TECHNICAL FIELD OF THE INVENTION

[0001] This invention relates to a method of producing micro and nano-porous polymeric articles with well-defined pore structures. The porous articles can be used in a variety of applications, including micro-transfer molding applications and micro/nano-filtering applications. Such applications enable useful products in a variety of fields, including the inhalation and intravenous drug delivery and immunoprotection fields.

BACKGROUND OF THE INVENTION

[0002] The ability to produce polymeric substrates with micro and nano-pores wherein the pore structures are well-defined and the arrangement, size, and shape of the pores is controlled is of great use in differing applications.

[0003] One application contemplated by the present invention includes micro-transfer molding. The present invention tailors the transfer-molding method to render it useful for making particles of a micron and submicron scale. Transfer molding is widely used in polymer processing. Transfer molded products include, for example, rubber o-rings, gaskets, encapsulated IC chips, and contact lenses. Commonly, heat and pressure are used to transfer polymer material from the transfer pot into the mold cavity via a “sprue,” or tube.

[0004] An area in which it is highly desirable to quickly and efficiently mold polymer-type material into micron and submicron-sized particles of particular shape is related to the field of inhalation drug therapy. Certain drugs, including peptides and proteins, are unable to withstand stomach and intestine enzymes, and therefore need to be directly administered into the bloodstream. One way of achieving this is through the lungs. As such, inhalation devices such as nebulizers, metered dose inhalers (MDI's), and dry particle inhalers (DPI's) attempt to provide a means for delivering drugs to lung alveoli. The alveoli structures in the lung permit mass transfer to the blood stream. However, most mass transfer occurs in the deepest recesses of the lung, where the alveoli are located most densely. The repeated bifurcation of lung passageways provide a tortuous duct system for the airflow to follow to reach these alveoli. See generally, A. L Adjei & P. K. Gupta, ed., Inhalation Delivery of Therapeutic Peptides and Proteins, 5, 185 (1997). Since the branched system creates complicated air flow patterns and a tortuous path, and since most of the passages are lined with fluid to capture and remove particles, most particulate matter is removed before reaching the alveoli.

[0005] In general, the ability of particles to reach the alveoli depends on the size and density of the particles. Large particles, for instance particles above 5 μm in diameter, typically encounter the air-passage walls before reaching the alveoli, as inertial effects tend to override airstream currents. Smaller particles, for instance particles below 1 μm in diameter, tend to agglomerate, making their effective diameter large, and thereby also tend to encounter air-passage walls prior to reaching the alveoli. See Robert F. Service, Drug Delivery Takes a Deep Breath, 277 Science 1199 (1997). One way to overcome this challenge is to make particles more aerodynamic, thereby increasing the ability of the particles to stay suspended in the airstream along its tortuous path to the alveoli.

[0006] The present invention further contemplates novel micro and nano-filtering, or sieving, devices and methods for making the same. The ability to repeatably control the arrangement, shape, and size of micro and nano-pores in a polymeric substrate allows the filtering devices of the present invention to be utilized in a variety of useful applications including applications related to the biomedical industry.

[0007] Examples of such filtering applications include cell-based delivery and immunoprotection devices. One such immunoprotection device is produced by a method wherein a container is formed to encompass immuno-active cells, for instance insulin-producing cells. One side of the container, for instance the bottom, has well-defined nano-pores, or nano-tubes, that restrict the flow of particles of a size greater than the effective diameter of the nano-pores, while permitting the flow of particles smaller than the effective diameter of the nano-pores. In this example, producing a container with a side containing nano-tubes ranging in effective diameter from about 10 nanometers to about 100 nanometers (preferably about 10 to about 30 nanometers) allows for an insulin-producing device. Insulin-producing cells are contained within the container and are not permitted to escape, as they are generally an order or magnitude greater than the nano-pores just described. In the same manner, material noxious to the cells such as bacteria, viruses, and antibody molecules is prevented from entering the container, as it is also generally at least an order of magnitude larger than the container's nano-pores. More importantly, salutary materials such as insulin, salts and sugars are permitted to flow into and out of the container, as these substances are generally an order of magnitude smaller than the nano-pores previously described.

[0008] One can easily imagine, then, that present invention enables one to tailor such filtering, or sieving, devices in relation to one's need based on the ability to control the size, shape, and arrangement of pores, or tubes, in a polymeric substrate on a nano-scale.

SUMMARY OF THE INVENTION

[0009] An embodiment of the present invention concerns a polymeric plate containing a plurality of nano-tubes arranged in a predetermined manner. Each nano-tube has two openings, or apertures. Each nano-tube can comprise any tube-like structure wherein the effective diameter of at least one aperture is less than about 100 microns. The use of the term “tube” should not connote a limitation to vertical structures per se, but encompasses any structure generally having two apertures connected by a conduit, including conical, pyramidal, square, and rectangular conduits, and the like. Similarly, the use of the term “tube” encompasses a “pore” structure, in that the depth of the tube can generally be less than the effective diameter of the apertures. The aforementioned tube apertures may or may not be equal in area or shape.

[0010] In one embodiment of the present invention, particularly useful in immunoprotective devices, at least one of each tube's apertures has an effective diameter in the range from about 10 nanometers to about 100 nanometers (preferably about 10 to about 30 nanometers). In another embodiment of the present invention, the polymeric plate is any photocurable or thermoplastic polymer.

[0011] The polymeric plate of the present invention provides the basis for nano-filtering and micro-transfer molding devices. In a micro-transfer molding device, the polymeric plate serves as a “sprue plate” for channeling the moldable material into the mold cavities. In a filtering device, nanoparticles with an effective diameter greater than the effective diameter of each of the plate's nano-tubes are blocked from passing through the nano-tube while particles with smaller effective diameters are permitted to pass through the tube. As one can easily see, the control over the size, shape and arrangement of the nano-tubes determines the effective functionality of a “micro-sprue” plate. Also, as one can easily see, the control over the size and shape of each nano-tube aperture permits the nano-filters of the present invention to be highly effective at screening nano-particulates based on size and shape. Such control over the size and shape of each nano-tube is accomplished by the precise manufacture of a nano-member array, which array is generally used as a template for the nano-tubes, as generally described below.

[0012] A nano-member array generally consists of any array of projections that will permit the formation of nano-tubes of the desired size and shape. Generally, any method capable of forming micro or nano surface features in a substrate is suitable for forming such a nano-member array. An array with micro-sized features can be manufactured, for example, through photolithography or DRIE followed by electroplating. An array with nano-sized features can be manufactured, for example, through differential etching, self-assembly, x-ray lithography, EBL, AFM indentation, or surface machining with a sacrificial layer.

[0013] In one embodiment of the present invention, a nano-member array of conical projections is manufactured by differentially etching a fiber optic bundle. Another method for manufacturing a nano-member array of conical projections is through the anisotropic etching of silicon. Such processes can yield conical projections with tip widths less than about 100 nanometers, and optionally the tip widths can be less than about 10 nanometers. Such processes are well-known in the art, and described in, for example, T. H. Dam and P. Pantano, Review of Scientific Instrumentation, 70, 3982 (1999); S. Henry, D. V. McAllister, M. G. Allen and M. R. Prausnitz, Journal of Pharmaceutical Sciences, 87(8), 922 (1998).

[0014] In another embodiment of the present invention, a nano-member array of pyramidal projections is manufactured by indenting a PMMA substrate using a diamond-tipped AFM probe, followed by casting PDMS on the indented substrate, whereby the resulting cast PDMS plate contains pyramidal projections as defined by the pyramidal indentations of the PMMA casting substrate.

[0015] It is to be understood that the preceding examples are not intended to limit the geometry of the nano-member array projections of the present invention. Any geometry capable of being manufactured by the previously mentioned methods and their equivalents is within the scope of the present invention.

[0016] One embodiment of the present invention concerns a method for making a polymeric plate containing a plurality of nano-tubes through the use of a sacrificial layer. A starting material arrangement is obtained comprising a dimensionally stable support substrate—for instance silicon, glass, or teflon; a sacrificial layer on the support substrate; and a non-sacrificial layer on the sacrificial layer. An array of nano-members is then impressed through the non-sacrificial layer and into the sacrificial layer and the sacrificial layer is subsequently removed.

[0017] The sacrificial layer may be any material capable of being preferentially removed from the non-sacrificial layer, including any suitable soluble polymer.

[0018] The non-sacrificial layer may optionally be in precursor form prior to impressing an array of nano-members through it. The method then contemplates setting the non-sacrificial layer prior to the removal of the sacrificial layer. An embodiment of the precursor material comprises any relatively low viscosity polymeric or oligomeric material, including thermoplastic solutions and spin-coated photocurable resins.

[0019] In a particular embodiment of the present invention, the nano-member array comprises projections having size and shape capable of defining nano-tubes with effective diameters on either of their ends from about 10 nanometers to about 100 nanometers (preferably about 10 to about 30 nanometers), or otherwise capable of being effective in filtering noxious materials in immunoprotective devices.

[0020] A further embodiment of the method of making a nano-tube plate for use in micro-transfer molding or filtering devices involves the additional step of providing a patterned layer over the non-sacrificial layer. Such a layer can act as a material container, or “transfer pot,” in association with the non-sacrificial layer. The patterned layer may be achieved by any suitable process. In one particular embodiment of the invention, the patterned layer is achieved by, but not limited to, photolithography.

[0021] The present invention contemplates a method of making a polymeric plate containing a plurality of nano-tubes that does not involve the use of a sacrificial layer. Such method comprises obtaining a polymeric bulk material that is sufficiently impressionable to accept an array of nano-members; impressing an array of nano-members into the bulk material; setting the bulk material; removing the nano-member array; and cleaving the bulk material in such a way as to form a plate having a plurality of nano-tubes, wherein both ends of the tubes have apertures. That is, cleaving the material so as to leave substantially all the nano-tube ends open.

[0022] Particular embodiments of the polymeric bulk material can comprise a partially cured thermoset polymer, for instance PDMS, or a heated thermoplastic, for instance PMMA.

[0023] Another embodiment of the present invention comprises a polymeric container having a plurality of nano-tubes arranged in a predetermined manner in a portion of it, and a method for making such a container. The container defines an inner volume and the nano-tubes are arranged so as to permit the inner volume to be in fluid contact with the environment outside the container. The container is capable of being any size and shape as determined by the method of making the container described below, but in one embodiment the container defines a volume about 1 microliter, and the tubes are of such a size and shape as to permit the nano-filtering of noxious immunological materials as described above. In a specific embodiment, the nano-tubes each have an effective diameter in the range from about 10 nanometers to about 30 nanometers. In another embodiment, the nano-tubes of said container have conical or pyramidal geometry.

[0024] In another embodiment of the present invention, two polymeric containers as described above are bonded together so as to form a closed capsule, wherein a portion of it contains a plurality of nano-tubes arranged in a predetermined manner.

[0025] The present invention contemplates a method of making a polymeric container having a plurality of nano-tubes arranged in a predetermined manner in a portion of it. The method comprises obtaining a container mold having a support structure. The support structure merely corresponds to the portion of the molded container to contain the aforementioned nano-tubes, and will generally define the inner volume of the container to be formed. A sacrificial layer is then supported by the support structure. A non-sacrificial moldable material is then discharged into the container mold, thereby covering said sacrificial layer. A nano-member array, as described above, is then impressed through the moldable material and into the sacrificial layer. The sacrificial layer is subsequently removed to reveal a plurality of nano-tubes. The tubes provided by this method will necessarily be arranged so that the inner volume of the container will be in fluid contact to the environment outside the container through the nano-tubes.

[0026] In another embodiment of the present invention, the aforementioned sacrificial layer comprises a soluble polymer. In yet another embodiment, the non-sacrificial material is in precursor form, and the method additionally comprises the step of setting the precursor material prior to the removal of the sacrificial layer. In yet another embodiment, the precursor material is selected from the group comprising thermoplastic solutions and spin-coated photocurable resins.

[0027] In general, the nano-member array utilized in the method for making a container can be any array as outlined above, and in one embodiment comprises an array of conical or pyramidal nano-members.

[0028] In an embodiment of the method of making a container, the support structure corresponds to an inner volume of the molded container of about 1 microliter.

[0029] The present invention contemplates a method for making a polymeric closed capsule containing a plurality of nano-tubes arranged so that the inner volume of the capsule is in fluid contact with the outer environment via the nano-tubes. The method comprises obtaining two polymeric containers having a plurality of nano-tubes arranged in a predetermined manner in a portion of at least one of the containers. The containers can be obtained by the method described above. The containers are then bonded together to form a capsule, wherein the capsule has an inner volume defined by inner volumes of the constituent polymeric containers. Bonding can be accomplished by any suitable means, including welding (ultrasonic, laser, or IR), lamination (adhesive tape, film thermal bonding), or resin-gas assisted bonding. In one embodiment, at least one of the containers has material deposited in it, such that the resultant closed container encloses the material. In another embodiment, the material comprises insulin-producing cells.

[0030] The present invention contemplates a micro-transfer mold comprising a polymeric plate containing a plurality of nano-tubes, whereby the nano-tubes are arranged in a predetermined manner, and a cavity plate arranged adjacent the polymeric plate, wherein the cavity plate contains a plurality of mold cavities dimensioned so as to provide nanoparticles. The cavity plate arranged adjacent the nano-tube plate may be obtained by any process capable of effecting micron or sub-micron cavities in a bulk material. Several embodiments of processes capable of effecting micron and sub-micron cavities in bulk material include, but are not limited to, differential etching, dry etching, photolithography, micro-injection molding, and embossing. These methods can effect mold cavities of varying sizes (<10 nm to >100 μm) and shapes (e.g. thin circular, oval, square or rectangular disk).

[0031] An embodiment of the micro-transfer mold comprises an additional layer arranged adjacent the polymeric plate, on the side of the plate opposite the cavity plate, wherein the additional layer is patterned so as to provide one or a series of material containers, or “transfer pots.” Such pots can, for instance, hold the moldable material to be urged through the nano-tubes into the mold cavities.

[0032] The patterned layer can be achieved by any means generally capable of imprinting a material in a predetermined manner so as to provide for such a transfer pot arrangement, such as photolithography. The present invention also contemplates the micro-transfer mold arrangement wherein the transfer pot arrangement is not a separate layer from the polymeric plate, but is achieved by forming the polymeric plate in a manner that provides such an arrangement. Such a plate itself defines the transfer pot or pots, or the volumes to contain the material to be urged through the nano-tubes of the micro-transfer mold. Such a plate can be manufactured in a manner analogous to that used to manufacture the polymeric container described above, wherein a portion of the container contains nano-tubes. In such a method as applied to achieving a molding apparatus, the volume defined by the container would be dimensioned for the purpose of forming a transfer pot.

[0033] The present invention contemplates a method of micro-transfer molding whereby a micro-transfer mold is obtained as outlined above and a moldable material is then urged through the nano-tubes into the mold cavities and allowed to set so as to form nanoparticles. In one embodiment the cavities of the cavity plate are partially filled with pre-deposited material prior to urging a moldable material through the nano-tubes into the mold cavities. The moldable material is then allowed to set so as to form microparticles containing said pre-deposited material. In a further embodiment, the pre-deposited material comprises any dry powder or granular material.

[0034] In one embodiment of the micro-transfer molding process, the additional step is added whereby the cavity plate containing the molded particles is packaged such that the cavity plate becomes the packaging carrier for the microparticles.

[0035] In another embodiment of the micro-transfer molding process a moldable material is urged through the nano-tubes into the mold cavities in an amount such that the cavities are only partially filled. The step of urging material through the nano-tubes is then repeated as necessary to fill the cavities, creating layered molded microparticles. In yet another embodiment, the successive iterations of partially filling the mold cavities utilize moldable material different from prior iterative step of partially filling the mold cavity, such that layered nanoparticles are formed wherein the layers comprise differing moldable materials.