Patent Application
20080039805
While the above-identified drawing figures set forth several embodiments of the invention, other embodiments are also contemplated, as noted in the discussion. In all cases, this disclosure presents the invention by way of representation and not limitation. It should be understood that numerous other modifications and embodiments can be devised by those skilled in the art, which fall within the scope and spirit of the principles of the invention. The figures may not be drawn to scale. Like reference numbers have been used throughout the figures to denote like parts.
The present invention provides patch application devices that may be useful for a variety of purposes. For example, the patch application devices may be used to deliver a patch to a skin surface in order to pierce the stratum corneum at a delivery site on a patient's skin. For example, the patch application device may be used to deliver drugs (including any pharmacological agent or agents) through the skin in a variation on transdermal delivery, or to the skin for intradermal or topical treatment, such as vaccination.
In some embodiments, the patch application device may be used in conjunction with microneedles to effectively deliver therapeutic drugs. Patch application devices of the present invention may have utility for a number of drugs and therapeutic indications. In one aspect, drugs that are of a large molecular weight may be delivered transdermally. Increasing molecular weight of a drug typically causes a decrease in unassisted transdermal delivery. Patch application devices of the present invention have utility for the delivery of large molecules that are ordinarily difficult to deliver by passive transdermal delivery. Examples of such large molecules include proteins, peptides, nucleotide sequences, monoclonal antibodies, DNA vaccines, polysaccharides, such as heparin, and antibiotics, such as ceftriaxone.
In another aspect, patch application devices of the present invention may have utility for enhancing or allowing transdermal delivery of small molecules that are otherwise difficult or impossible to deliver by passive transdermal delivery. Examples of such molecules include salt forms; ionic molecules, such as bisphosphonates, preferably sodium alendronate or pamedronate; and molecules with physicochemical properties that are not conducive to passive transdermal delivery.
In another aspect, patch application devices of the present invention may have utility for enhancing delivery of molecules to the skin, such as in dermatological treatments, vaccine delivery, or in enhancing immune response of vaccine adjuvants. In one aspect, the drug may be applied to the skin (e.g., in the form of a solution that is swabbed on the skin surface or as a cream that is rubbed into the skin surface) prior to applying a microneedle array.
Referring now to
Referring to
The driver 44 may be provided by any mechanism capable of providing acceleration sufficient to reach the desired velocities as discussed herein. For example, the driver 44 may be in the form of a mechanical spring (e.g., a coil spring, leaf spring, etc.), compressed resilient member (e.g., rubber, etc.), compressed fluids (e.g., air, liquids, etc.), piezoelectric structure, electromagnetic structure, hammer device, etc. Regardless of the precise form of the driver 44, it should be capable of storing sufficient energy to accelerate the mass of the piston 42 and patch 20.
As shown in
Referring to
The collar should have a sufficient height (i.e., the distance between the distal and proximal ends of the collar) to allow a patch to be contained and protected within the collar. The height of the collar will typically be about 5 cm or less, often about 2.5 cm or less, and sometimes about 1.0 cm or less. The obstructions (i.e., the portion of the obstructions that contact the patch adhesive) are spaced a sufficient distance away from the distal end of the collar in order to protect the patch from external contact. This distance may vary depending on a number of factors, such as the size and nature of the microneedle array, the type of surface to which the patch is to be applied, the force with which the collar is pressed against the application surface, and the desired velocity of the patch upon contact with the application surface. The obstructions will be spaced away from the distal end by a distance equal to or less than the height of the collar, typically by a distance of 2.0 cm or less, often by a distance of 1.0 cm or less, and sometimes by a distance of 0.6 cm or less. The collar will most typically have a inner cross-sectional area slightly larger than the area of the patch, so as to allow the patch to freely move from the collar when expelled by the drive mechanism. The relative size of the patch to the inner cross-sectional area of the collar may vary depending on the patch construction and the intended use of the device. In one embodiment, the patch diameter will be between about 1 and 5 mm smaller, and sometimes between about 2 and 3 mm smaller, than the inner diameter of the collar.
Each obstruction 50 is configured to hold and retain the patch 20 previously described herein. The obstructions 50 are dimensioned so that the patch 20 is retained within the internal surface of the collar 34. The obstructions 50 are in contact with the adhesive 24 on the distal-facing surface of the patch 20. In the second released position, shown in
The adhesive 24 serves a dual purpose. That is, the adhesive 24 serves the function of retaining the patch within the collar of the application device for storage, shipment, transport, and/or handling. Additionally, the adhesive 24 adheres to an application surface, such as the skin, when the patch is expelled from the device in the second released position. In some embodiments, the adhesive is a pressure sensitive adhesive. In other embodiments, the adhesive can be a medical grade adhesive. In some embodiments, the adhesive may be waterproof or water-resistant so that the patch remains adhered for a desired time period to a surface that is wet, contains moisture, or otherwise comes into contact with water during the time period that the patch is adhered to the surface. In one embodiment, the bond formed between the adhesive and the surface is not permanent, so that the patch can be removed when desired. When the adhesive is to be applied to a living organism or host, the adhesive should also be compatible with the host so that undue irritation at the treatment site is avoided.
Examples of suitable pressure-sensitive adhesives that may be used include acrylate and/or methacrylate polymers and copolymers, silicones, polyisobutylenes, synthetic rubbers, such as styrene-isoprene-styrene, and mixtures and blends of the foregoing. A particularly beneficial class of adhesives is the class of (meth)acrylate polymers, preferably acrylate embodiments thereof, suitable for use as pressure sensitive adhesives (PSAs). Representative embodiments of such (meth)acrylate PSAs are described in U.S. Pat. Nos. 4,693,776 (Krampe et al.); 4,751,087 (Wick); 4,737,577 (Brown); and Re 24,906 (Ulrich); all of which are incorporated herein by reference in their respective entireties.
The bond between the adhesive of the patch and the obstructions of the collar may vary depending on a number of factors, including the size and shape of the obstructions, the contact area between the adhesive and the obstructions, the adhesive properties, the material composition of the obstructions, the surface treatment of the obstructions (if any), the amount of pressure used to secure the patch to the obstructions, or the storage conditions. The bond between adhesive and obstructions is preferably chosen so that it is high enough to prevent accidental dislodgement of the patch during storage and handling, but low enough to allow complete and easy release of the patch during application.
In one embodiment of this invention, the obstructions can be treated with a release coating material prior to attaching the patch to the obstructions. In another embodiment, release coating may be applied to the entire collar such as by dip coating the whole collar in a release coating solution, or by applying the coating solution only to the inner surface of the collar including protrusions. In another embodiment, the release coating can be applied to or extruded toward the inner surface of the collar including protrusions during the extrusion/manufacturing process of the collars. In one aspect, a release coating may prevent the patch from remaining adhered to one or more obstructions after the piston contacts the patch thus allowing the patch to release completely and easily from the collar. Examples of suitable release coatings include silicones, such as polydimethylsiloxane (U.S. Pat. No. 3,061,567, U.S. Pat. No. 4,216,252, U.S. Pat. No. 4,386,135 and references included therein,); Epoxysiloxanes (WO 81/02424); fluorocarbon polymers; fluorosilicones; composite flurochemical-silicone relelase coating (U.S. Pat. No. 4,171,397): silicone-organic hybrids, such as silicone-polyureas, silicone acrylates, polydimethylsiloxane-grafted copolymer (U.S. Pat. No. 4,728,571); polyurethanes (U.S. Pat. No. 3,342,625), and polymers having long alkyl side chains, which typically consists of a copolymer of an acrylic ester, vinyl ether, and acrylamide derivatives or the like. Silicones are preferred release coating materials which may be delivered from a solvent or a combination of solvents or coated as 100 percent solids. Silicones can be cured by condensation such as those described in U.S. Pat. No. 4,530,882 and U.S. Pat. No. 4,525,566, and D. R. Thomas in “Siloxane Polymer”, S. J. Clarson, J. A. Semlyen, Eds. PTR Prentice Hall, Englewood Cliffs, N.J. 1993, or by radiation as such as described in U.S. Pat. No. 3,655,713 process are herein incorporated by reference. Additional release coatings include UV cured silicones, such as UV9500 and UV9390C (both available from GE Silicones) or thermally cured silicones, such as Syl-off® 292, Syl-off® 291, Syl-off® 294, Syl-off® 7075 (available from Dow Corning), or addition cure silicones Syl-off® 7010, Syl-off® 7020, Syl-off® 7395 (also available from Dow coming) In one embodiment, a mixture of 10 parts Syl-off® 292, 10 parts Syl-off(® C4-2109 (release additive), 1.07 parts Syl-off® 297 (anchorage additive), 0.56 parts Syl-off® C4-2117 (fast cure additive), and 0.85 parts Dow Corning(® 176 catalyst in a mixture of 91 parts heptane and 23 parts methyl ethyl ketone may be used as a release coating solution that can be cured at 150° C. for 2 minutes to provide a suitable release coating. In one embodiment, the peak force required to push a patch past the obstructions with a cylindrical probe is less than 400 grams and in some instances may be less than 200 grams.
In another embodiment of the present invention it may be desired that when actuated, the piston 42 reaches a distance x away from the distal end 48 of the collar 34. For example, this may allow the patch application device 30 to achieve improved patch adhesion upon the application surface 38 when the piston 42 travels beyond the distal end 48 of the collar 34. For example, it may be preferred that after actuation the distance x between the distal end 48 and the patch 20 is between about 0.000 inches (0.00 cm) and about 0.500 inches (1.27 cm), more preferably between about 0.050 inches (0.127 cm) and about 0.250 inches (0.635 cm), most preferably about 0.125 inches (0.318 cm).
The patch application device according to the present invention may include a piston designed to deliver microneedles at velocities that may enhance perforation of the stratum corneum while limiting the sensation of pain experienced at the delivery site. To accomplish this goal, the patch application device may use movable components with limited mass to reduce the tendency of the apparatus to stimulate nerves during delivery of the therapeutic drugs using the patch application device. In addition, the delivery apparatus includes a collar that, in one embodiment, may be forced against the skin around the patch application device to increase reliability of the application, minimize interaction with the patch, and decrease the risk of contamination to the patch.
Delivery of a patch using a patch application device in accordance with the methods of the present invention may involve acceleration of the patch application device itself to a desired velocity.
As discussed above, referring to
Because of the variability in the location of skin, it may be preferred that the apparatus be designed such that the patch and/or piston travels at a velocity at or above the desired minimum velocities over a distance that is sufficient to accommodate the variations in skin location relative to the patch application device. For example, it might be preferred that the patch and/or piston in a patch application device moves at or above the minimum velocity over a distance of one millimeter or more. In some embodiments, it may be sufficient that the patch and/or piston move at or above the minimum velocity over a distance of 5 millimeters or more. Piston velocity of an application device as a function of displacement from the first stored position is shown in
The force required to reach the desired velocities may vary based on the mass of the piston 42. That mass may also be controlled or selected to reduce the likelihood that nerve tissue underneath the delivery site is stimulated sufficiently to result in the sensation of pain. For example, the mass of the piston may be less than about 8 grams or less. It may be preferred that the mass of the piston be about 6 grams or less, more preferably about 4 grams or less.
The present invention also provides a kit that includes a cartridge for use with an applicator in a patch application device, a patch 20 within the collar characterized in that at least a portion of the distal-facing surface of the patch 20 contains an adhesive 24, and an applicator device having a first stored position and a second released position. The kit also provides instructions for attaching and detaching the collar 34 from the applicator device; and instructions for engaging the applicator from the first stored to the second released position and thereby applying the patch 20 to a target application surface 38, and packaging material to protect the applicator and the cartridge from environmental contamination. As contemplated herein, the kit is configured to store and provide at least one applicator device and cartridge in a ready-to-use condition. In one embodiment, the kit may include one applicator device and a plurality of cartridges, such that multiple treatments may be provided using a single kit. In one embodiment, the kit may include a jig or apparatus to assist in returning the application device from the second released position to the first stored position. Such a jig, for example, may be configured to assist in returning a piston to the first stored position when the device is in the second released position after application of a patch, preferably without having to manually handle the piston.
Patch application devices of the present invention are intended to deliver a patch which is intended to be left in place for a period of time during drug administration. As used in connection with the present invention, the term “microneedle” (and variations thereof) refers to structures having a height above the surface from which they protrude of about 500 micrometers or less.
Where the patch application devices are to be used for piercing the stratum corneum in preparation for transdermal drug delivery, the height of the microneedles is preferably sufficient to pass through the stratum corneum. It is also, however, preferable that the height of the microneedles is not sufficiently large to cause significant pain when inserted at a delivery site. In some instances, microneedles of the present invention may have a height of about 250 micrometers or less. In some instances, microneedles of the present invention may have a height of about 100 micrometers or more.
Referring to
The microneedles may preferably be manufactured integrally with the substrate. In other words, the various features may preferably be formed as a one piece, completely integral unit. Alternatively, the microneedles may be provided separately from the substrate.
The microneedle substrates may be manufactured from a variety of materials including polymeric materials or metals. Material selection may be based on a variety of factors including the ability of the material to accurately reproduce the desired pattern; the strength and toughness of the material when formed into the microneedles; the compatibility of the material with, for example, human or animal skin; the compatibility of the materials with any fluids that will be expected to contact the microneedle devices, etc.
Still another suitable microneedle construction comprises the structures described in U.S. Pat. No. 6,091,975 (Daddona, et al.) which describes blade-like microprotrusions for piercing the skin. Still another microneedle construction comprises metal as a blade material as described in U.S. Pat. No. 6,611,707 (Prausnitz, et al.).
Among polymeric materials, it may be preferred that the microneedles be manufactured of thermoplastic polymeric materials. Suitable polymeric materials for the microneedles of the present invention may include, but are not limited to: acrylonitrile-butadiene-styrenes, polyphenyl sulfides, polycarbonates, polypropylenes, acetals, acrylics, polyetherimides, polybutylene terephthalates, polyethylene terephthalates, etc. Polymeric microneedles may be manufactured of a single polymer or a mixture/blend of two or more polymers.
In one embodiment, the patch 20 contains a pressure sensitive adhesive 24 on the distal-facing surface and a backing 26 on the proximal facing surface. Typical examples of flexible backings employed as conventional tape backings which may be useful for the present invention include those made from polymer films such as polypropylene; polyethylene, particularly low density polyethylene, linear low density polyethylene, metallocene polyethylenes, and high density polyethylene; polyvinyl chloride; polyester (e.g., polyethylene terephthalate); ethylene-vinyl acetate copolymer; polyurethane; cellulose acetate; and ethyl cellulose. Fabrics and non-wovens are also suitable. Coextruded multilayer polymeric films are also suitable, such as those described in U.S. Pat. No. 5,783,269 (Heilmann et al.), the disclosure of which is incorporated herein by reference.
The backing 26 may be of thickness of about 0.010 inches (254 μm) or less, and more preferably about 0.005 inches (127 μm) or less, and even more preferably about 0.001 inches (25.4 μm). In some embodiments, the patch may comprise microneedles that may be coated with a drug formulation. Also, it should be noted that there is no requirement that the patches 20 be uniform, layered patches 20 such as those shown. For example, the patches may vary in size or shape and may include various structures, such as drug reservoirs.
It should be understood that the patch 20 is sufficiently flexible to allow for uniform adhesion to the application surface 38. Additionally, the patch is sufficiently flexible to bend around the obstructions in the collar thus preventing inadvertent contact between the patch and the obstructions. One skilled in the art will appreciate that the types of material used for the backing and pressure sensitive adhesive are sufficiently flexible. The patch may include other features, such as those described in U.S. patent application Ser. No. 60/634,905, filed Dec. 10, 2004 and entitled Medical Device (Attorney Docket No. 59760US002).
While the patch 20 is depicted essentially in a circular configuration, it will be appreciated that the patch 20 may be configured in any useful or ornamental configuration desired. It will further be appreciated that the description herein of the various embodiments of the invention are merely exemplary of patches that embody the principles of the present invention and that the described embodiments are not intended to be limitation on the broader concepts inherent in the described embodiments.
In one embodiment, by providing truncated tapered microneedles, patch application devices of the present invention may provide for effective penetration of, e.g., the stratum corneum, without stimulating the underlying nerve tissue that would result in the sensation of pain. As used herein, “effective penetration” means that the pathways opened through the stratum corneum by microneedles with larger tops may provide for enhanced transfer of materials through the stratum corneum. In addition, the tapered shape of the microneedles may enhance penetration of the stratum corneum as compared to microneedles with more column-like shapes that are not tapered.
Another manner in which the microneedles of patch application devices of the present invention may be characterized is based on the aspect ratio of the microneedles.
As used herein, the term “aspect ratio” is the ratio of the height of the microneedle (above the surface surrounding the base of the microneedle) to the maximum base dimension, that is, the longest straight-line dimension that the base occupies (on the surface occupied by the base of the microneedle). In connection with the present invention, it may be preferred that the microneedles have an aspect ratio of 2:1 or higher, and in some instances 3:1 or higher.
In on embodiment, the microneedles used in connection with the present invention may have generally vertical wall angles, i.e. the microneedles may be in the form of pins, with sidewalls that are largely orthogonal to the surface of the substrate from which they protrude.
Although not depicted, the microneedle devices may include other features such as channels which are described in U.S. Patent Application Publication No. 2003-0045837. Furthermore, the microneedle devices may include covers pierced by the microneedles as described in U.S. Patent Publication No. 2003-0135161. Additionally, the microneedle arrays may be manufactured by several molding methods as described in co-pending U.S. Patent Application Ser. No. 60/546,780, filed on Feb. 23, 2004 and entitled METHOD OF MOLDING FOR MICRONEEDLE ARRAYS.
All patents, patent applications, and publications cited herein are each incorporated herein by reference in their entirety, as if individually incorporated by reference. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth herein.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US05/20283 | 6/9/2005 | WO | 00 | 12/4/2006 |
| Number | Date | Country | |
|---|---|---|---|
| 60578651 | Jun 2004 | US |
