Microlayer coextrusion to create a time-release drug substance delivery product

Abstract

The present disclosure relates to medical devices containing time-release drug substance, and more particularly, to medical tubing, catheters, stents, cables (including fiber optic cables), pills, capsules, sheaths, threads, clamps, sutures, and endotracheal devices. The invention also generally relates to a method for extruding multiple laminated flow streams using microlayer coextrusion to create these various time-release drug delivery products.

Claims

1. An extrusion process for preparing a medical device comprising the steps of: combining at least two flow streams of laminated polymer, wherein the laminated polymer flow streams contain laminations which have micro or nanometer thickness; joining the at least two flow streams of laminated polymer within a die to form a continuous cumulated laminated flow within the die, extruding the continuous cumulated laminated flow to produce an extruded multilayered polymer solid of two or more annular rings, a cross-section of the extruded multilayered polymer solid having two or more annular rings with a micro or nanometer radial thickness, wherein said extruded multilayered polymer solid is further processed into a medical device which is an implantable device.

2. The process of claim 1 wherein the medical device further includes a drug substance core wherein said one or more of said annular rings emanates from the drug substance core.

3. The process of claim 2 wherein the drug substance core in the implantable device is time-released.

4. The process according to claim 1 wherein said extruded multilayered polymer solid of two or more annular rings additionally comprises at least one induced confined polymer crystallization barrier between adjacent annular rings.

5. The process according to claim 1 wherein said joined at least two flow streams of laminated polymer within a die forming the continuous cumulated laminated flow are concurrently co-extruded and additionally comprising an induced confined polymer crystallization barrier between layers of the continuous extruded multilayered polymer solid.

6. The process of claim 1 wherein the two or more of said annular rings contains a drug substance.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In the drawings:

(2) FIG. 1 illustrates a cross section of one embodiment of an annular layer drug substance made using the nanolayer die.

(3) FIG. 2 illustrates one embodiment of a product created by the nano die.

(4) FIG. 3 illustrates another embodiment of a product created by the nano die.

(5) FIG. 4 illustrates another embodiment of a product created by the nano die.

(6) FIG. 5 illustrates a further embodiment of a product created by the nano die.

(7) FIG. 6 illustrates a typical flow channel for a product created by the nano die.

(8) FIGS. 7a-c illustrate examples of fold structures using a layer folding technique.

DETAILED DESCRIPTION

(9) General principles regarding the methods and the extrusion die may be found in United States Patent Publication No. 2012/0189789 Method and Apparatus for Forming High Strength Products and in U.S. Pat. No. 7,690,908 issued Apr. 6, 2010. Other methods are described in U.S. Pat. Nos. 6,669,458, 6,533,565 and 6,945,764. Each of the aforesaid publication or patent is herein incorporated by reference in its entirety.

(10) General methods for the preparation of drug substance containing flows is known in the art. See for example Drug Dev Ind Pharm., 2005 May 31 (4-5):339-47; U.S. Pat. No. 6,488,963 to McGinity issued Dec. 3, 2002; United States Patent Publication 2011/0229526 published Sep. 22, 2011; U.S. Pat. No. 8,323,760 issued Dec. 4, 2012; and U.S. Pat. No. 8,221,778 issued Jul. 17, 2012.

(11) General methods for further processing the cumulated laminated output into the particular sustained delivery product are well known in the art. See for example European Journal of Pharmaceutics and Biopharmaceutics, Volume 54, Issue 2, September 2002, Pages 107-117; Breitenbach J., et al., Two Concepts, One Technology: Controlled-Release Solid Dispersions Using Melt Extrusion (Meltrex), Drugs and the Pharmaceutical Sciences, 2008, vol. 183, pp. 179-185; U.S. Pat. No. 5,356,630 issued Oct. 18, 1994, U.S. Pat. No. 4,720,384 issued Jan. 19, 1988, U.S. Pat. No. 4,675,381 issued Jun. 23, 1987; United States Patent Publication 2007/0287800 to Acquarulo published Dec. 13, 2007; United States Patent Publication 2005/0238721 published Oct. 27, 2005 and United States Patent Publication 2004/0259969 published Dec. 23, 2004.

(12) Implantable drug delivery systems possessing electronic conduction properties such that the implantable device may actuate a target tissue or sense a parameter associated with the target tissue are described in United States Patent Publication 2011/0230747 published Sep. 22, 2011 Rogers et al., entitled Implantable Biomedical Devices On Bioresorbable Substrates and U.S. Provisional Patent application 61/0658743, filed Jun. 12, 2012.

(13) For example, a non-conductive material, such as a polymer may be transformed into an electronically conducting material by introducing an electrically conductive material into the nano-flow die processing the polymer. Making an electrically conductive product comprises filling the polymer with one or more metals or other conducting materials. The term filling is generally used to define a state where there are sufficient conductive particles within the product to establish a conductive state. As will generally be understood in the art, this can include a product layer that only partially comprises conductive elements or particles. Any suitable material that enables or provides for electrical conductivity can be used to create an electrically conductive product using the polymer, including metals. Circuits prepared by such methods can be controlled externally or can respond autonomously to endogenous signals within the patient such as neurotransmission including epilepsy, psychosis, or cardiac dysfunction.

(14) Geometries

(15) The flow streams optionally containing drug substance can be morphed into laminated ribbons retaining a layered structure corresponding to the number of laminations from gradually thinner laminations formed within the extrusion flow, thereby obtaining smaller and smaller grain features and eventually obtaining nano-sized features. These flows may possess distinct boundary features.

(16) FIG. 1 illustrates a cross section of one embodiment of an annular layer drug substance made using the nanolayer die.

(17) The nano die may also be used to create products which will have an increased interfacial surface area (see FIGS. 2-5). Sections of the layers mentioned above may be separated by stems comprised of a single material or mixture. Each stem may be made of its own respective material or mixture allowing for the properties desired in that stem. A layer, stem or combination of the two may then be removed by some process, whether it is mechanical in nature such as peeling or chemical in nature such as dissolving. If one of the materials or mixtures used in the stem along with one or more of the materials used in the layers may all be removed, the result would be a core with stems protruding from the surface. These stems would have branches (layers) attached with a large surface area exposed to the environment. In the figure above, there are alternating layers of grey and black material separated by alternating grey and black stems. Only six layers are shown in each stream for illustrative purposes but may comprise of thousands of layers. If all the black material were removed, the result would be a grey core with four stems each with six branches of material. This greatly increases the surface area exposed to the environment. By tailoring the rate at which the different materials dissolve along with the geometry, one could control the release rate of a drug substance by controlling the amount of surface area exposed to the environment. If the stems were to dissolve faster, a drug substance that broke up into sections could also be made.

(18) In FIG. 3, the stems are tapered radially inwards. The stems may also be made to be tapered radially outwards. The stems and branches may all be made to have different thicknesses and there may be any number of each.

(19) In FIG. 4, above, the core is comprised of a tube made of the grey material. Examples of a core include a solid rod, a hollow tube, a wire, or a profile all of which may either be coextruded or extruded onto and may be comprised of any materials with or without layers. The core may also be absent. An outer and/or inner layer may also be added and may be composed of multiple layers and may be comprised of any suitable material or materials.

(20) Multiple layers of streams and stems may also be used to be able to create geometries like the one pictured in FIG. 5. Theses layers may contain different numbers of layers, streams and stems in different orientations.

(21) Folding in a Coextrusion Die

(22) Time released drug substances may also be made through a typical coextrusion head but with layers manipulated through folding to create additional layers. Such technology is described in Patent Publication 2012/0189789 entitled Method and Apparatus Forming High Strength Products and U.S. Pat. No. 7,690,908 issued Apr. 6, 2010.

(23) This approach to creating multilayered products begins with a typical flow channel for a product, as is illustrated in FIG. 6 (in the example of FIG. 6 the cross-section of this flow channel is an annular ring). The flow channel is then morphed to create folds in the flow channel (steps 1 to 3). These folds are oriented and propagated in such a way so that the flow may be converged back to a flow passage with a typical cross section but now with a multiplied number of layers (step 3 to 4). One advantage of this method of layer multiplication over others is that the layers remain continuous around the product.

(24) Some other examples of how the folds may be oriented are illustrated in FIG. 7.

(25) The initial flow may contain any number of suitable materials in any number of layers and the layer multiplication process may be performed multiple times. The number of folds and the relative length that they stretch may also vary.

(26) These layer geometries formed through this method allow for a way of controlling the time release of a drug substance much like the nano die.

(27) Stent

(28) This aforesaid layer folding technique may also be used to create an expanding product such as a stent. A natural weakness at the interface of the folds or skin layer may be designed into a stem such that the stem can separate from the underlying support which may be dissolved either ex vivo or in vitro. The product so formed could break or separate at this interface and expand into a larger shape. This expanding product could contain a drug substance and be used in such applications as a drug substance releasing stent.

(29) Implantable

(30) Steams including geometric FIGS. 3 and 4 may be extruded as a hollow core or as an exudate surrounding a preformed pharmaceutical product. Such post flow extrusion work up is known to those in the art.