or a polypropylene sheet, the needles could not be pulled out together with the substrate . This is thought to be because using a porous substrate allows the needles to be dried inside the female mold, and the thread-forming base diffuses the pores of the substrate, whereby the substrate and the needles are solidly bonded by the anchor effect.
Ethyl cellulose or cellulose acetate was placed in a mortar of a single punch tableting machine, and a tablet substrate having a diameter of 1.5 cm was produced at a pressing force of about 15 kN. Then, in the same manner as in Example 2, a viscous dense solution prepared by dissolving ovalbumin serving as a model antigen, sodium chondroitin sulfate, and evans blue in purified water was coated onto the holes of the female mold.
Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force. Purified water was added to sodium chondroitin sulfate to prepare a viscous dense solution (glue). This viscous dense solution was coated on the female mold, and the tablet substrate produced by tableting was covered thereon. The whole female mold was dried and cured using the table-top centrifugal machine. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array could be obtained.
However, as drying progressed, the peripheral portion of the tablet substrate warped.
A sodium chondroitin sulfate glue was coated also on the side faces of the substrate. A sample produced by coating glue on the side faces of a tablet substrate made of cellulose acetate or ethyl cellulose did not exhibit warping of a peripheral portion of the tablet substrate even when excessively dried.
Comparing Examples 8 and 9, it can be seen that by coating the glue which is to be coated on the substrate not only on the upper face but also on the side faces, the advantageous effect that warping of the finished microneedle array can be prevented is obtained.
Thus, coating a glue made from a thread-forming polymeric substance on the side faces of the substrate as well can be said to be a preferred method for avoiding substrate warping. However, if a glue made from a thread-forming polymer base is coated on the side faces of the tablet as well, this adds one step to the operation. The reason why the substrate warps and peels away from the surface is that the contraction force of the glue during drying is stronger than the binding force of the constituent materials of the substrate. Therefore, to more strongly bind the substrate constituent materials together during drying, the properties of a substrate produced by mixing a water-insoluble polymer and an adhesive polymer (also referred to as “adhesive polymeric substance”) were investigated. Here, the term “adhesive polymeric substance” includes substances categorized as binders for a pharmaceutical additive.
Specifically, a carboxy vinyl polymer (trade name: Hiviswako 103 (“Hiviswako” is a registered trademark of Wako Pure Chemical Industries, Ltd.)), carboxymethyl cellulose sodium (Wako Pure Chemical Industries, Ltd.), a polyvinyl alcohol (Nacalai Tesque Inc.), and hydroxy propyl cellulose (Nippon Soda Co., Ltd.), which are adhesive polymers, were mixed into cellulose acetate and ethyl cellulose, which are water-insoluble polymers, in various blending ratios. The resultant mixtures were tableted to produce a tablet-shaped substrate.
Cellulose acetate (AC), ethyl cellulose (EC), Hiviswako 103 (HV), carboxymethyl cellulose sodium (CMC-NA), polyvinyl alcohol (PVA), and hydroxy propyl cellulose (HPC) are respectively abbreviated as AC, EC, HV, CMC-NA, PVA, and HPC.
Chondroitin sulfate (CDR: Nacalai Tesque Inc.) and dextran (DEX: Nacalai Tesque Inc., polymer) were used as the glue. The glue was coated on one face only of a tablet substrate produced by applying pressure to the above-described materials. Then, microneedle arrays were produced using a resin female mold. Each microneedle array was left for 3 weeks at room temperature under conditions of about 35% humidity, and then observed. The results are shown in Tables 1 and 2.
Table 1 shows the test results for substrates produced by combining cellulose acetate (AC) with Hiviswako 103 (HV), carboxymethyl cellulose sodium (CMC-NA), polyvinyl alcohol (PVA), and hydroxy propyl cellulose (HPC). For the “Glue” column, a chondroitin sulfate (CDR) column and a dextran (DEX) column are provided. The horizontal direction of the table shows the results for when the mixing ratio of cellulose acetate and the other materials was varied from 10:1 to 7:3.
In the tables, “circle” represents that a good microneedle array was obtained without any warping, and “cross” represents that warping occurred.
Table 2 shows the results for when ethyl cellulose (EC) was used instead of the cellulose acetate (AC) of Table 1.
For all of the samples, it was possible to pull out all of the needles while still stuck to the tablet substrate. Therefore, the samples in Tables 1 and 2 are all the samples according to the present invention. However, for some compositions the periphery warped even when a water-insoluble polymer and an adhesive polymer were mixed to improve warping of the substrate periphery. Specifically, carboxymethyl cellulose sodium (CMC-NA) and polyvinyl alcohol (PVA) could not overcome the drying contraction force of chondroitin sulfate (CDR) even if they were mixed with cellulose acetate (AC) or mixed with ethyl cellulose (EC).
Especially, the combination of ethyl cellulose (EC) and carboxymethyl cellulose sodium (CMC-NA) could not overcome the drying contraction force of dextran (DEX) . Specifically, when a substrate is produced using these materials, it is necessary to select a glue having less contraction, or employ a method in which the tablet substrate is more strongly solidified. When a filter made of a porous polymer resin or a porous metal filter is used as the substrate, there is no warping of the substrate periphery.
However, for other combinations, generally, an effect from adding the adhesive polymer was seen. Specifically, a good microneedle array free from periphery warping could be obtained even when the glue was coated on only one face of the substrate.
A viscous dense solution produced by adding degassed purified water to ovalbumin used as a model antigen, sodium chondroitin sulfate, and evans blue was coated onto the holes of a resin substrate having, per square centimeter block, a hundred to several hundred inverted cone-shaped pores with a depth of about 500 microns and an opening diameter of about 300 microns.
Residual matter on the female mold was removed with a squeegee. Then, using a table-top centrifugal machine, the whole female mold was rotated, thereby the female mold was filled under application of a load by centrifugal force. A viscous dense solution produced by adding purified water to sodium chondroitin sulfate was coated on the female mold, and a porous metal filter (substrate) was covered thereon. The whole female mold was rotated by a table-top centrifugal machine to perform drying and curing. Subsequently, when the substrate was peeled from the female mold, all of the needles could be pulled out while stuck to the substrate, so that a microneedle array could be obtained.
If a water-soluble thread-forming polymer is used as a base, unless a base dense viscous solution containing a macromolecular drug such as a vaccine antigen and insulin in a dissolved or suspended state followed by filling a base dense viscous solution (glue) is dried and cured while still inserted in the female mold of a microneedle array, a microneedle array for a pharmaceutical preparation cannot be produced. In order to dry and cure a base including a target substance in a female mold for a microneedle array and strongly bind to the microneedle array to a substrate, it is important that the substrate promotes adsorption and evaporation of the solvent. To achieve this, there is a need for a substrate which has excellent solvent adsorption and permeability, and which meets the various grades as a pharmaceutical preparation, such as sterility.
According to the present invention, a viscous dense solution of a base containing a target substance can be dried and cured in the female mold of a microneedle array, thereby enabling a microneedle array suited for applications such as a pharmaceutical and a cosmetic to be efficiently produced.
11 female mold
12 concavities formed in female mold
13 one unit of microneedle array on female mold
15 solution containing target substance and the like
16 squeegee
19 target substance injected into the bottom of concavity
21 base
24 protrusion
25 substrate
26 glue
30 microneedle array
31 needle
32 base portion
33 target substance portion
| Number | Date | Country | Kind |
|---|---|---|---|
| 2009-133750 | Jun 2009 | JP | national |
| 2010-031317 | Feb 2010 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2010/053338 | 3/2/2010 | WO | 00 | 5/21/2010 |
