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. For instance, the concentration of glycol used interchangeably to mean non-toxic C2 to C12 linear or must be between 15 percent to 40 percent by weight to branched hydrocarbon having at least 2 hydroxy groups, control the Swelling of the ion exchange resin drug com non-toxic C5 to C12 cyclic or heterocyclic hydrocarbon plexes; however, even with Such concentrations of glycol having at least 2 hydroxy groups, e.g., Sorbitol, mannitol, there remains swelling of the ion exchange resins drug polyglycitol, maltitol, lactitol, isomalt, erythritol, glycerin, complex. In addition, many compounds are not compatible polydextrose, fructose, maltose Xylitol. 1,3-dihydroxypro with glycols, e.g., penicillin, bicitracine, iodine, potassium pane inositol and the carbohydrates such as glucose, Sucrose. iodide, tannic acid, and bismuth salts. 0022. The term “immediate release' is used herein to 0015. In accordance with the present invention, a method describe a release profile to effect the delivery of an active and composition are provided that includes an ion exchange as soon as possible, that is, as soon as practically made resin treated with from about 0.1 percent to about 10 percent available to a subject, whether in active form, as a precursor by weight of one or more Sugar alcohols in contact with one and/or as a metabolite. Immediate release may also be or more ionic pharmaceutically active compounds. Specifi defined functionally as the release of over 80 to 90 percent cally, the ion exchange resin is a cationic exchange resin (%) of the active ingredient within about 60,90, 100 or 120 treated with less than five percent sorbitol to control the minutes or less. Immediate release as used herein may also Subsequent Swelling of the drug resin complex, while main be defined as making the active ingredient available to the taining a low concentrations of impregnating agents. Subject regardless of uptake, as some drugs may never be 0016 For example, the present invention includes a phar absorbed by the animal. Immediate release formulations of maceutical composition having a pharmaceutically active the active on a carrier, Such as rolled or compressed beads, Substance in communication with an ion exchange resin, may be formulated Such that the Surface area is maximized wherein the ion exchange resin is treated with from about on beads and the active is exposed immediately. Various 0.01 percent to about 10 percent by weight of one or more immediate release dosage forms may be designed readily by Sugar alcohols. one of skill in art to achieve drug delivery to the stomach and 0017. In accordance with the present invention, a method Small intestine, depending upon the choice of compression, is provided that reduces the Swelling of a pharmaceutical adhesive materials and/or beading. composition by contacting one or more cationic exchange 0023 The terms “extended release,”“controlled release” resin particles with a solution containing from about 0.01 and “delayed release' as used herein is used to define a percent to about 10 percent by weight of Sugar alcohol, release profile to effect delivery of an active over an based on the combined weight of the Sugar alcohol and the extended period of time, defined herein as being between one or more ionic exchange resin particles. about 60 minutes and about 2, 4, 6 or even 24 hours. 0018. In addition, the present invention includes a Extended release may also be defined functionally as the method for preparing a pharmaceutical ion exchange resin release of over 80 to 90 percent (%) of the active ingredient drug complex that does not require washing. The method after about 60 minutes and about 2, 4, 6 or even 8 hours. includes contacting one or more grossly wetted cationic Extended release as used herein may also be defined as exchange resin particles with a drug and adding about 0.1 making the active ingredient available to the Subject regard percent to about 10 percent by weight of one or more Sugar less of uptake, as Some drugs may never be absorbed by the alcohols, based on the combined weight of the Sugar alcohol, Subject. Various extended and delayed release dosage forms the drug and the one or more grossly wetted ionic exchange may be designed readily by one of skill in art as disclosed resin particles. herein to achieve delivery to both the small and large US 2007/0059270 A1 Mar. 15, 2007

intestines, to only the Small intestine, or to only the large ment of the present invention, the ionic exchange resin is a intestine, depending upon the choice of coating materials Sulfonic acid cationic exchange resin. The present invention and/or coating thickness. As used herein, “a subject' is a also uses a Sulphonic acid cation exchange resin, which patient, animal, insect, mammal or human, who will benefit includes phenol-Sulphonic acid cation exchange resins and from the method of this invention. carboxylic-Sulphonic acid cation exchange resins. Gener 0024 Pharmaceutical compositions designed for sus ally, the resin salt is obtained from the reaction of a sul tained release of active drugs and taste masking commonly phonic acid with an alkali, e.g., amine. The basic Sulphonic use ion exchange resins particles. The present invention acid cation exchange resin has a cation of an amphetamine provides controlled-release pharmaceutical compositions adsorbed thereon. The skilled artisan will recognize that obtained by complexing a drug with a pharmaceutically other cationic exchange resins may be used. acceptable ion-exchange resin, treating with a Sugar alcohol 0031 Similarly, a wide range of cationic (for the basic and in Some cases coating the complex with a Substance that drugs) or anionic (for the acidic drugs) exchange resins can will act as a barrier to control the diffusion of the drug from be used to form ion exchange resin drug complexes. In its core complex into the gastrointestinal fluids. general, ion-exchangers Suitable for use in ion-exchange chromatography and for Such applications as deionization of 0.025 For example, the present invention provide a water are Suitable for use as controlled release drug prepa method and composition that control the Swelling of an ion rations. For examples, a model large ion exchange particle exchange resin particle with one or more ionic pharmaceu includes the cationic exchange resin AmberliteR IR-120 tically active drug that includes treating with from about having a 20-30 mesh spherical particles and a model Small 0.01 to about 10 percent by weight of one or more sugar ion exchange particle resin includes Amberlite(RXE-69 with alcohols. a 100-200 mesh fractured resin particles of Amberlite(R) 0026. The ion exchange resin particles and pharmaco IR-120. The parent resin of Amberlite RIR-120 and Amber logical drug are mixed in an aqueous solution, dried and lite(R) XE-69 is described by the manufacturer as gel-type coated with a water-permeable diffusion barrier. Sorbitol is divinylbenzene Sulfonic acid cation exchange resin that added to the ion exchange resin-drug complex to control the Swells in water. Other Suitable ion exchange resin candidates Swelling of the ion exchange resins drug complex upon include synthetic ion exchange resins with different poly contact with bodily fluids and in-turn reducing the rupturing meric matrices (e.g., methacrylic, acrylic, phenol formalde and peeling of the coating. hyde), ion exchange agents with cellulosic or dextran poly 0027. For example, a pharmaceutical composition may mer matrices and inorganic ion exchange matrices. have an ionic pharmaceutically active drug that is in com 0032. The ionic exchange resin includes sulfonic acid munication with an ion exchange resin, wherein the ionic cationic exchange resin and may be made from a polyester exchange resin has been treated with from about 0.01 to polymer containing Sulphonic groups, additionally contain about 10 percent by weight of one or more Sugar alcohols, ing units derived from ethylene glycol, units derived from based on the combined weight of the one or more Sugar tri- and tetraethylene glycol and units derived from tereph alcohols and the complex particles. Optionally, the pharma thalate, neutralized polyesters having a terminal amine func ceutical composition may be coated with a water-permeable tional group, polyester block copolymers, block copolymers diffusion barrier coating, whereby a selective, prolonged of phthalic and Sulphonphthalic acid/ethylene glycol/poly continuous release of the drug is obtainable under conditions methyl siloxane C. Y-hydroxypropyl and vinyl acetate/vinyl encountered in the gastrointestinal tract. butylbenzoate/crotonic acid. In addition, the polymer resin may be crosslinked. The crosslinkers include poly(2-acry 0028. The present invention includes a pharmaceutical lamido-2-methylpropanesulphonic acid) polymer with one grade cationic ion-exchange resin to bind anionic molecules. monomer containing at least two olefinic double bonds, e.g., Ion exchange resins can be described simply as insoluble dipropylene glycol diallyl ether, polyglycol diallyl ether, polymers that contain ionizable groups distributed regularly triethylene glycol divinyl ether, hydroquinone diallyl ether, along the polymer backbone. As a consequence, any counter tetraallyloxyethanoyl, allyl ether, vinyl ether, a polyfunc ion associated (e.g., drug) with the ion exchange resin is tional alcohol, tetraethylene glycol diacrylate, triallylamine, ionically bound to the ion exchange resin and physically trimethylolpropane diallyl ether, methylenebisacrylamide or separated from the Surrounding fluid. divinylbenzene. 0029. The cationic exchange resin of the present may be strongly or weekly acidic and have a variety of functional 0033 Representative pharmaceutical grade ion exchange groups, e.g., weakly acidic type of resin containing carboxy resins for use in accordance with the present invention are lic acid group, or strongly acidic type of resins containing known to those skilled in the art. For example, pharmaceu Sulfonic functional groups. Generally, the carboxylic func tical grade ion exchange resins are commercially available, tional groups are derived from polymers or copolymers of e.g., the Rohm and Haas company and Dow Corning, e.g., methacrylic acid or polymethacrylic acid and the Sulfonic Amberlite(R) IR-20, AmberliteR IRP-69, Amberlite(R). IRP functional groups are generally derived from polymers or 64, Amberlite(R). IRP-58, Amberlite(R) IRC-50, Amberlite(R) copolymers of styrene and divinylbenzene. Other polymeric IRP-69 and Dow(R) XYS-40010.00, Dow(R) XYS-40013.00, matrices, organic ion exchange matrices or inorganic ion etc. The pharmaceutical grade cationic ion-exchange resins exchange matrices may be used as Suitable ion exchange may include particles of varying size ranges, and as either a resins, e.g., methacrylic, acrylic and phenol formaldehyde. monodisperse or a polydisperse mixture. The ion exchange resin particles may range in size from 40 to 1500. In one 0030. In addition, ion exchange agents may be used in example, the gel-type divinylbenzene Sulfonic acid cation conjunction with polymer matrices (e.g., cellulosic or dex exchange resin Amberlite(R). IRP-69 consisting of 100-200 tran) to form a Suitable ion exchange resin. In one embodi mesh was used. US 2007/0059270 A1 Mar. 15, 2007

0034. In general, all acidic and basic drugs, especially codeine, aminocaproic acid, aminosalicylic acid, hydromor those having short biological half-lives in the order of up to phone, isoxSuprine, levorphanol, melphalan, morphine, nali about 12 hours, are potential candidates for inclusion in the dixic acid, paraminosalicylic acid and mixtures and combi present invention. Many drugs exist in the free acid, free nations thereof. base, and a salt form. For example, a base drug may exist as either a free base form or a salt form, e.g., a base drug, 0037 Examples of acidic and basic drugs that may be lidocaine has an amine free base form and a hydrochloride used with the present invention include phenylpropanola acid addition salt form. Conversely, an acid drug may exist mine (PPA), dextromethorphan, ephedrin, pseudoephedrine, in either a free acid form or in the form of a salt made by paraamino Salicyclic acid, acetyl salicylic acid, phentermine reacting the free acid with a base, e.g., Salicylic acid exists (phenyl-tertiary-butyl-amine) and acetaminophen. The as a salt, typically as sodium salicylate. For example, a skilled artisan will recognize the variety of drugs and resins cationic resin interacts with the basic nitrogen group of an that may be used and the modifications to alter the polymer, organic molecule. Generally, the functional groups on the copolymer, cross linking agent that may be used to alter the drug dictate the interaction with the ion exchange resin, and characteristics of the drug-resin complex. The pharmaceu thus, influence the adsorption and the elution characteristics tically active compounds useful in the practice of the present of the drug. A Substantial portion of the active drug is invention include antihistamines, decongestants, antitus adsorbed within the polymer matrix and elutes therefrom. To sives and/or expectorants. Other drugs for use with the control the elution rate the size of the particle and the size present invention include, but are not limited to non-steroi of the adsorbed drug may be altered by modifying the cross dal anti-inflammatory drugs (NSAIDs) and other analgesic linkage of the ion exchange resin. drugs, e.g., acetaminophen and phenacetin. These materials are incorporated into the immediate or controlled release 0035) Suitable pharmaceutically active drugs include nar formulations of the invention in amounts governed by the cotic analgesics, (e.g., codeine, dihydrocodeine, hydromor desired release characteristics of the material in Such excipi phone, morphine, pentazocine and propoxyphene), sym ent base and Such that conventional dosages comply with pathomimetics, (e.g., norephedrine and pseudoephedrine), applicable FDA or other regulations. The drug may be antitussives, (e.g., dextromethorphan, gauifenesin), analge loaded in a specific concentration to allow the specific sics, (e.g., aspirin and tramadol), antiemetics, (e.g., meto release of the drug over a given time range. In general, the clopramide), anticholinergics, (e.g., atropine, ipratropium maximum concentration of bound drug may be in excess of bromide and Scopolamine), muscle relaxants, (e.g., about 60%; however, ranges between about 1% and about cyclobenzaprine and papaverine), bronchodilators, (e.g., 50% are contemplated with the present invention. salbutamol, terbutaline and theophylline), antibiotics, (e.g., amoxycillin, amplicillin, azlocillin, bacampicillin, cefaman 0038. The present invention may be used to deliver dole, cefonicid, cefotaxime, cefotetan, cefoxitin, ceftriax bioactive agents including pharmaceuticals and drugs, bio one, mezlocillin and piperacillin), antidepressants, (e.g., active synthetic organic molecules, genetic materials, pro bupropion, nomifensine, and nortriptyline), antiasthmatics, teins, peptides, polypeptides, vitamins, Steroids, polyanionic (e.g., cromolyn), antineoplastics, (e.g., tamoxifen), antiepi agents, genetic material, and diagnostic agents. Bioactive leptics, (e.g., valproic acid and phenvtoin), cardiovascular Vitamins, steroids, proteins, peptides and polypeptides can agents, (e.g., propranolol) phenylephrine, and gauifenesin. be of natural origin or synthetic. Exemplary polyanionic Acid addition salts or if appropriate, alkali or alkaline earth agents include but are not limited to Sulphated polysaccha metal salts of the above drugs would be particularly suitable rides, negatively charged serum albumin and milk proteins, for use in the present invention. synthetic Sulphated polymers, polymerized anionic Surfac 0.036 Specific examples of suitable pharmaceutically tants, and polyphosphates. Suitable diagnostic agents active drugs include but not limited to dehydrocholic acid, include but are not limited to dyes and contrast agents for diflunisal, ethacrynic acid, fenoprofen, furosemide, gemfi use in connection with magnetic resonance imaging, ultra brozil, ibuprofen, naproxen, phenyloin, probenecid, Sulin Sound or computed tomography of a patient. In addition, the dac, theophylline, Salicylic acid, acetylsalicylic acid, pharmaceutically active drug may be any pesticide known to acetophenazine, amitriptyline, amphetamine, benztropine, the skilled artisan for use in the extended release pesticide biperiden, bromodiphenhydramine, brompheniramine, control of insects, rodents and other pests. carbinoxamine, chlorcyclizine, chlorpheniramine, chlorphe 0039 Suitable genetic material includes nucleic acids, noxamine, chlorpromazine, clemastine, clomiphene, cloni nucleosides, nucleotides, and polynucleotides that can be dine, codeine, cyclizine, cyclobenzaprine, cyproheptadine, either isolated genomic, synthetic or recombinant material; desipramine, desloratadine, dexbrompheniramine, dexchlo either single or double stranded; and either in the sense or rpheniramine, dextroamphetamine, dextromethorphan, antisense direction, with or without modifications to bases, dicyclomine, diphemanil, diphenhydramine, doxepin, doxy carbohydrate residues or phosphodiester linkages. Exem lamine, ergotamine, fluphenazine, haloperidol, hydroc plary sources for the genetic material include but are not odone, hydroxychloroquine, hydroxy Zine, hyoscyamine, limited to deoxyribonucleic acids (DNA), ribonucleic acids imipramine, levopropoxyphene, loratadine, maprotiline, (RNA), complementary DNA (cDNA), messenger RNA meclizine, mepenZolate, meperidine, mephentermine, (mRNA), ribosomal RNA (rRNA), short interfering RNA mesoridazine, methadone, methdilazine, methScopolamine, methysergide, metoprolol, nortriptylene, noscapine, nylin (siRNA), ribozymes, and mixed duplexes and triplexes of drin, orphenadrine, papaverine, pentazocine, phendimetra RNA and DNA. Zine, phentermine, phenylephrine, phenylpropanolamine, 0040 Genetic materials are genes carried on expression pyrilamine, tripelennamine, triprolidine, promazine, pro vectors including but not limited to helper viruses, plasmids, poxyphene, propanolol, pseudoephedrine, pyrilamine, qui phagemids, cosmids, and yeast artificial chromosomes. The nidine, Scopolamine, dextromethorphan, chlorpheniramine, genetic material Suitable for the present invention is capable US 2007/0059270 A1 Mar. 15, 2007 of coding for at least a portion of a therapeutic, regulatory, muramyldipeptide, muramyltripeptide, microbial cell wall and/or diagnostic protein. Moreover, genetic materials can components, lymphokines (e.g., bacterial endotoxin Such as preferably code for more than one type of protein. For lipopolysaccharide, macrophage activation factor), Sub example, a bioactive agent may include plasmid DNA units of bacteria (such as Mycobacteria, Corynebacteria), the having genetic material encoding therapeutic protein and a synthetic dipeptide N-acetyl-muramyl-L-alanyl-D-isog selectable or diagnostic marker to monitor the delivery of lutamine; anti-fungalagents such as ketoconazole, nystatin, the plasmid DNA, e.g., psRed-human insulin promoter. griseofulvin, flucytosine (5-fc), miconazole, amphotericin Such proteins include but are not limited to histocompat B. ricin, and beta-lactam antibiotics (e.g., penicillin, ampi ibility antigens, cell adhesion molecules, growth factors, coagulation factors, hormones, insulin, cytokines, chemok cillin, Sulfazecin); hormones such as growth hormone, ines, antibodies, antibody fragments, cell receptors, intrac PDGF, EGF, CSF, GM-CSF, melanocyte stimulating hor ellular enzymes, transcriptional factors, toxic peptides mone, estradiol, beclomethasone dipropionate, betametha capable of eliminating diseased or malignant cells. Other Sone, betamethasone acetate and betamethasone sodium genetic materials that could be delivered by this technique phosphate, Vetamethasonedisodiumphosphate, Vetametha included adenovirus, adeno-associated virus, retrovirus, len Sone sodium phosphate, cortisone acetate, dexamethasone, tivirus, RNA, siRNA, or chemicals that selectively turn on dexamethasone acetate, dexamethasone sodium phosphate, or off specific genes, such as polyamides or peptide frag flunsolide, hydrocortisone, hydrocortisone acetate, hydro ments. Modifications to wild-type proteins resulting in ago cortisone cypionate, hydrocortisone sodium phosphate, nists or antagonists of the wild type variant fall in the scope hydrocortisone sodium Succinate, methylprednisolone, of this invention. The genetic material may also include a methylprednisolone acetate, methylprednisolone sodium tissue-specific promoter or expression control sequences Succinate, paramethasone acetate, prednisolone, prednisolo Such as a transcriptional promoter, an enhancer, a transcrip neacetate, prednisolone sodium phosphate, prednisolone tional terminator, an operator or other control sequences. rebutate, prednisone, triamcinolone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexac 0041 Examples of active agents for use with the present etonide and fludrocortisone acetate; Vitamins such vitamin invention include, but are not limited to, hormone products C, E, A, K, ascyanocobalamin, neinoic acid, retinoids and Such as, Vasopressin and oxytocin and their derivatives, derivatives such as retinolpalmitate, and alpha-toco glucagon and thyroid agents as iodine products and anti pherol(s); peptides (e.g., T cell epitopes such as MAGE, thyroid agents; cardiovascular products as chelating agents GAGE, DAGE, etc.); proteins, such as manganese Super and mercurial diuretics and cardiac glycosides; respiratory oxide dimutase, alcohol dehydrogenase, nitric oxide syn products as Xanthine derivatives (theophylline and amino thase; enzymes Such as alkaline phosphatase; anti-allergic phylline); anti-infectives as aminoglycosides, antifungals agents such as amelexanox; anti-coagulation agents such as (e.g., amphotericin), penicillin and cephalosporin antibiot phenprocoumon and heparin; circulatory drugs such as ics, antiviral agents (e.g., Zidovudine, ribavirin, amantadine, propranolol, metabolic potentiators such asglutathione; anti Vidarabine and acyclovir), antihelmintics, antimalarials, and tuberculars such as para-aminosalicylic acid, isoniazid, antituberculous drugs; biologicals such as antibodies (e.g., capreomycin Sulfate cycloserine, ethambutol hydrochloride antitoxins and antivenins), vaccine antigens (e.g., bacterial ethionamide, pyrazinamide, rifampin, and streptomycin Sul vaccines, viral vaccines, toxoids); antineoplastics (e.g., fate; antivirals such as acyclovir, amantadine azidothymi nitrosoureas, nitrogen mustards, antimetabolites (fluorou dine (AZT or Zidovudine), Ribavirin andvidarabine mono racil, hormones, progestins and estrogens agonists and/or hydrate (adenine arabinoside, ara-A); antianginals such antagonists); mitotic inhibitors (e.g., etoposide and/or Vinca asdiltiazem, nifedipine, Verapamil, erythrity1 tetranitrate, alkaloids), radiopharmaceuticals (e.g., radioactive iodine isosorbidedinitrate, nitroglycerin (glyceryl trinitrate) and and phosphorus products); and interferon, hydroxyurea, pentaerythritoltetranitrate; anticoagulants such as phenproc procarbazine, dacarbazine, mitotane, asparaginase and oumon, heparin; antibiotics such as dapsone, chlorampheni cyclosporins, including mixtures and combinations thereof. col, neomycin, cefaclor, cefadroxil, cephalexin, cephradine 0042. Other suitable therapeutics include, but are not erythromycin, clindamycin, lincomycin, amoxicillin, ampi limited to: thrombolytic agents such as urokinase; coagu cillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, lants such as thrombin; antineoplastic agents, such as plati picloxacillin, hetacillin, methicillin, nafcillin, oxacillin, num compounds (e.g., spiroplatin, cisplatin, and carbopl penicillin G, penicillin V. ticarcillin rifampin and tetracy atin), methotrexate, adriamycin, taxol, mitomycin, cline; antiinflammatories Such as difunisal, ibuprofen, ansamitocin, bleomycin, cytosine arabinoside, arabinosyl indomethacin, meclofenamate, mefenamic acid, naproxen, adsnine, mercaptopolylysine, Vincristine, buSulfan, oxyphenbutaZone, phenylbutaZone, piroxicam, Sulindac, tol chlorambucil, melphalan (e.g., PAM, L-PAM or phenylala metin, aspirin and Salicylates; antiprotozoans such as chlo nine mustard), mercaptopurine, mitotane, procarbazine roquine, hydroxychloroquine, metronidazole, quinine and hydrochloride dactinomycin (actinomycin D), daunoru meglumine antimonate; antirheumatics Such as penicil bicinhydrochloride, doxorubicin hydrochloride, mitomycin, lamine; narcotics such as paregoric; opiates Such as codeine, plicamycin (mithramycin), aminoglutethimide, estramustine heroin, methadone, morphine and opium; cardiac glycosides phosphate Sodium, flutamide, leuprolide acetate, megestrol Such as deslanoside, digitoxin, digoxin, digitalin and digi acetate, tamoxifen citrate, testolactone, triloStane, amsacrine talis; neuromuscular blockers such as atracurium besylate, (m-AMSA), asparaginase (L-asparaginase), erwinaasparagi gallamine triethiodide, hexafluorenium bromide, metocurine nase, etoposide (VP-16), interferon alpha-2a, interferon iodide, pancuronium bromide, Succinylcholine chloride alpha-2b, teniposide (VM-26), vinblastine sulfate (VLB). (suxamethonium chloride), tubocurarine chloride and vecu Vincristine Sulfate, bleomycin, bleomycin Sulfate, methotr ronium bromide; sedatives (hypnotics) such as amobarbital, exate, adriamycin, and arabinosyl; blood products Such as amobarbital sodium, aprobarbital, butabarbital sodium, parenteral iron, hemin, biological response modifiers such as chloral hydrate, ethchlorVynol, ethinamate, flurazepam US 2007/0059270 A1 Mar. 15, 2007

hydrochloride, glutethimide, methotrimeprazine hydrochlo resin/fluid slurry is filtered. Unlike methods currently used ride, methyprylon, midazolam hydrochloride, paraldehyde, in the art it is not necessary to wash the ionic exchange pentobarbital, pentobarbital sodium, phenobarbital sodium, resin-complex after the additions. Furthermore, the present secobarbital Sodium, talbutal, temazepam and triazolam; invention provides for equilibrium redistribution by allow local anesthetics such as bupivacaine hydrochloride, chlo ing the unbound drug, the free drug or any water soluble roprocaine hydrochloride, etidocainehydrochloride, swelling agent to redistribute themselves in equilibrium. The lidocaine hydrochloride, mepivacaine hydrochloride, equilibrium distribution allows the free drug to be further procainehydrochloride and tetracaine hydrochloride; gen taken up by the resin. eral anesthetics such asdroperidol, etomidate, fentanyl cit 0047 For example, the present invention includes a rate with droperidol, ketaminehydrochloride, methohexital method of making a pharmaceutical composition by con Sodium and thiopental Sodium; and radioactive particles or tacting one or more ion exchange resin particles and one or ions such as strontium, iodide rhenium and yttrium, and more pharmaceutically active drugs to form a cationic combinations and mixtures thereof. exchange resin pharmaceutically active drugs complex. The 0043. The ion exchange resin is treated with one or more ionic exchange resin drug complex is treated to control the Sugar alcohols. The ion exchange resin may be treated Swelling of the resin by adding one or more Sugar alcohols. before, during or after the addition of the pharmaceutical The one or more Sugar alcohols make up between about drug and formation of the drug-resin complex. Additionally, 0.01% and about 10% by weight of one or more sugar the drug-resin complex may be treated before, during or alcohols, based on the combined weight of the Sugar alcohol, after the addition of a coating to the drug-ion exchange resin the drug(s) and the one or more ionic exchange resin complex. The Sugar alcohol may be added as a solid, liquid particles. The composition may then be formulated into the or gel. The Sugar alcohols may be in an aqueous solution or desired pharmaceutical composition delivery forms. mixtures containing varying amounts of organic compounds 0048 Generally, the present invention is formulated into known to those skilled in the art. Furthermore, when more a liquid, gel, tablet, caplet, or capsule; however, other than one Sugar alcohol is used the Sugar alcohols may be pharmaceutical composition delivery forms may be use, similar or different depending on the particular application while taking advantage of the present invention. Other and conditions. In some embodiments, the ionic exchange agents may be added including binders, lubricants, diluents, resin may be treated with between about 1 to 10 percent by disintegrating agents, coloring agents, Sweeteners, flavoring weight of sorbitol, based on the combined weight of the agents, preservatives and flow-inducing agents. The tablets sorbitol and the drug-resin particles. Other concentrations of can be compressed, multiple compressed, tablet triturates or sorbitol may be used including about 0.1% to about 5% by coated, e.g., enteric coating, Sugar coating, or film coating. weight. When in the form of a liquid, the liquid oral dosage may be 0044) The sugar alcohols may be of many types known to in the form of aqueous and nonaqueous Solutions, emul persons of skill in the art to control the swelling of the sions, Suspensions, and solutions granules, containing Suit pharmaceutical grade ion exchange drug-resins complex. able, emulsifying agents, solvents, preservatives, Suspend The Sugar alcohol is generally Sorbitol; however, polyhydric ing agents, diluents, Sweeteners, coloring agents, and alcohols such as mannitol; Sorbitol; Xylitol; maltitol; lactitol, flavoring agents. 1,3-dihydroxypropane, or other non-toxic C2 to C12 linear 0049. The present invention provides a method of pre or branched hydrocarbon having at least 2 hydroxy groups paring a resin drug complex without washing. Preparing the known to the skilled artisan may be used. Additionally, ion exchange resin drug complex from the ion exchange non-toxic C5 to C12 cyclic or heterocyclic hydrocarbon resin includes mixing the ion exchange resin with a solution having at least 2 hydroxy groups (e.g., inositol and the and allowing sufficient time for loading. The resin/fluid carbohydrates Such as glucose, Sucrose) may be used as slurry is filtered. Unlike methods currently used in the art, it well. The Sugar or the Sugar alcohol present in the Solution is not necessary to wash the ionic exchange resin-complex. has a molecular weight of from 90 to 550, and especially from molecular weights of between 150 and 370. The sugars 0050. The present invention also provides a method of are monosaccharides or disaccharides and reduced controlling the Swelling of a pharmaceutical composition by monosaccharides or disaccharides and Substituted monosac contacting one or more cationic exchange resin particles charides or disaccharides. Suitable Sugars/sugar alcohols are with about 0.01% to about 10% by weight of sugar alcohol, Sucrose, dextrose, maltose, fructose, lactose, mannitol, Sor based on the combined weight of the Sugar alcohol, the bitol or xylitol. drug(s) and the one or more ionic exchange resin particles. 0045. The general method for preparing controlled 0051. In accordance with the present invention, it is release cationic exchange resin drug complex using the necessary to combine the Sugar alcohol with the ion present invention involves: (i) preparation of an ion exchange resin to form a mixture (e.g., slurry). Generally, exchange resin drug complex; (ii) treating the ion exchange the mixture is an aqueous solution; however, other Solutions, resin drug complex with a suitable Sugar alcohol; and (iii) compositions or mixtures are acceptable. The ratio of ion drying the treated ion exchange resin drug complex. The ion exchange resin to Sugar alcohol is from about 1:1 to about exchange resin drug complex may be optionally coated with 50:1, i.e., from about 1 gram of resin per gram of the Sugar a water-permeable diffusion barrier. alcohol to about 1 gram of resin per 20 mg. of polyol. Other ratios may be used depending on the method of incorpora 0046 Preparing the ion exchange resin drug complex tion and the particular Sugar alcohol and resin, e.g., about from the ion exchange resin is generally includes mixing the 1:0.01 to about 5:0.01, about 0.01:1 to about 0.01:5, and ion exchange resin with a solution in the presence of a combinations thereof. In Example I, the ratio of the amount polyalcohol and allowing Sufficient time for loading. The of ion exchange resin in Suspension to the amount of Sugar US 2007/0059270 A1 Mar. 15, 2007 alcohol is about 1.7:1 (e.g., 300 gram of resin per 175 gram 0057 The present invention optionally includes a phar of molecule) with most of the Sugar alcohol not remaining macologically active drug-resin complex coated to prolong in the product. In another example, the concentration of the the continuous release of drugs, under harsh biological sugar alcohol is between about 1 and 10% by weight, i.e., conditions, e.g., such as those encountered in the gas about 10 mg to about 100 mg of molecule. trointestinal tract. Conventional coating solvents (e.g., etha nol, a methylene chloride/acetone mixture or other compo EXAMPLE I nent known to the skilled artisan) or aqueous based coatings and procedures can be employed to coat the ion exchange 0052) resin drug complex. In one illustrative example, air Suspen sion spray coating techniques may be carried out using a Wurster coating apparatus. However, other techniques may Resin 300 g be used to coat the particle including other types of fluid bed Drug 300 g spray, coacervation, solvent evaporation or other methods 70% Sorbitol 250 mL. known to persons of skill in the art. Generally, the coating Purified Water 750 L is applied to the drug-resin complex. Alternatively, the coating can be applied to the resin before complexing with 0053. In Example I, the water, sorbitol, drug and resin are the drug. slurried together and sufficient time is allowed for the drug 0058 Particle coating. Another example of a coated par to load onto the resin. When the loading operation is ticle of the present invention provides a selective, prolonged completed the components of the slurry are separated (e.g., continuous release of pharmacologically active drugs, under filtered or centrifuged) into liquid and solid fractions. conditions such as those encountered in the gastrointestinal Because the sugar alcohol is highly water soluble most of the tract by the application of a diffusion barrier coating to an Sugar alcohol remains in the aqueous phase, leaving about ion exchange drug-resin complex treated with a Solvating 4% sorbitol in the solids. The solids are not washed, but are agent. Another prolonged release formulation of the present dried to yield material suitable for coating. invention includes the addition of a second ionic Substance (e.g., a combination drug, a dye, a dispersing agent or the EXAMPLE II like) having the same ionic charge as the drug on the drug-resin complex by employing the second ionic Sub 0054) stance in the ion form of an exchange resin complex. The manufacture of a formulation of any drug for liquid dosage usage requires that the final formulation have the drug Resin 300 g dissolved or Suspended in a liquid that possess extended Drug 300 g shelf-life stability and exhibit no change in active drug Sorbitol 7.5 g. dosage level over a period of time and has acceptable taste. Purified Water 992.5 mL. Thus, to prepare a liquid formulation of any type drug it may be necessary to employ extenders such as water or syrup and to add flavors, Sweeteners, thickening agents, dyes and the 0055. In Example II, the water, drug and resin are slurried like. To control the dissolution profile of the formulation together and sufficient time is allowed for the drug to load versus the dissolution profile of the same drug in water, the onto the resin. When the loading operation is completed the coated particles may also be included in the presence of slurry is separated (e.g., filtered or centrifuged) into liquid ionic Substances bearing the same ionic charge as the and solid fractions. The liquid fraction is discarded. The solid fraction is not washed and is dried. Sorbitol is dis Sustained release drug present in the formulation as a coated solved in 100 grams water, added to the dried drug resin drug-resin complex. The second ionic material need not be complex and the drug resin complex is allowed to absorb the coated with the water-permeable diffusion barrier coating. sorbitol solution. The treated resin may then be dried and 0059. The water-permeable, diffusion barrier coating coated. materials can be any of the conventional synthetic or natural film-forming materials with diffusion barrier properties and 0056 To form the cationic exchange resin drug complex with no inherent pharmacological or toxic properties. For it is necessary to combine an ion exchange resin with one or example, ethylcellulose, a water insoluble film-forming more molecules, e.g., one or more ionic drug compounds. agent, may be used as a diffusion barrier membrane material. The adsorption of molecules to the surface of a resin is well A plasticizer, (e.g., Durkex 500 vegetable oil) may be used known to persons of skill in the art. In addition, the ionic to improve the film forming characteristics of ethylcellulose drug molecule may be attached to a linker that allows and/or to alter the permeability characteristics of the film. attachment of the drug to the ion exchange resin via the The amount of coating used depends on the degree of drug linker. The combination of ion exchange resins and drug release prolongation desired and is a function of particle may be in the form of a slurry or other mixture, depending size, drug solubility, film permeability and other factors. By on the particular application. In addition, a coating may be varying the amount of coating, and/or by blending coated applied to the drug-resin complex. The mixture (e.g., an drug-resin complex with uncoated drug-resin complex, and/ admixture of a slurry of the ion exchange resin, the drug and or blending different coatings it is possible to selectively the sugar alcohol) may be dried to remove the water. The drying may be carried out using methods know to the skilled modify the preparation's drug dissolution profile as desired. artisan including conventional means, i.e., filtered, dried 0060. In general, the major components of the coating over a purge of nitrogen, under vacuum, in a fluid bed, in an should be insoluble in, and permeable to, water. Alterna oven, etc. tively, a water-soluble Substance. Such as methyl cellulose US 2007/0059270 A1 Mar. 15, 2007 may be incorporated, to alter the permeability of the coating, emulsion, film, granule, gum, insert, jelly, foam, paste, or an acid-insoluble, base-soluble Substance to act as an pastille, pellet, spray, troche, lozenge, disk, magma, poul enteric coating may be used. The water-permeable diffusion tice, or wafer and the like. In addition the resin-drug barrier will generally include a water insoluble material such complex of the present invention is Suitable for dosages as a wax, a fatty alcohol, shellac, Zein, shellac, polyvinylpyr varying over a wide range, e.g., from about 0.01 to about rolidone, a water insoluble cellulose derivative, ethyl cellu 2000 mg. depending on the nature of the drug, resin and its lose, a polymethacrylate, or methyl cellulose. The coating intended usage. materials may be applied as a Solution or Suspension in an 0066. In addition the present invention may include other aqueous fluid or as a Solution in organic solvents. In some additives conventionally used in pharmaceutical composi instances, the present invention may include a water-perme tions and known to those of skill in the art., e.g., anti able diffusion barrier in contact with at least a portion of the adherents, anti-sticking agents, glidants, flow promoters, ionic pharmaceutically active drug in communication with lubricants, talc, magnesium Stearate, fumed silica), micron an ionic exchange resin. ized silica, Surfactants, waxes, Stearic acid, Stearic acid salts, Stearic acid derivatives, starch, hydrogenated vegetable oils, EXAMPLE III Sodium benzoate, Sodium acetate, leucine and magnesium 0061 The water-permeable diffusion barrier coated drug lauryl sulfate. resin complex includes: 0067. In accordance with the present invention is a method of reducing the handling of a pharmaceutical com position during preparation by contacting one or more Drug Resin Complex 2000 g grossly wetted cationic exchange resin particles with an Ethylcellulose 300 g active drug and adding about 0.1% to about 5% by weight Ethyl acetate 5700 g of Sugar alcohol, based on the combined weight of the Sugar alcohol, drug Substance and the one or more grossly wetted ionic exchange resin particles. Additionally, the pharmaceu 0062) The drug resin complex was placed in a fluid-bed tical composition can be coated with a water-permeable coating apparatus and fluidized with intake air. The ethyl diffusion barrier. cellulose was dissolved in the ethyl acetate and applied at a rate of about 20-25 grams per minute until 6000 g had been EXAMPLE V applied. Fluidization was continued with the heated air for an additional ten minutes after termination of the application 0068 of the coating solution.

EXAMPLE IV Purified Water USP 45.26 Kg Sorbitol USP 9.59 Kg 0063 Another water-permeable diffusion barrier coated Amberlite IRP69 16.50 Kg drug resin complex includes: Dextromethorphan HBr USP 16.50 Kg

Drug Resin Complex 2000 g 0069. In Example V, the water, sorbitol, drug and resin Ethylcellulose 119 g are slurried together and sufficient time is allowed for the Myvacet 11 g drug to load onto the resin. When the loading operation is Ethanol 2470 g completed the slurry is separated (e.g., filtered or centri fuged) into liquid and solid fractions. Because the Sugar alcohol is highly water soluble most of the sugar alcohol 0064. The drug resin complex was placed in a fluid-bed remains in the aqueous phase leaving with about 4% Sorbitol coating apparatus and fluidized with intake air. The myvacet in the solids. The solids are not washed, but are dried to yield was dissolved in the ethanol and the ethylcellulose was material Suitable for coating. dissolved in the my vacet Solution and applied at a rate of 20-25 g/minute until 2600 g of coating solution had been EXAMPLE VI applied. 0070) 0065. The present invention may be incorporated into a pharmaceutical composition and include immediate release, extended release or delayed release compositions. The Purified Water USP 41.15 Kg present invention relates to oral administration of cationic Sorbitol USP (70%) 13.70 Kg exchange resin drug complex, although other delivery meth Amberlite IRP69 16.50 Kg ods are also contemplated, e.g., topical, rectal, injectable, Pseudoephedrine HCl 16.50 Kg Subcutaneous, vaginal or nasal administration. The pharma ceutical compositions of the present invention can take the form of tablets, powders, capsules, gels, hydro-gels, Solids, 0071. In Example VI, the Water, sorbitol, drug and resin lyophilized suspensions, liquid Suspensions or other con are slurried together and time allowed for the drug to load ventional dosage forms. The present pharmaceutical com onto the resin. When the loading operation is completed the position may also be provided in a variety of dosage forms, slurry is separated (e.g., filtered or centrifuged) into liquid e.g., Solution, Suspension, cream, ointment, lotion, capsule, and Solid fractions. Because the Sugar alcohol is highly caplet, Softgel, gelcap. Suppository, enema, elixir, Syrup. water soluble most of the Sugar alcohol remains in the US 2007/0059270 A1 Mar. 15, 2007 aqueous phase leaving with about 4% Sorbitol in the Solids. The solids are not washed, but are dried to yield material TABLE I-continued suitable for coating. Product from examples V and VI were coated in fluidized bed processing unit using ethylcellulose Pharmaceutical compounds and drug resins: plasticized with dibutyl sebacate from acetone/alcohol solu Pharmaceutical Compounds Resins tion. It is recognized that the release profile may be modified Hyoscyamine, Imipramine, Levopropoxyphene, by varying the coating level. Maprotiline, Meclizine, Mepenzolate, Meperidine, Mephentermine, Mesoridazine, 0072 Release profiles for Examples V and VI are shown: Methadone, Methodilazine, Methscopolamine, Methysergide, Metoprolol, Nortriptylene, NoScapine, Nylindrin, Orphenadrine, Papaverine, Amberlite (R) IR-120 Example V Example VI Pentazocine, Phendimetrazine, Phentermine, Phenylpropanolamine, Pyrilamine, 30 min 43% SO% Tripelennamine, Triprolidine, Promazine, 60 min 47 55 Propoxyphene, Propanolol, Pseudoephedrine, 180 min 53 63 Pyrilamine, Quinidine, Scopolamine, 360 min 57 68 Chlorpheniramine, Codeine, Aminocaproic Acid, Aminosalicylic Acid, Hydromorphone, ISOXSuprine, Levorphanol, Dow (R) XYS-40013.OO Melphalan, Morphine, Nalidixic Acid, 0.073 Table I is a Exemplary table of possible pharma Paraaminosalicylic Acid Phenylpropanolamine (PPA), ceutical compounds that may be used in conjunction with Dextromethorphan, Ephedrin, available resins. The skilled art will recognize that other Pseudoephedrine, Paraamino Salicyclic Acid, compounds may be used with the present invention and that Acetyl Salicylic Acid, Phentermine (Phenyl compounds may be modified or the particular chemical Tertiary-Butyl-Amine) and Acetaminophen group modified in a compound to allow the use of that Acetominophen and Phenacetin Dow (R) XYS-40010.OO compound with the present invention.

TABLE I 0074 The samples were evaluated under conditions that simulate those encountered in the gastrointestinal tract. The Pharmaceutical compounds and drug resins: samples were evaluated using USP Dissolution Apparatus 2 Pharmaceutical Compounds Resins and Simulated Gastric Fluid USP. Additional tests are applied as deemed Suitable, i.e. USP Apparatus 4 using Codeine, Dihydrocodeine, Hydromorphone, Amberlite (R) IR-20 Simulated Gastric Fluid or selected buffer solutions. The Morphine, Pentazocine and Propoxyphene Norephedrine and Pseudoephedrine changes in absorption at the selected wavelength as a Dextromethorphan, gauifenesin, function of time was recorded as the drug was released from phenylephrine a drug-resin complex sample. Aspirin and Tramadol, naprisin Metoclopramide 0075 Table II is a comparison of the release curves in Atropine, Ipratropium Bromide and Amberlite (R) IRC-50 Scopolamine simulated gastric conditions for the present invention and Cyclobenzaprine and Papaverine resin complexes made by methods used in the art. In Table Salbutamol, Terbutaline and Theophylline I the percent release is charted as a function of time for the Amoxycillin, Ampicillin, AZlocillin, present invention (A), a sample made using the post treat Bacampicillin, Cefamandole, Cefonicid, Cefotaxime, Cefotetan, Cefoxitin, ment protocol under U.S. Pat. No. 4,847,077 (B) and a Ceftriaxone, Mezlocillin and Piperacillin sample made using no treatment under the protocol of U.S. Bupropion, Nomifensine, and Nortriptyline Amberlite (R) IRP-58 Pat. No. 4,996,047 (C). The data represented in Table II Cromolyn Valproic Acid and Phenvtoin demonstrates that while high drug loading can be used to Propranolol prepare coated, slow release drug resin complex, the use of Tamoxifen higher levels of treatment under the 077 patent result in a Dehydrocholic Acid, Diflunisal, Ethacrynic slower, better controlled release profile. It also shows that Acid, much lower levels of treating agent as prepared by the Fenoprofen, Furosemide, Gemfibrozil, Amberlite (R) IRP-64 buprofen, Naproxen, Phenytoin, Probenecid, present invention result in comparable, lower release rates. Sulindac, Theophylline, Salicylic Acid, Acetylsalicylic Acid, Acetophenazine, Amitriptyline, Amphetamine, Benztropine, Biperiden, Bromodiphenhydramine, % Released Brompheniramine, Carbinoxamine, Chlorcyclizine, Time (hours) A. B C Chlorpheniramine, Chlorphenoxamine, Amberlite (R) IRP-69 Chlorpromazine, Clemastine, Clomiphene, O.1 14.3 18.3 19.3 Clonidine, Codeine, Cyclizine, O.S 29.3 29.1 32.5 Cyclobenzaprine, Cyproheptadine, 1 33.9 33.1 37.5 Desipramine, Dexbrompheniramine, 2 37.9 36.9 41.6 Dexchlorpheniramine, Dextroamphetamine, 3 40.3 39.1 44.1 Dicyclomine, Diphemanil, Diphenhydramine, 4 42.1 41.O 45.6 Doxepin, Doxylamine, Ergotamine 5 43.6 423 47.2 Fluphenazine, Haloperidol, Hydrocodone, Amberlite (R) XE-69 6 44.8 43.7 48.8 Hydroxychloroquine, Hydroxyzine, 7 45.9 44.3 49.7 US 2007/0059270 A1 Mar. 15, 2007 10

prothiofos, Sulprofos, profenofos, azinphosmethyl, pyraclo -continued fos, salithion, tetrachlorvinphos, dichlorvos, monocroto phos, naled, dimethylvinphos, propaphos, acephate, meta % Released midofos and ethion; carbamate compounds such as carbaryl, Time (hours) A. B C metolcarb, isoprocarb, fenobcarb, propoxur, XMC, ethiofen 8 46.9 45.3 SO4 carb, bendiocarb, pyrimicarb, carbosulfan, carbofuran, ben 9 47.8 46.2 51.1 furacarb, furathiocarb, methomyl, thiodicarb, oxamyl. 10 48.6 47.1 52.1 alanycarb, metoxadiaZone and fenothiocarb); neonicotinoids (e.g., nitroiminoimidazolidine derivatives, nitrovinylidene diamine derivatives e.g. N-(6-chloro-3-pyridylmethyl)-N- 0.076 Table III is a comparison of the relative amounts ethyl-N'-methyl-2-nitrovinylidenediamine (common name: and combinations of drug and resin complexes of the present nitenpyram), nitroguanidine derivatives, cyanoacetamidine invention. Table III is only an exemplar table and the skilled derivatives, N1-(6-chloro-3-pyridyl)methyl-N-2-cyano-N- artisan will recognize the numerous combinations of drug 1-methylacetamidine, cyanoiminothiazolidine derivatives, and resin complexes. 1-(2-chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine,

Drug Aspirin Ings PropoxyPhene? Naproxen DextroMethorphan PseudoePhedrinef Resin Codeine acetaminophen Gauifenesin Carbinoxamine Phenylephrine RP-69 SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 R-2O SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 RC-SO SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 RP-58 SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 RP-64 SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 RP-69 SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 XE-69 SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 R-12O SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 XYS-40013.OO SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000 XYS-4001O.OO SO-1 OOO SO-1 OOO SO-1OOO SO-1OOO SO-1 OOO 80-2000

0077. In addition to pharmaceutical compounds used in nitroiminotetrahydro-1,3,5-oxadiazine derivatives, 3-(2- conjunction with available resins the inventors have con chloro-5-thiazolyl)methyl-5-methyl-4-nitroiminotetrahy templated the use of other known active compounds with the dro-1,3,5-oxadiazine (common name: thiamethoxam), present invention, e.g., herbicides, fungicides, insecticides, nitroiminohexahydro-1,3,5-triazine derivatives, 3,5-dim acaricides, nematicides, bird repellants, plant nutrients and ethyl-1-(2-chloro-5-thiazolyl)methyl-2-nitroiminohexahy agents that improve Soil structure. dro-1,3,5-triazine; nereistoxin derivatives (e.g., cartap, ben 0078 Examples of the insecticide, acaricide and nema Sultap and thiocyclam); chlorinated hydrocarbon tocide that may be used with the present invention include compounds (e.g., benzoepin, dicofol and tetradifon; forma pyrethroid compounds (e.g., permethrin, cypermethrin, fen midine derivatives (e.g., amitraz and chlordimeform); phe varelate, esfenvarelate, fempropathrin, biphenthrin, delta nylpyrazole derivatives (e.g., ethiprole); benzoylphenylurea methrin, fluvalinate, flucythrinate, allethrin, d-allethrin, compounds (e.g., diflubenzuron, teflubenZuron, chlorfluaZu prallethrin, cyphenothrin, phenothrin, resmethrin, tefluthrin, ron, flufenoXuron, triflumuron, hexaflumuron, lufenuron and empenthrin, acrinathrin, cyhalothrin, cyfluthrin, etofenprox. novaluron); triazine derivatives (e.g., cyromazine); thiadi halfenprox, silafluofen, tralomethrin, cycloprothrin, esbio azine derivatives (e.g., buprofeZine); juvenoid compounds thrin, transfluthrin, terallethrin, imiprothrin and 1-ethynyl 2-fluoro-2-pentenyl 3-(2,2-dichlorovinyl)-2,2-dimethylcy (e.g., methoprene, hydroprene, fenoxycarb and diofenolan); clopropanecarboxylate); organophosphorus compounds tebufenozide; methoxyfenozide; halofenozide; chroma (e.g., cyanophos, fenthion, fenitrothion, parathion, meth fenozide; chlorofenapir; phenisobromolate; quinomethion ylparathion, pirimiphos-methyl, diazinon, isoxathion, ate; propargit; fenbutatin oxide; hexythiazox: etoxazole; pyridaphenthion, chlorpyrifos, chlorpyrifos-methyl, oxy clofentezine; fenpyroximate; tebufenpyrad; pyrimidifen; deprofos, vamidothion, malathion, phenthoate, dimethoate, polynactin complex; milbemectin; avermectin; ivermectin thiometon, disulfoton, phosalone, phosmet, methidathion, and azadirachtin. US 2007/0059270 A1 Mar. 15, 2007

0079 Specific examples of a insecticides include: 2,3,5, 0082 All of the compositions and/or methods disclosed 6-tetrafluorobenzyl-chrysanthemate; 2,3,5,6-tetrafluoroben and claimed herein can be made and executed without undue Zyl-2,2-dimethyl-3-(1-propenyl)cyclopropane carboxylate; experimentation in light of the present disclosure. While the 4-methyl-2,3,5,6-tetrafluorobenzyl-chrysanthemate: 4-me compositions and methods of this invention have been thyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl-3-(2,2-dichlo described in terms of preferred embodiments, it will be rovinyl)cyclopropane carboxylate: 4-methyl-2,3,5,6-tet apparent to those of skill in the art that variations can be rafluorobenzyl-2,2-dimethyl-3-(2,2- applied to the compositions and/or methods and in the steps difluorovinyl)cyclopropane carboxylate: 4-methoxymethyl or in the sequence of steps of the method described herein 2,3,5,6-tetrafluorobenzyl-chrysanthemate; without departing from the concept, spirit and scope of the 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2,2-dimethyl invention. All Such similar Substitutes and modifications 3-(1-propenyl)cyclopropane carboxylate; 2,3,4,5,6-pen apparent to those skilled in the art are deemed to be within tafluorobenzyl-2,2-dimethyl-3-(2-chloro-2-trifluorometh the spirit, scope and concept of the invention as defined by ylvinyl)cyclopropane carboxylate; and 4-propargyl-2,3,5,6- the appended claims. tetrafluorobenzyl-3-(1-propenyl)-2,2-dimethylcyclopropane carboxylate. Further, as examples of compounds other than What is claimed is: those expressed by formula (I), the following chemicals may 1. A pharmaceutical ion exchange resin composition be given: 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl-2.2.3, treated to control resin Swelling comprising: 3-tetramethylcyclopropane carboxylate; and 4-propargyl-2, a pharmaceutically active drug in contact with an ion 3,5,6-tetrafluorobenzyl-2,2,3,3-tetramethylcyclopropane exchange resin coated with a barrier film, wherein the carboxylate. ion exchange resin has been treated with from about 0.01 to about 10 percent by weight of one or more sugar 0080 Suitable herbicides include: anilides (e.g., alcohols and barrier film integrity is maintained. diflufenican and propanil), arylcarboxylic acids (e.g., 2. The composition of claim 1, wherein the ion exchange dichloropicolinic acid, dicamba and picloram), aryloxyal resin is a Sulfonic acid cation exchange resin. kanoic acids (e.g., 2,4-D, 2.4-DB, 2,4-DP. fluroxypyr, 3. The composition of claim 1, wherein the one or more MCPA, MCPP and triclopyr), aryloxy-phenoxy-alkanoic Sugar alcohols comprise mannitol, Sorbitol. Xylitol, maltitol, esters (e.g., diclofop-methyl, fenoxaprop-ethyl, fluazifop lactitol. 1,3-dihydroxypropane, inositol glucose, Sucrose or butyl, haloxyfop-methyl and quizalofop-ethyl), azinones combinations and mixtures thereof. (e.g., chloridazon and norflurazon), carbamates (e.g., chlo rpropham, desmedipham, phenmedipham and propham), 4. The composition of claim 1, further comprising a chloroacetanilides (e.g., alachlor, acetochlor, butachlor, water-permeable diffusion barrier in contact with at least a metaZachlor, metolachlor, pretilachlor and propachlor), dini portion of the pharmaceutically active drug in contact with troanilines (e.g., oryzalin, pendimethalin and trifluralin), an ion exchange resin. diphenyl ethers (e.g., acifluorfen, bifenox, fluoroglycofen, 5. The composition of claim 1, wherein the one or more fomesafen, halosafen, lactofen and oxyfluorfen), ureas (e.g., sugar alcohol comprises between about 0.01% and about chlortoluron, diuron, fluometuron, isoproturon, linuron and 10% sorbitol by weight. methabenzthiaZuron), hydroxylamines (e.g., alloxydim, 6. The composition of claim 1, wherein the pharmaceu clethodim, cycloxydim, Sethoxydim and tralkoxydim), imi tical ion exchange resin composition comprises a solution, a dazolinones (e.g., imazethapyr, imazamethabenz, imazapyr Suspension, a cream, an ointment, a lotion, a capsule, a and imazaquin), nitriles (e.g., bromoxynil, dichlobenil and caplet, a softgel, a gelcap, a tablet, a Suppository, an enema, ioxynil), oxyacetamides (e.g., mefenacet), Sulphonylureas an elixir, a syrup, an emulsion, a film, a granule, a gum, an (e.g., amidosulfuron, benSulfuron-methyl, chlorimuron insert, a jelly, a foam, a paste, a pastille, a pellet, a spray, a ethyl, chlorSulfuron, cinosulfuron, metSulfuron-methyl, troche, a lozenge, a disk, a magma, a poultice, a wafer or nicosulfuron, primisulfuron, pyrazosulfuron-ethyl, thifen combinations thereof. sulfuron-methyl, triasulfuron and tribenuron-methyl), thio 7. The composition of claim 1, wherein the ion exchange carbamates (e.g., butylate, cycloate, di-allate, EPTC, espro resin comprises dipropylene glycol diallyl ether, polyglycol carb, molinate, prosulfocarb, thiobencarb and tri-allate), diallyl ether, triethylene glycol divinyl ether, hydroquinone triazines (e.g., atrazine, cyanazine, Simazine, simetryne, diallyl ether, tetraallyloxyethanoyl, vinyl ether, vinyl terbutryne and terbutylazine), triazinones (e.g., hexaZinone, acetate, vinyl butylbenzoate, crotonic acid, polyfunctional metamitron and metribuzin), others (e.g., aminotriazole, alcohol, tetraethylene glycol diacrylate, triallylamine, trim benfuresate, bentaZone, cinmethylin, clomaZone, clopyralid, ethylolpropane diallyl ether, methylenebisacrylamide, divi difenZoquat, dithiopyr, ethofumesate, fluorochloridone, glu nylbenzene, phthalic, Sulphonphthalic acid, ethylene glycol, fosinate, glyphosate, isoxaben, pyridate, quinchlorac, quin polymethyl siloxane C. Y-hydroxypropyl or combinations merac, Sulphosate and tridiphane). thereof. 8. The composition of claim 1, wherein the pharmaceu 0081. It will be understood that particular embodiments tically active drug comprises narcotic analgesics, sympatho described herein are shown by way of illustration and not as mimetics, antitussives, analgesics antiemetics, anticholin limitations of the invention. The principal features of this ergics, muscle relaxants, bronchodilators, antibiotics, invention can be employed in various embodiments without antidepressants, antiasthmatics, antineoplastics, antiepilep departing from the scope of the invention. Those skilled in tics, cardiovascular agents, mixtures and combinations the art will recognize, or be able to ascertain using no more thereof. than routine experimentation, numerous equivalents to the 9. The composition of claim 1, wherein the pharmaceu specific procedures described herein. Such equivalents are tically active drug comprises codeine, dihydrocodeine, considered to be within the scope of this invention and are hydromorphone, morphine, pentazocine, propoxyphene, covered by the claims. norephedrine, pseudoephedrine, dextromethorphan, aspirin, US 2007/0059270 A1 Mar. 15, 2007

tramadol, metoclopramide, atropine, ipratropium bromide, 16. The method of claim 15, further comprising the step Scopolamine, cyclobenzaprine, papaverine, Salbutamol. of coating the ion exchange resin particles with a water terbutaline and theophylline, amoxycillin, ampicillin, permeable diffusion barrier. aZlocillin, bacampicillin, cefamandole, cefonicid, cefo 17. A pharmaceutical composition made according to the taxime, cefotetan, cefoxitin, ceftriaxone, meZlocillin, piper method of claim 16. acillin, bupropion, nomifensine, nortriptyline, cromolyn, tamoxifen, valproic acid and phenvtoin, propranolol mix 18. A method of preparing a single wash preparation of an tures and combinations thereof. ion exchange resin active Substance complex comprising the 10. A method of controlling the swelling of a pharmaceu steps of tical ion exchange resin composition comprising the step of contacting one or more grossly wetted cationic exchange contacting one or more ion exchange resin particles resin particles with an active drug; and with-between about 0.01% and 10% by weight of one loading one or more active Substances; and or more Sugar alcohols, based on the combined weight of the Sugar alcohol and the one or more ionic exchange adding about 0.01% to about 10% by weight of one or resin particles. more Sugar alcohols, based on the combined weight of 11. The method of claim 10, wherein the one or more the one or more Sugar alcohols and the one or more Sugar alcohols comprise an aqueous solution. grossly wetted ionic exchange resin particles, wherein 12. The method of claim 10, wherein the one or more the loading of the one or more active Substances and the Sugar alcohols comprise mannitol, Sorbitol. Xylitol, maltitol, Swelling of the cationic exchange resin particles are lactitol. 1,3-dihydroxypropane, inositol glucose, Sucrose, accomplished without the need for Subsequent washing mixtures and combinations thereof. operation. 13. The method of claim 10, wherein the ion exchange 19. The method of claim 18, further comprising the step resin particles comprise Sulfonic acid cationic exchange of coating the cationic exchange resin particles with a resin particles. water-permeable diffusion barrier. 14. The method of claim 10, wherein the ionic exchange resin comprises dipropylene glycol diallyl ether, polyglycol 20. A method of making a pharmaceutical composition diallyl ether, triethylene glycol divinyl ether, hydroquinone comprising the steps of: diallyl ether, tetraallyloxyethanoyl, vinyl ether, vinyl contacting one or more cationic exchange resin particles acetate, vinyl butylbenzoate, crotonic acid, polyfunctional and one or more pharmaceutically active substances: alcohol, tetraethylene glycol diacrylate, triallylamine, trim and ethylolpropane diallyl ether, methylenebisacrylamide, divi nylbenzene, phthalic, Sulphonphthalic acid, ethylene glycol, adding one or more Sugar alcohols to the one or more polymethyl siloxane C, Y-hydroxypropyl or combination cationic exchange resin particles and one or more thereof. pharmaceutically active Substances, wherein the one or 15. The method of claim 10, further comprising the step more sugar alcohols comprise between about 0.01% to of adding one or more pharmaceutically active drug com about 10% by weight of one or more sugar alcohols, prises narcotic analgesics, sympathomimetics, antitussives, based on the combined weight of the Sugar alcohol, one analgesics antiemetics, anticholinergics, muscle relaxants, or more pharmaceutically active Substances and the one bronchodilators, antibiotics, antidepressants, antiasthmatics, or more ionic exchange resin particles. antineoplastics, antiepileptics, cardiovascular agents, mix tures and combinations thereof.