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(12) Patent Application Publication (10) Pub. No.: US 2007/0059270 A1 Hall Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0059270 A1 Hall Et Al US 2007005927OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0059270 A1 Hall et al. (43) Pub. Date: Mar. 15, 2007 (54) ION EXCHANGE RESIN TREATED TO (22) Filed: Sep. 13, 2005 CONTROL, SWELLING Publication Classification (75) Inventors: Harlan Hall, Oregon, WI (US); J. Scott Madsen, Cottage Grove, WI (US) (51) Int. Cl. A 6LX 3L/795 (2006.01) Correspondence Address: (52) U.S. Cl. ............................................................ 424/78.1 CHALKER FLORES, LLP 2711 LBJ FRWY (57) ABSTRACT Suite 1036 DALLAS, TX 75234 (US) The present invention provides a method and composition are provided that includes an ion exchange resin treated with (73) Assignee: The Coating Place, Inc., Verona, WI from between about 0.01 to about 10 percent by weight of one or more Sugar alcohols in contact with one or more ionic (21) Appl. No.: 11/225,834 pharmaceutically active drug. US 2007/0059270 A1 Mar. 15, 2007 ON EXCHANGE RESIN TREATED TO CONTROL drug bound to an ion-exchange resin to provide a drug-resin SWELLING complex having a drug content above a specified value. The drug-resin complex is Subsequently coated with a water TECHNICAL FIELD OF THE INVENTION permeable diffusion barrier coating that is insoluble in 0001. The present invention relates general to the con gastrointestinal fluids. Thus, the release of drug is controlled trolled release of active agents, and in particular, to phar under conditions encountered in the gastrointestinal tract. macologically active drugs adsorbed to ion exchange resin. 0007 One of the major disadvantages with the use of an ion exchange resin as a pharmaceutical delivery agent is that BACKGROUND OF THE INVENTION ion exchange resin particles are Susceptible to Swelling. For 0002 Without limiting the scope of the invention, its example, ion exchange resins drug complexes can undergo background is described in connection with ion exchange significant Swelling when the dry, non-hydrated drug com resins, as an example. Currently, ion exchange resins used in plex contacts fluids, e.g., water, biological fluids, gas pharmaceutical applications serve a variety of functions, trointestinal fluids. The Swelling of the ion exchange resin e.g., providing Sustained release, masking tastes, eliminating often ruptures the diffusion barrier coating, which causes a polymorphism, improving the dissolution of poorly soluble loss of control of the diffusion rate of the drug. drugs, eliminating deliquescence, reducing water uptake, improving stability, reducing abuse liability and improving 0008 U.S. Pat. No. 4,847,077 discloses sulfonic and cationic exchange resins treated with a critical amount of physical characteristics of pharmacologically active drugs. glycerin to enhance their coatability. The specification dis For example, ion exchange resins are used to prolonged the closes methods to achieve prolonged continuous release of continuous release of pharmacologically active drugs by a pharmacologically active monobasic drug absorbed on a absorbing the drug to the ionic exchange resin to form a Sulfonic acid cationic exchange resin treated with a critical drug-resin complex. In certain instances, a rate controlling amount of glycerin. Specifically, the controlled release phar coating is applied to the drug-resin complex. maceutical preparations containing coated Sulfonic acid cat 0003. The sustained release drug-resin complex provides ionic exchange resin drug complex particles is taught, that a controlled release of the pharmacologically active drug are treated prior to coating, with about 15 to 25% by weight over a given period of time. Thus, these complexes allow a of glycerin. continuous or intermittent Supply of the active drug to a Subject. The Sustained release drug-resin complex provides 0009 Finally, U.S. Pat. No. 4.221,778 teaches a pharma a convenient dosage form that provides a therapeutic level of ceutical preparation containing a diffusion barrier coated ion the drug throughout a an extended period. The release of the exchange resin drug complex treated with a solvating agent. drug maintains a therapeutically effective plasma level sig The Solvating agent retards the rate of Swelling in water but nificantly longer than that given by a typical drug dosage does not reduce the overall amount of Swelling, only the rate form. at which Swelling occurs. 0004. In a general sense, an ion exchange resin can be SUMMARY OF THE INVENTION described as an assembly of polymers that contain ionizable groups distributed along the polymer backbone. The poly 0010. The present inventors recognized a need for a mer has ions that associate with the ionizable groups of the pharmacologically active drug-resin complex that does not backbone. When the polymer is combined with a solution of swell or alter the release rate when contacted with fluids, counter ions, the counter ions in the Solution exchange with while reducing the concentration of Swelling agent used in the ions of the polymer and the counter ions are physically the formulations and increasing the compatibility of the removed from the solution. Therefore, drug ions (e.g., Swelling reducing agent with pharmacologically active counterion) in Solution can exchange with the ions of the ion drugs. exchange resin (e.g., polymer) through an ionic interaction, 0011. The foregoing problems have been recognized for as opposed to a covalent interaction. The pharmacologically many years and while numerous solutions have been pro active drug ions can then be eluted from the ion exchange posed, none of them adequately address all of the problems resin to treat the subject. in a single composition, e.g., controlling the Swelling, reduc 0005. A substantial portion of the active drug is ionically ing the concentration of Swelling agent, increasing the bound within the polymer matrix of the ion exchange resin. effectiveness of the Swelling controlling agent and increas The active drug elutes from the polymer matrix over time to ing the compatibility of the Swelling reducing agent with provide a specific release profile. The size of the adsorbed pharmacologically active drugs. drug molecule and/or the size of the polymer resin particle 0012. The present inventors have recognized that the (e.g., the cross linkage of the cationic exchange resin) may nature of the material used as pharmaceutically acceptable be altered to control the elution rate. The process of adsorp ion exchange resins result in the resin undergoing significant tion of a pharmacologically active drug to ion exchange Swelling (e.g., up to about a 60% increase in Volume) when resin is a well-known technique to the skilled artisan and the the non-hydrated resin-drug complex is placed in contact Subject of many United States and foreign patents. Gener with fluids, e.g., water, biological fluid, gastrointestinal ally, adsorption is accomplished by mixing a pharmacologi fluids. When an ion exchange resin-drug complex is coated cally active drug and an ion exchange resin an aqueous with a water-permeable diffusion barrier the swelling of the Solution, filtering, drying and optionally coating with a ion exchange resin often ruptures the diffusion barrier coat water-permeable diffusion barrier. ing. The damage to the water-permeable diffusion barrier 0006 U.S. Pat. No. 4,996,047 discloses oral pharmaceu coating results in a loss of control of the rate of diffusion of tical preparations, which include a pharmacologically active the drug from the resin-drug complex. In addition, the US 2007/0059270 A1 Mar. 15, 2007 Swelling of the ion exchange resin affects the dimensions DETAILED DESCRIPTION OF THE and shape of the ion exchange resin-drug complex. Addi INVENTION tionally, the coating can peel from the resin-drug complex. 0019 While the making and using of various embodi 0013 In an effort to reduce the swelling of ion exchange ments of the present invention are discussed in detail below, resins, the prior art methods teach treating the ion exchange it should be appreciated that the present invention provides resin-drug complexes with an impregnating agent, e.g., many applicable inventive concepts that can be embodied in polyethylene glycol, propylene glycol, mannitol, lactose, a wide variety of specific contexts. The terminology used methylcellulose or propylene glycol. However, the amount and specific embodiments discussed herein are merely illus of impregnating agents used to control the Swelling is trative of specific ways to make and use the invention and do dependent on a variety of factors (e.g., the polymer, the not delimit the scope of the invention. The present invention Solvent composition, the salt concentration, the polarity of may also be used for waste treatment, corrosion control, the solvent, the degree of cross-linking, the exchange capac pesticide release and many other areas using ion-exchange ity, the strong or weak Solvation tendency of the ion groups, precepts, in both consumer and industrial applications. the size and extent of the solvation of counter ions, the concentration of the external solution, the extent of the ionic 0020. A number of definitions are provided herein to dissociation of functional groups and so forth) and ranges facilitate an understanding of the present invention. As used from 15 to 40 percent by weight. For example, one formu herein, the term "pharmaceutical composition’ also means a lation currently used includes Amberlite IR-120 phenylpro Solution, Suspension, cream, ointment, lotion, capsule, panolamine complex with a 35 percent drug loading treated caplet, Softgel, gelcap. Suppository, enema, elixir, Syrup. with polyethylene glycol 4000 at about 30 parts by weight emulsion, film, granule, gum, insert, jelly, foam, paste, of the solvating agent to 100 parts by weight of the resin to pastille, pellet, spray, troche, lozenge, disk, magma, poul reduce Swelling. tice, or wafer and the like. 0014 Specifically, the use of glycols to control the swell 0021. As used herein, the term "sugar alcohol.”“organic ing of ion exchange resin drug complexes offers many polyol.'"polyhydric alcohol.'"polyalcohol or “polyol are disadvantages.
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